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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, DC 20549

_________________________________________________________

FORM 10-K

_________________________________________________________

x			ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended December 31, 2024
For the fiscal year ended December 31, 2025
o			TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the transition period from______ to
Commission file number 001-37722

_________________________________________________________

SPYRE THERAPEUTICS, INC.

(Exact name of Registrant as specified in its charter)

_________________________________________________________


Delaware						46-4312787
(State or Other Jurisdiction of Incorporation or Organization)						(I.R.S. Employer Identification No.)

221 Crescent Street Building 23, Suite 105 Waltham, MA						02453
(Address of Principal Executive Offices)						(Zip Code)

Registrant’s Telephone Number, including area code: (617) 651-5940

Securities registered pursuant to Section 12(b) of the Exchange Act:


Title of each class	Trading Symbol(s)	Name of each exchange on which registered
Common Stock, $0.0001 Par Value Per Share	SYRE	The Nasdaq Stock Market LLC (Nasdaq Global Select Market)

Securities registered pursuant to Section 12(g) of the Exchange Act: None

_________________________________________________________

Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes o No x

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Exchange Act. Yes o No x

Indicate by check mark whether the Registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes x No o

Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was required to submit such files). Yes x No o

Indicate by check mark whether the Registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer

Accelerated filer

Non-accelerated filer

Smaller reporting company

Emerging growth company

If an emerging growth company, indicate by check mark if the Registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. o

Indicate by check mark whether the Registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C 7262(b)) by the registered public accounting firm that prepared or issued its audit report. x

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the Registrant included in the filing reflect the correction of an error to previously issued financial statements. o

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the Registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). o

Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes o No x

The aggregate market value of the voting and non-voting common equity held by non-affiliates of the Registrant on June 30, ~~2024~~2025 (the last business day of the Registrant’s second fiscal quarter), based upon the closing price of $2314.5197 of the Registrant’s common stock as reported on The Nasdaq Global Select Market, was approximately $1.1 billion.

Indicate the number of shares outstanding of each of the Registrant's classes of common stock, as of the latest practicable date.

Class						Outstanding at February 1912, ~~2025~~2026
Common stock, $0.0001 par value per share						6078,~~275~~540,~~561~~164 shares

DOCUMENTS INCORPORATED BY REFERENCE

~~None~~Portions of the Registrant’s Definitive Proxy Statement (“Proxy Statement”) relating to the 2026 Annual Meeting of Stockholders will be filed with the Commission within 120 days after the end of the Registrant’s 2025 fiscal year and is incorporated by reference into Part III of this Report.

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TABLE OF CONTENTS

		Page
PART I
Item 1.	Business	1
Item 1A.	Risk Factors	3742
Item 1B.	Unresolved Staff Comments	7890
Item 1C.	Cybersecurity	7890
Item 2.	Properties	7991
Item 3.	Legal Proceedings	7991
Item 4.	Mine Safety Disclosures	7991
PART II
Item 5.	Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities	8092
Item 6.	[Reserved]	8093
Item 7.	Management’s Discussion and Analysis of Financial Condition and Results of Operations	8194
Item 7A.	Quantitative and Qualitative Disclosures About Market Risk	92107
Item 8.	Financial Statements and Supplementary Data	93109
Item 9.	Changes in and Disagreements with Accountants on Accounting and Financial Disclosure	~~141~~159
Item 9A.	Controls and Procedures	~~141~~159
Item 9B.	Other Information	~~143~~160
Item 9C.	Disclosure Regarding Foreign Jurisdictions that Prevent Inspections	~~143~~160
PART III
Item 10.	Directors, Executive Officers and Corporate Governance	~~144~~161
Item 11.	Executive Compensation	~~149~~161
Item 12.	Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters	~~157~~161
Item 13.	Certain Relationships and Related Transactions, and Director Independence	161
Item 14.	Principal Accountant Fees and Services	~~163~~161
PART IV
Item 15.	Exhibits and Financial Statement Schedules	~~165~~162
Item 16.	Form 10-K Summary	~~168~~165
SIGNATURES		~~169~~166

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NOTE ABOUT FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K, or Annual Report, contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, or the Exchange Act, and Section 27A of the Securities Act of 1933, as amended, or the Securities Act. All statements contained in this Annual Report other than statements of historical fact, including statements regarding any future payouts under our contingent value rights ("CVRs") issued in connection with the Asset Acquisition (as defined herein); our ability to achieve the expected benefits or opportunities and related timing with respect to our acquisition of the assets of Spyre Therapeutics, Inc. ("Pre-Merger Spyre") (the "Asset Acquisition"); our future results of operations and financial position; our business strategy, including our ability to develop best-in-class therapeutics for inflammatory bowel disease (IBD), or rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA) and other immune-mediated diseases that meaningfully improve both efficacy and convenience compared to today's standard of care and our ability to develop first-in-class therapeutics for RArheumatic diseases (RD); our plans to expand the development of our product candidates, including SPY002, to indications beyond IBD and RARD; the potential consistency of the SPY001, SPY002, SPY072 and SPY003 Phase 1 trial final data readouts ~~not being consistent~~ with orpreviously ~~being~~disclosed ~~different~~data ~~than~~for ~~the~~our ~~interim Phase 1 results~~programs; the planned induction and maintenance dosing regimen for SPY001 and our other product candidates, including the potential for a Q3M-Q6M dosing profile; the potential for increased or accelerated efficacy; ~~the expected design and timing of the platform Phase 2 trial, including timing of each cohort and data readouts;~~ potential alignment with regulatory authorities and anticipated regulatory submissions; expected timing for regulatory feedback; the length of time that we believe our existing cash resources will fund operations; estimated market sizes and potential growth opportunities; expected competitors and competing products; our nonclinical and clinical development activities, including clinical trial designs, submission of investigational new drug ("IND") applications and biologics license applications ("BLA"), as well as foreign equivalents, our plans for and ~~further~~timing of cohort initiation and data readouts for the ongoing SKYWAY Phase 2 basket trial and SKYLINE Phase 2 platform trial, enrollment of clinical ~~evaluation~~trials, the inclusion of ~~therapeutic~~each ~~combinations~~rational combination in Part B of the SKYLINE-UC Phase 2 platform trial and the number of data readouts expected to be delivered in 2026 and 2027, and related regulatory feedback; the potential efficacy, tolerability, convenience, commercial viability and safety profile of our product candidates, including in combinations; the potential therapeutic benefits and economic value of our product candidates as monotherapies or in combinations and their extended half-life; ~~use~~our ofability ~~net~~to ~~proceeds~~provide ~~from~~anticipated ~~our~~readouts ~~public~~ahead ~~offerings;~~of ~~the~~any ~~timing~~disclosed ~~and~~bispecific ~~results~~approaches ofagainst ~~nonclinical~~our ~~studies~~targets; ~~and~~expectations ~~clinical~~regarding ~~trials~~our intellectual property portfolio, including ~~commencement~~our ofcurrent ~~first-in-human~~and ~~("FIH")~~future patents and ~~Phase~~patent 2applications; ~~trials~~use ~~and~~of ~~timing~~net ofproceeds ~~data~~from ~~readouts~~our public offerings; the expected impact of macroeconomic conditions, including inflation, increasing interest rates and volatile market conditions, current or potential bank failures, as well as global events, including the ongoing military conflict in Ukraine, conflict between Israel and various other parties, recent events in Venezuela, geopolitical tensions between ~~China and~~ the United States and other countries, including China, on our operations, and the implementation of tariffs, sanctions, export or import controls, and other measures that restrict international trade by the United States, China or other governments,; and the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates, are forward-looking statements. The words “believe,” “may,” “will,” “potentially,” “estimate,” “continue,” “anticipate,” “predict,” “target,” “intend,” “could,” “would,” “should,” “project,” “plan,” “expect,” and similar expressions that convey uncertainty of future events or outcomes are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.

These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including those described in Item 1A, “Risk Factors” included in this Annual Report. Moreover, we operate in a very competitive and rapidly changing environment, and new risks emerge from time to time. It is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements we may make. In light of these risks, uncertainties, and assumptions, the forward-looking events and circumstances discussed in this Annual Report may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements.

You should not rely upon forward-looking statements as predictions of future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. We undertake no obligation to update publicly any forward-looking statements for any reason after the date of this report to conform these statements to actual results or to changes in our expectations, except as required by law. You should read this Annual Report with the understanding that our actual future results, levels of activity, performance and events and circumstances may be materially different from what we expect.

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looking statements will be achieved or occur. We undertake no obligation to update publicly any forward-looking statements for any reason after the date of this report to conform these statements to actual results or to changes in our expectations, except as required by law. You should read this Annual Report with the understanding that our actual future results, levels of activity, performance and events and circumstances may be materially different from what we expect.

Unless the context indicates otherwise, as used in this Annual Report, the terms “Spyre,” "Aeglea BioTherapeutics, Inc.," "Aeglea," “the Company,” “we,” “us,” and “our” refer to Spyre Therapeutics, Inc., a Delaware corporation, and its consolidated subsidiaries taken as a whole. “Spyre” and all product candidate names are our common law trademarks. This Annual Report contains additional trade names, trademarks and service marks of other companies, which are the property of their respective owners. We do not intend our use or display of other companies’ trade names, trademarks or service marks to imply a relationship with, or endorsement or sponsorship of us by, these other companies.

All references to “our product candidates,” “our programs” and “our pipeline” in this Annual Report refer to the research programs with respect to which we have signed a license agreement for, exercised the option to acquire intellectual property license rights to or have the option to acquire intellectual property license rights to pursuant to that certain antibody discovery and option agreement, dated May 25, 2023 and subsequently amended and restated on September 29, 2023 and May 14, 2024, by and among us, Paragon Therapeutics, Inc. (“Paragon”) and Parapyre Holding LLC (“Parapyre”) (the “Paragon Agreement”).

Please be advised that on September 8, 2023, we effected a reverse stock split of our common stock at a ratio of 1-for-25 (the “Reverse Split”). Except as indicated otherwise, all share numbers related to our common stock disclosed in this Annual Report have been adjusted on a post-Reverse Split basis. In addition, on November 28, 2023, we changed our name from “Aeglea BioTherapeutics, Inc.” to “Spyre Therapeutics, Inc.”

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PART I

ITEM 1. BUSINESS

Company Overview

Spyre Therapeutics, Inc. (NASDAQ: SYRE) is a clinical-stage biotechnology company ~~utilizing~~pioneering ~~potential best~~long-~~in-class~~acting ~~antibody~~antibodies ~~engineering, dose optimization,~~ and ~~rational~~antibody ~~therapeutic~~ combinations to ~~target~~redefine ~~improved~~the ~~efficacy~~standard ~~and~~of ~~convenience~~care infor ~~the~~inflammatory ~~treatment~~bowel ofdisease (“IBD”) and ~~other~~rheumatic ~~immune-mediated~~ diseases. Spyre’s pipeline includes extended half-life antibodies targeting α4β7, TL1A, and IL-23 in development as monotherapies and pair-wise combinations.

Our Strategy

Our goal is to develop next-generation therapeutics to redefine the standard of care for the treatment of IBD and other immune-mediated diseases, relying on three strategic pillars:

•Advancing a portfolio of next-generation monotherapies - novel, antibody candidates engineered for optimized potency, selectivity, and pharmacokinetics ("PK") against validated IBD targets

•Evaluating paradigm-changing IBD combinations - fixed-dose-combinations of our engineered investigational antibodies designed to enable superior efficacy, safety, and convenience

•Expansion of our anti-TL1A program into additional indications - pipeline-in-a-product potential in diseases with first-in-class and best-in-class opportunity, starting with rheumatoid arthritis ("RA"), psoriatic arthritis ("PsA"), and axial spondyloarthritis ("axSpA")

Next-generation monotherapies

Our next-generation monotherapy antibody candidates targeting α~~4ß7~~4β7, TL1A, and IL-23 are engineered to match or exceed the potency of comparator first generation molecules (Figure 1), maintain selectivity, incorporate Fc domain modifications called YTE substitutions in order to increase pharmacokinetic half-life (Figure 2), and are formulated as high-concentration, citrate-free formulations. Combined, these attributes have the potential to enable ~~infrequent~~quarterly or twice annual subcutaneous ("SC") maintenance dosing ~~compared to competitor molecules~~, and have upside potential to increase or accelerate efficacy via increasing PK exposures, based on published exposure-response or dose-response relationships for each mechanism in IBD.

~~Paradigm~~Figure 1. Potency of SPY001, SPY002, and SPY003 compared to first-~~changing~~generation ~~IBD~~in-class ~~combinations~~molecules

~~Each~~Source: ofData ~~our~~on ~~next-generation~~file. ~~monotherapy~~Potency ~~antibody~~refers ~~candidates~~to ~~was selected for its attractive risk-benefit profile~~ in ~~preclinical~~vitro ~~development~~potency: ~~and~~SPY001 ~~targets~~assay ~~distinct~~reports ~~pathways~~inhibition ~~involved in the pathogenesis~~ of ~~IBD,~~cells ~~with~~expressing ~~the~~a4b7 ~~goal~~binding ofto ~~developing~~MAdCAM-1. ~~pairwise~~SPY002 ~~combination~~assay ~~therapies.~~reports ~~The~~inhibition ~~benefits~~ of coTL1A-~~administration~~induced ofapoptosis ~~two targeted therapies~~ in ~~IBD were previously demonstrated by a third~~TF-~~party~~1 ~~clinical trial where combination treatment with an anti-TNF antibody and an anti-IL-23 antibody resulted in approximately additive efficacy (47% clinical remission for the combination vs~~cells. ~~25%~~SPY003 ~~and~~assay ~~24%~~reports ~~for~~inhibition ~~each~~ of ~~the~~cellular ~~monotherapy~~STAT3 ~~agents)~~signaling. ~~Spyre's portfolio of investigational combination therapies has unique potential to deliver products with superior efficacy~~Vedolizumab, ~~safety~~tulisokibart, and ~~convenience~~risankizumab ~~compared~~are tosynthesized ~~the~~comparator ~~other combination products in clinical development in IBD~~antibodies.

~~Anti~~Figure 2. Increased pharmacokinetic half-~~TL1A~~life ~~indication~~of ~~expansion~~SPY001, SPY002, and SPY003 compared to first-generation in-class molecules

TL1A has been implicated in a wide range of human diseases beyond IBD based on genetic, translational, and/or preclinical data, including diseases within but not limited to: RA, axial spondyloarthritis, psoriatic arthritis, systemic sclerosis-interstitial lung disease, asthma, pulmonary sarcoidosis, psoriasis, hidradentis suppurativa, and atopic dermatitis. Among these diseases, multiple publications support anti-TL1A as a potential treatment option for RA, with further validation from in-house in vivo experiments:

•TL1A is elevated in RA patients relative to healthy controls and increases with disease duration and severity

•TL1A administration exacerbates arthritis in murine models of RA and administration of anti-TL1A antibodies reduces arthritis

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~~•TL1A~~SPY001 ~~blockade~~PK ~~using~~simulation ~~Spyre's~~based ~~anti-TL1A~~on ~~antibodies~~PK ~~matched~~data oras ~~exceeded~~of ~~the~~03/19/2025 ~~efficacy~~cutoff; ofSPY002 ~~anti~~PK simulation based on PK data from 5/31/2025 cutoff; SPY003 PK simulation based on PK data from 9/15/2025 cutoff. Vedolizumab, Afimkibart, and Risankizumab simulations based on published data (Rosario, M, et. al. (2015); Danese, Silvio, et al. (2024); Thakre, Neha et. al. (2024)); no head-~~TNF~~to-head ~~treatment~~clinical intrials ahave ~~collagen~~been ~~induced~~conducted. ~~rat~~Concept ~~model~~image of RAdrug delivery device shown for illustrative purposes only.

~~If successful in development and in obtaining regulatory approval, SPY002's projected quarterly to twice~~Paradigm-~~annual~~changing ~~subcutaneous~~IBD ~~dosing in a single autoinjector has the potential to be the most convenient product available for RA and represents an attractive opportunity to expand the value of our portfolio.~~combinations

~~Inflammatory~~Each ~~Bowel~~of ~~Disease~~our next-generation monotherapy antibody candidates was selected for its attractive risk-benefit profile in preclinical development and targets distinct pathways involved in the pathogenesis of IBD, with the goal of developing pairwise combination therapies. The benefits of co-administration of two targeted therapies in IBD were previously demonstrated by a third-party clinical trial where combination treatment with an anti-TNF antibody and an anti-IL-23 antibody resulted in approximately additive efficacy (47% clinical remission for the combination vs. 25% and 24% for each of the monotherapy agents, Figure 3). Spyre's portfolio of investigational combination therapies has unique potential to deliver products with superior efficacy, safety, and convenience compared to the other combination products in clinical development in IBD.

~~IBD~~Figure ~~is a chronic condition characterized by inflammation within the gastrointestinal tract~~3. ItThird-party ~~encompasses~~demonstration ~~two main disorders: UC and CD. UC primarily affects the colon and the rectum. Inflammation occurs in the innermost lining~~ of ~~the~~combination ~~colon.~~therapy Symptoms include bloody diarrhea, abdominal pain, bowel urgency, and frequent bowel movements. CD can affect any part of the gastrointestinal tract, from the mouth to the anus. It is characterized by inflammation that extends through multiple layers of the bowel wall. Symptoms include abdominal pain, diarrhea, weight loss, fatigue, and complications such as strictures or fistulas. Both conditions can significantly impact patients’ quality of life in ~~terms of physical health, emotional well-being, and the unpredictability of symptom onset.~~IBD

~~IBD~~Source: ~~affects millions of individuals worldwide~~Feagan, ~~with~~B. ~~increasing~~G. ~~prevalence~~et ~~and~~al. ~~incidence~~Lancet ~~in both developed and developing countries~~Gastroenterol. ~~In the United States, it is estimated that approximately 2~~Hepatol.4 ~~million individuals currently have IBD~~8, ~~with~~307–320 ~~approximately 70,000 patients newly diagnosed every year~~(2023). ~~Based~~mMS=modified onmayo research from the Crohn's and Colitis Foundation of America, the market for IBD therapeutics is expected to experience steady growth, driven by rising disease prevalence, increasing diagnosis rates, and evolving treatment paradigms.score

A range of pharmaceutical options exists, including anti-inflammatory drugs, immunosuppressants, and biologics. Treatment plans are often tailored to the individual patient’s disease severity, location, and response to therapy. In some cases, surgical interventions such as bowel resection or ostomy formation may be necessary to manage complications or improve quality of life.

Despite available treatments, there remain substantial unmet needs in IBD management, including:

•Inadequate response or loss of response to existing therapies,

•Side effects and safety concerns associated with long-term medication use,

•Limited options for patients with refractory or severe disease, and

•Poor adherence to frequent and/or inconvenient dosing regimens.

Rheumatoid Arthritis

A range of pharmaceutical options exist including conventional synthetic disease-modifying antirheumatic drugs ("DMARDs") (methotrexate, leflunomide, sulfasalazine), biological DMARDs (TNF inhibitors, CD80/86 inhibitor, IL-6 inhibitors, CD20 inhibitors), and targeted synthetic DMARDs (JAKs). Despite available treatments, there remains substantial unmet need in RA management, including:

•Inadequate response or loss of response to existing therapies

•Side effects and safety concerns associated with long-term medication use

•Limited options for patients with refractory or severe disease

•Poor adherence to frequent and/or inconvenient dosing regimens

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~~Our~~Anti-TL1A ~~Portfolio~~indication expansion

WeTL1A ~~are~~has ~~advancing~~been implicated in a ~~pipeline~~wide range of ~~monoclonal~~human ~~antibodies~~diseases ~~(“mAbs”)~~beyond ~~for~~IBD ~~the~~based ~~treatment~~on ofgenetic, ~~IBD~~translational, and/or ~~other~~preclinical ~~immune-mediated~~data, including diseases. ~~The~~within ~~following~~but ~~table~~not ~~summarizes~~limited ~~our~~to: ~~programs~~rheumatic diseases such as RA, PsA, and ~~strategy~~axSpA, as well as systemic sclerosis-interstitial lung disease, asthma, pulmonary sarcoidosis, psoriasis, hidradentis suppurativa, and atopic dermatitis. Among these diseases, multiple publications support anti-TL1A as a potential treatment option for rheumatic disease, with further validation from in-house in vivo experiments:

~~Through~~•TL1A ~~the~~is ~~Asset~~elevated ~~Acquisition,~~in ~~we received the option to license the intellectual property rights related to four research programs (collectively~~RA, ~~the "Option") pursuant to the Paragon Agreement~~PsA, and ~~subsequently~~axSpA ~~executed~~patients ~~license~~relative ~~agreements for our α4β7, TL1A, and IL-23 programs. As of the date of this Annual Report on Form 10-K, we have exercised our Option with respect~~ to ~~and~~healthy ~~nominated~~controls ~~development candidates for our SPY001, SPY002,~~ and ~~SPY003~~increases ~~programs. We executed license agreements~~ with ~~Paragon~~disease ~~for~~duration ~~SPY001 (the "SPY001 License Agreement")~~ and ~~SPY002~~severity (~~the~~Figure ~~"SPY002 License Agreement"~~4) in the second quarter of 2024 and we executed a license agreement with Paragon for SPY003 (the "SPY003 License Agreement" and, together with the SPY001 License Agreement and the SPY002 License Agreement, the "License Agreements") in the fourth quarter of 2024. The SPY001 and SPY002 licenses are indication agnostic, and the SPY003 license is restricted to IBD. We additionally have an exclusive option under the Paragon Agreement for a discovery stage program targeting a novel mechanism of action (“MOA”) that also incorporates half-life extension (SPY004). See the section titled “Paragon Agreement” in this Annual Report on Form 10-K for more discussion about the Paragon Agreement and the License Agreements.

~~SPY001~~•TL1A –administration exacerbates arthritis in murine models of arthritis and administration of anti-~~α4β7~~TL1A ~~mAb~~antibodies reduces arthritis

~~Our~~•TL1A ~~most~~blockade ~~advanced~~using ~~product~~Spyre's ~~candidate,~~anti-TL1A ~~SPY001,~~antibodies ismatched aor ~~highly~~exceeded ~~potent, highly selective, and humanized monoclonal immunoglobulin G1 antibody designed to bind selectively to~~ the ~~α4β7~~efficacy ~~integrin~~of ~~being~~anti-TNF ~~developed for the~~ treatment of IBD (UC and CD). The α4β7 integrin is a protein found on the surface of immune cells. This integrin regulates the migration of immune cells to the gut where they contribute to the inflammatory process in ~~IBD. By selectively binding to the α4β7 integrin, SPY001 is designed to prevent the interaction of these immune cells with MAdCAM-1,~~ a ~~molecule~~collagen ~~expressed~~induced onrat ~~endothelial~~model cells lining the blood vessels in the gut. This interaction is responsible for guiding lymphocytes from the bloodstream into the gut tissue, where they cause inflammation. By blocking the interaction between α4β7 integrin and MAdCAM-1, SPY001 aims to reduce the recruitment of ~~immune~~arthritis cells to the gut, leading to a decrease in inflammation. Since it specifically targets the gut immune system, SPY001 is designed to minimize systemic immunosuppressive effects unrelated to IBD pathology.

•Robust ~~SPY001 preclinical characterization studies were conducted in~~anti-~~house~~TL1A ~~with~~activity ~~support~~further ~~from~~replicated ~~third party vendors. SPY001 demonstrates similar potency and selectivity as synthesized vedolizumab~~ in ~~preclinical~~mouse ~~in vitro~~ models ~~including~~of ~~surface~~arthritis ~~plasmon residence (n=5 concentrations)~~ and ~~cellular~~match ~~adhesion~~the ~~assays~~efficacy ~~(see~~of ~~Figure 1, n=6 replicates per group). The 28~~anti-~~day~~TNF ~~GLP toxicity study in non-human primates~~ (~~“NHPs")~~Figure ~~(n=42~~5) ~~for SPY001 was completed with the highest dose level tested determined as the no-observed-adverse-effect-level.~~

•Additionally, ~~The~~anti-TL1A ~~Company~~treatment ~~initiated~~led ato ~~FIH~~comparable ~~Phase~~improvements ~~1 trial for SPY001~~ in ~~June~~psoriatic ~~2024.~~skin ~~The~~lesions ~~SPY001 Phase 1 trial is a double blind, placebo-controlled trial~~ in ~~healthy~~mouse ~~volunteers~~IMQ ~~and~~model ~~consists~~as ~~of a single~~anti-~~ascending~~IL-23 ~~dose (SAD) component~~ and ~~a multi~~anti-~~ascending~~TNF ~~dose~~ (~~MAD)~~Figure ~~component. The trial design includes enrolling 56 healthy adult~~ 6)

If successful in development and in obtaining regulatory approval, SPY072's projected quarterly to twice-annual subcutaneous dosing in a single autoinjector has the potential to be the first-in-class and best-in-class anti-TL1A for these rheumatic diseases and represents an attractive opportunity to meaningfully expand the value of our portfolio.

Figure 4. Upregulation of TL1A in RA, PsA, and axSpA relative to healthy controls

Spyre analysis of RA-MAP, Li, Sifang, et al. BMC Musculoskeletal Disorders 25.1 (2024), and Johnsson, Hanna, et al. Arthritis Research & Therapy. ** P≤0.01, *** P ≤0.001, **** P ≤0.0001. Unpaired tailed t-test used for RA and axSpA analysis, One-way ANOVA used in PsA. RA=rheumatoid arthritis; PsA=psoriatic arthritis; axSpA=axial spondyloarthritis; HC=healthy controls.

Figure 5. TL1A blockade matched or exceeded the efficacy of anti-TNF in rodent models of arthritis

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~~participants~~Source: ~~into~~Data ~~five~~on ~~SAD cohorts and two MAD cohorts in the main portion of the study~~file. ~~The~~**** ~~primary~~P ~~endpoint is safety, with pharmacokinetics (PK) and anti-drug antibodies (ADA) serving as secondary endpoints~~≤0. Additional cohorts have been added to the study to evaluate pharmacokinetics in healthy volunteers of various ethnicities to facilitate subsequent global clinical trials. Trial enrollment is now complete.0001

~~Interim~~Figure ~~results~~6. ~~were~~Anti-TL1A ~~presented~~treatment inimproved ~~November~~IMQ-induced ~~2024~~psoriatic ~~with~~skin uplesions toin ~~four~~mice ~~months~~with ofcomparable ~~follow~~efficacy ~~up.~~to ~~Findings~~anti-IL-23 ~~from the interim SAD~~ and ~~MAD portions of the Phase 1 trial were as follows:~~anti-TNF

~~•Safety~~Source: ~~(See~~Data ~~Figure~~on ~~2) - SPY001 was well tolerated across all dose groups (single doses of up to 1,000mg and multiple doses of up to 600 mg) with a favorable safety profile~~file. ~~The~~**** ~~most~~P ~~common treatment-emergent adverse events ("TEAEs") were headache and nasopharyngitis~~≤0.0001

~~•PK~~Inflammatory -Bowel SPY001 demonstrated a meaningfully differentiated PK profile relative to vedolizumab. The half-life is estimated at greater than 90 days by population PK modeling, which is approximately four times that of vedolizumab's 25-day human half-life in a cross-trial comparison (See Figure 3), supporting the potential for Q3M-Q6M SC maintenance dosing.Disease

~~•Pharmacodynamics~~IBD is a chronic condition characterized by inflammation within the gastrointestinal tract. It encompasses two main disorders: ulcerative colitis ("PDUC") -and ~~complete~~Crohn's ~~occupancy~~disease ("CD"). UC primarily affects the colon and the rectum. Inflammation occurs in the innermost lining of ~~α4β7~~the ~~receptors~~colon. ~~was~~Symptoms ~~observed~~include ~~with~~bloody adiarrhea, ~~single~~abdominal ~~dose~~pain, bowel urgency, and frequent bowel movements. CD can affect any part of ~~300~~the mggastrointestinal uptract, from the mouth to ~~Day~~the 85anus. ~~(See~~It ~~Figure~~is ~~4),~~characterized ~~which~~by ~~was~~inflammation that extends through multiple layers of the ~~longest~~bowel ~~follow~~wall. upSymptoms ~~available~~include atabdominal ~~data~~pain, ~~cutoff~~diarrhea, weight loss, fatigue, and complications such as strictures or fistulas. Both conditions can significantly impact patients’ quality of life in terms of physical health, emotional well-being, and the unpredictability of symptom onset.

IBD ~~Longer-term~~affects ~~data~~millions ~~from~~of ~~this~~individuals ~~Phase~~worldwide, 1with ~~trial~~increasing ~~will~~prevalence beand ~~presented~~incidence atin aboth ~~medical~~developed ~~meeting~~and ~~later~~developing ~~this year~~countries. ~~Based~~In onthe ~~these~~United ~~interim results~~States, weit ~~plan~~is toestimated ~~advance~~that ~~SPY001~~approximately to2.4 amillion ~~Phase~~individuals 2currently ~~clinical~~have ~~trial~~IBD, inwith UCapproximately 70,000 patients innewly ~~mid-2025~~diagnosed every year. Based on research from the Crohn's and Colitis Foundation of America, the market for IBD therapeutics is expected to

Figure 1. Potency and selectivity of SPY001 relative to synthesized vedolizumab in cellular assays (Data on file).

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~~Figure~~experience 2.steady ~~Interim~~growth, ~~SPY001~~driven ~~Phase~~by 1rising ~~safety~~disease ~~data~~prevalence, increasing diagnosis rates, and evolving treatment paradigms.

~~Figure~~A 3.range ~~Interim~~of ~~SPY001~~pharmaceutical ~~simulated~~options ~~concentration~~exists, including anti-~~time~~inflammatory ~~profile~~drugs, ~~compared~~immunosuppressants, and biologics. Treatment plans are often tailored to ~~vedolizumab~~the individual patient’s disease severity, location, and response to therapy. In some cases, surgical interventions such as bowel resection or ostomy formation may be necessary to manage complications or improve quality of life.

~~Figure~~Despite 4.available ~~Interim~~treatments, ~~SPY001~~there ~~pharmacodynamic~~remain ~~data~~substantial unmet needs in IBD management, including:

•Inadequate response or loss of response to existing therapies;

•Side effects and safety concerns associated with long-term medication use;

•Limited options for patients with refractory or severe disease; and

•Poor adherence to frequent and/or inconvenient dosing regimens.

Rheumatoid Arthritis

RA is a chronic inflammatory autoimmune condition that primarily affects the joints. It is characterized by pain, stiffness and swelling of one or more joints and can progress from mild swelling of the joints in early stages to severe deformations of the feet, ankles, and hands in late/severe stages. RA is thought to arise from an aberrant immune response to modified proteins in mucosal tissue and the synovium, driven by genetic risk factors and environmental stressors. RA affects more than 1.5 million individuals in the U.S., with stable-to-increasing incidence of ~40 per 100,000 individuals. Despite several advanced treatment options, a significant number of people living with RA continue to suffer from active disease. Today’s treatments are associated with many challenges, including low rates of remission, loss of response, and a high frequency of injections that may lead to poor compliance.

Psoriatic Arthritis

PsA is a chronic inflammatory autoimmune condition that typically affects both the joints and skin. It is characterized by pain, stiffness, and swelling of one or more joints and can progress from mild swelling of the joints in early stages to severe deformations of the joints in late/severe stages. Other characteristics can include psoriasis (PsO; scaly patches on the skin and/or nail discoloration and pitting), dactylitis (swollen fingers and toes), and spondylitis (painful inflammation in the spine). PsA is thought to arise from genetic and environmental triggers, though the pathogenesis is multifactorial and not well understood. PsA affects approximately 0.8 million individuals in the U.S., with estimates suggesting that up to 15% of PsO patients may have undiagnosed PsA. Despite several advanced treatment options, a significant number of people living with PsA continue to suffer from active disease. Today’s treatments are associated with many challenges, including inability to adequately address both joint and skin symptoms, loss of response, and a high frequency of injections that may lead to poor compliance.

Axial Spondyloarthritis

AxSpA is a chronic inflammatory autoimmune condition that primarily affects the axial skeleton (spine), with radiographic and non-radiographic subtypes. It is characterized by persistent back pain, stiffness, fatigue, joint stiffness, and frequent occurrence of extra-articular manifestations, such as anterior uveitis, IBD, and psoriasis. AxSpA is thought to arise when biomechanical stress, genetics, environmental triggers, and other factors lead to overactivation of the immune system in the spine. AxSpA affects an estimated 3 million individuals in the U.S., though only approximately 1 million of those are diagnosed. Despite some advanced treatment options, a significant number of people living with axSpA continue to suffer from active disease.

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~~SPY002~~Today’s –treatments ~~anti-TL1A~~are ~~mAb~~associated with many challenges, including incomplete / loss of response, lack of MOAs to cycle through, and a high frequency of injections that may lead to poor compliance.

~~For~~Our our SPY002 program, we nominated two highly potent, highly selective, and fully human mAb candidates designed to bind to tumor necrosis factor-like ligand 1A (“TL1A”), both of which are being developed for the treatment of IBD (UC and CD) and RA. TL1A is a protein that plays a role in regulating the immune system and is elevated in the gut tissue of individuals with IBD and synovial tissue of individuals with RA. TL1A interacts with its receptor, death receptor 3 (“DR3”), which is expressed in various immune cells, including T cells. This interaction triggers signaling pathways that contribute to inflammation and immune system activation, leading to IBD or RA symptomology. The SPY002 candidates have been designed to block the interaction between TL1A and DR3, and thereby inhibit the downstream signaling events and dampen the inflammatory response. By neutralizing TL1A, we believe the SPY002 candidates have the potential to modulate the immune response in IBD and RA patients, potentially reducing disease activity.Portfolio

~~SPY002~~We ~~preclinical~~are ~~characterization~~advancing ~~studies~~a ~~were~~pipeline ~~conducted~~of ~~in-house~~monoclonal ~~with~~antibodies ~~support~~(“mAbs”) ~~from~~for ~~third~~the ~~party~~treatment ~~vendors.~~of ~~Our~~IBD ~~extensive discovery campaign has identified two lead candidates which bind TL1A monomers~~ and ~~trimers~~other ~~and~~immune-mediated ~~have~~diseases. ~~subnanomolar~~The ~~potency~~following intable ~~cellular assays~~ (~~see~~ Figure ~~5, n=4 replicates per group per study~~7). ~~The~~summarizes ~~candidates~~our ~~also~~pipeline ~~exhibited~~and ~~extended pharmacokinetic half-lives of greater than two to three-fold relative to synthesized competitor molecules in clinical~~ development ~~that do not incorporate half-life extending modifications~~strategy, ~~based~~including onour ~~head-to-head~~SKYLINE ~~preclinical~~Phase ~~studies~~2 inplatform ~~NHPs~~trial ~~(see~~evaluating ~~Figure~~SPY001, 6SPY002, ~~n=5~~SPY003, ~~per~~and ~~group).~~pairwise ~~The~~combinations ~~42-day~~thereof ~~GLP~~in ~~toxicity~~patients ~~studies~~with inmoderately ~~NHPs~~to ~~(n=42)~~severely ~~for~~active ~~both~~UC ~~SPY002~~and ~~candidates~~our ~~were~~SKYWAY ~~completed~~basket ~~with~~trial ~~the~~evaluating ~~highest~~SPY072 ~~dose~~in ~~level~~three ~~tested~~rheumatic ~~determined~~diseases: asRA, ~~the~~PsA, ~~no-observed-adverse-effect-level.~~and axSpA:

~~The~~Figure Company initiated two FIH trials in healthy volunteers in the fourth quarter of 2024, one for each of our SPY002 candidates, with interim safety and PK data from these trials expected in the second quarter of 20257. IfSpyre ~~successful, one or more SPY002 candidates will then advance to Phase 2 clinical trials (UC and RA).~~portfolio

Figure 5. Inhibition of TL1A induced TF-1 cell apoptosis (left) and IFNγ secretion in primary human whole blood 1 donor of 4 donors profiled (right) (Data on file. Duvakitug was not benchmarked in IFNγ secretion assay; Duvakitug, RO7790121, and tulisokibart are synthesized comparator antibodies).

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~~Figure~~SKYLINE 6.Phase ~~Pharmacokinetic~~2 ~~concentration-time~~Platform ~~curves~~Trial ~~of SPY002 candidates compared to synthesized competing anti-TL1A molecules~~ in ~~non-human~~UC primates (Data on file. Group size was n=5 for SPY002 mAbs and tulisokibart at final endpoints for half-life determination; No RO7790121 detected after day 28. Duvakitug not compared in these models given low human half-life (7-10 days).).

In May 2025, we initiated our SKYLINE Phase 2 platform trial evaluating SPY001, SPY002, SPY003, –as ~~anti-IL-23~~well ~~mAb~~as pairwise combinations thereof (six investigational agents in total), in patients with moderately to severely active UC (Figure 8). The trial consists of two parts:

~~SPY003~~•Part isA: ~~a preclinical~~Open-~~stage~~label ~~program~~assessment ~~designed~~of tothe ~~bind~~safety ~~to Interleukin 23 (“IL-23”)~~ and ~~incorporates~~preliminary ~~half-life~~efficacy ~~extending~~of ~~modifications. IL-23 is~~ a ~~cytokine~~single ~~that~~dose islevel ~~produced by immune cells and is involved in immune response regulation. IL-23 promotes the survival, expansion, and activity~~ of ~~Th17~~each ~~cells.~~investigational ~~Th17 cells produce inflammatory cytokines~~monotherapy, ~~such~~with asinduction ~~IL-17,~~data ~~which~~expected ~~contribute~~ to ~~the~~begin ~~inflammation~~reading ~~seen~~out in ~~IBD.~~Q2 ~~IL-23 also helps in the recruitment and activation of other immune cells, such as neutrophils, which further contribute to tissue damage in the gut~~2026.

~~SPY003~~•Part ~~preclinical~~B: ~~characterization~~Randomized ~~studies~~and ~~were conducted in~~placebo-~~house~~controlled ~~with~~assessment ~~support~~of ~~from third party vendors. Our extensive discovery campaign has identified a lead candidate which binds to~~ the ~~p19~~safety ~~subunit of IL-23 with subnanomolar potency in cellular assays (see Figure 7, n=2~~ and ~~n=3~~efficacy ~~for~~of ~~pSTAT~~monotherapies ~~assay~~ and ~~IL-17 assay~~combinations, ~~respectively).~~designed ~~The development candidate also exhibited extended pharmacokinetic half-life of greater than three-fold relative~~ to aprovide ~~synthesized risankizumab comparator that does not incorporate half~~dose-~~life~~ranging ~~extending~~data ~~modifications, based~~ on ~~head~~monotherapies, proof-toof-~~head~~concept ~~preclinical~~and ~~studies~~contribution inof ~~NHPs~~components ~~(see~~for ~~Figure 8~~combinations, ~~n=4 per group~~ with ~~n=4~~induction ~~and~~data ~~n=3~~expected atin ~~the final timepoint for half-life determination for SPY003 and risankizumab, respectively)~~2027.

~~The~~SKYLINE ~~Company~~is ~~expects~~currently toenrolling ~~initiate~~subjects ainto ~~FIH~~Part ~~trial~~A inof ~~healthy volunteers in~~ the ~~first quarter of 2025~~trial, with ~~interim~~Part ~~safety~~B ~~and PK data from this trial~~ expected into ~~the~~begin ~~second~~enrolling ~~half~~after ofall ~~2025.~~Part IfA ~~successful,~~arms ~~SPY003~~complete ~~will then advance to Phase 2 clinical trials~~enrollment.

Figure 8. SKYLINE trial design

mMS=modified mayo score; RHI=Robarts Histopathology Index; HEMI=Histo-Endoscopic Mucosal Improvement; P=primary endpoint; S=secondary endpoint. Initiation of each cohort subject to regulatory clearance.

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~~Figure~~SKYWAY 7.Phase ~~Inhibition~~2 ofBasket ~~IL-23~~Trial ~~induced STAT3 phosphorylation~~ in aRheumatic ~~human~~Diseases ~~lymphoma cell line~~ (~~DB)~~RA, ~~(left)~~PsA, ~~and IL-23 induced IL-17 secretion in human peripheral blood mononuclear cells (right~~axSpA) ~~by SPY003 and synthesized risankizumab (Data on file).~~

~~Figure~~In 8.September ~~Pharmacokinetic~~2025, ~~concentration-time~~we ~~curves~~initiated ofour ~~SPY003~~SKYWAY ~~candidate~~Phase ~~compared~~2 torandomized ~~synthesized~~and ~~risankizumab comparator in non~~placebo-~~human~~controlled ~~primates~~basket ~~(Data~~trial onof ~~file.~~SPY072 ~~Group size was n=4~~ in ~~the~~patients ~~NHP studies~~ with ~~n=4~~moderately ~~and~~to ~~n=3~~severely atactive ~~the~~RA, ~~final~~PsA, ~~timepoint~~or ~~for~~axSpA ~~half-life~~(Figure ~~determination~~9). ~~for~~The ~~SPY003~~trial ~~and~~consists ~~risankizumab,~~of ~~respectively).~~three sub-studies:

~~SPY004~~•RA –sub-study: ~~novel~~Double-blind, ~~MOA~~placebo-controlled ~~mAb~~safety and efficacy study of two dose levels of SPY072 at Week 12 with open-label follow-up through Week 36.

~~SPY004~~•PsA ~~has an undisclosed novel MOA and incorporates half~~sub-~~life~~study: ~~extension modifications. Upon development candidate nomination~~Double-blind, weplacebo-controlled ~~intend~~safety toand ~~exercise~~efficacy ~~our~~study ~~Option~~of toa ~~acquire~~single ~~intellectual~~dose ~~property~~level ~~rights~~of ~~for~~SPY072 ~~the~~at ~~SPY004~~Week ~~program~~16 ~~pursuant~~with toopen-label ~~the~~follow-up ~~Paragon~~through ~~Agreement~~Week 40.

•axSpA sub-study: Double-blind, placebo-controlled safety and efficacy study of a single dose level of SPY072 at Week 16 with open-label follow-up through Week 40.

Topline proof-of-concept data for all three indications are expected in Q4 2026.

Figure 9. SKYWAY trial design

RF=rheumatoid factor; ACPA= Anti-citrullinated protein antibodies; cs/b/tsDMARD=conventional synthetic, biologic, or targeted synthetic disease modifying antirheumatic drugs; BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; P=primary endpoint; S=secondary endpoint; E=exploratory endpoint. IR=inadequate response

SPY001 – anti-α4β7 mAb

SPY001 is a highly potent, highly selective, and humanized monoclonal immunoglobulin G1 investigational antibody designed to bind selectively to the α4β7 integrin being developed for the treatment of IBD (UC and CD). The α4β7 integrin is a protein found on the surface of immune cells. This integrin regulates the migration of immune cells to the gut where they contribute to the inflammatory process in IBD. By selectively binding to the α4β7 integrin, SPY001 is designed to prevent the interaction of these immune cells with MAdCAM-1, a molecule expressed on endothelial cells lining the blood vessels in the gut. By blocking the interaction between α4β7 integrin and MAdCAM-1, SPY001 aims to reduce the recruitment of immune cells to the gut, leading to a decrease in inflammation. Since it specifically targets the gut immune system, SPY001 is designed to minimize systemic immunosuppressive effects unrelated to IBD pathology.

SPY001 demonstrates similar potency and selectivity as synthesized vedolizumab in preclinical in vitro models including surface plasmon residence and cellular adhesion assays. We initiated a first-in-human ("FIH") Phase 1 trial for SPY001 in June 2024. The SPY001 Phase 1 trial was a double blind, placebo-controlled trial in healthy volunteers consisting of a single-ascending dose ("SAD") component and a multi-ascending dose ("MAD") component. The trial enrolled 56 healthy adult participants into five SAD cohorts and two MAD cohorts

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~~SPY120~~in -the ~~combination~~main portion of the trial. The primary endpoint was safety, ~~anti-α4β7~~with PK and anti-~~TL1A~~drug ~~mAbs~~antibodies ("ADA") serving as secondary endpoints. Additional cohorts were added to the trial to evaluate PK in healthy volunteers of various ethnicities to facilitate subsequent global clinical trials.

~~SPY120~~Interim ~~combines~~results ~~SPY001~~were ~~(anti-α4β7)~~initially ~~and~~presented ~~SPY002~~in ~~(anti-TL1A)~~November ~~antibodies~~2024, ~~pairing~~with ~~two~~additional ~~mechanisms~~data ~~studied~~presented in ~~third-party~~May ~~clinical~~2025 ~~trials~~with ~~targeting~~up ~~non-overlapping~~to ~~sites~~eight months of ~~action~~follow up. WeTo ~~are~~date, ~~currently~~SPY001 ~~evaluating~~has ~~SPY120~~demonstrated ina ~~nonclinical~~favorable ~~studies~~safety profile across all dose groups, a meaningfully differentiated PK profile supporting potential quarterly or twice annual maintenance dosing, and ~~have~~rapid, ~~initiated~~complete ~~combination~~saturation ~~toxicology~~of ~~studies~~α4β7 receptors beyond six months with a single dose of 600mg. ~~Subject~~Based toon ~~regulatory~~these ~~feedback~~results, weSPY001 ~~intend~~was toadvanced ~~initiate~~into ~~clinical~~the ~~trials~~SKYLINE inPhase ~~2025~~2 ~~that~~platform ~~will~~clinical ~~include SPY120~~trial.

InSPY002 ~~February~~and ~~2025,~~SPY072 ~~the~~– Company presented new preclinical data demonstrating that combination therapy resulted in additive or greater than additive in vivo biological activity relative to either monotherapy in murine hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS) and anti-~~CD40~~TL1A ~~colitis models (Figure 9). In addition, coadministration of SPY001 and SPY002 in NHPs demonstrated no drug effects on PK (Figure 10).~~ mAbs

~~Figure~~For 9.our ~~Combined inhibition of~~ anti-TL1A program, we nominated two highly potent, highly selective, and ~~anti~~fully human mAb candidates designed to bind to tumor necrosis factor-ß7like ligand 1A (~~anti-α4β7~~“TL1A”). ~~murine~~SPY002 ~~surrogate~~(formerly SPY002-091) is ~~superior~~being todeveloped ~~either~~for ~~monotherapy~~the intreatment ~~mouse~~of ~~models~~IBD (UC and CD) and SPY072 (formerly SPY002-072) is being developed for the treatment of ~~colitis~~RD.

~~Figure~~TL1A ~~10.~~is ~~Coadministration~~a protein that plays a role in regulating the immune system and is elevated in gut tissue of ~~SPY001~~individuals with IBD and ~~SPY002~~serum ~~demonstrates~~or nosynovial ~~drug~~tissue of individuals with RA, PsA, and axSpA. TL1A interacts with its receptor, death receptor 3 (“DR3”), which is expressed in various immune cells, including T cells and fibroblast-~~drug~~like ~~effects~~synoviocytes. onThis ~~exposure~~interaction triggers signaling pathways that contribute to inflammation and joint injury in ~~NHPs~~RD, leading to symptomology, such as pain and swelling. SPY002 and SPY072 have been designed to block the interaction between TL1A and DR3, and thereby inhibit the downstream signaling events to dampen the inflammatory response. By neutralizing TL1A, we believe that SPY002 and SPY072 have the potential to modulate the immune response in IBD and rheumatic disease patients, potentially reducing disease activity.

~~SPY130~~SPY002 -and ~~combination~~SPY072 bind ~~anti-α4β7~~and inhibit TL1A with subnanomolar potency in preclinical cellular assays. We initiated FIH Phase 1 trials for SPY002 and ~~anti~~SPY072 in the fourth quarter of 2024. The Phase 1 trials were each double blind, placebo-~~IL-23~~controlled ~~mAbs~~evaluations in healthy volunteers, consisting of five SAD cohorts. Each trial enrolled 40 healthy adult participants across the five SAD cohorts in the main portion of the trial. The primary endpoint is safety, with PK and ADAs serving as secondary endpoints, and PD markers as exploratory endpoints. Phase 1 trial enrollment is complete.

~~SPY130~~Phase ~~combines~~1 ~~SPY001~~data ~~(anti-α4ß7)~~were presented in June 2025 and ~~SPY003~~October ~~(anti~~2025, with up to 24-~~IL-23)~~weeks ~~antibodies~~of follow up. To date, ~~pairing~~SPY002 ~~two~~and ~~commercially~~SPY072 ~~validated~~have ~~mechanisms~~demonstrated ~~targeting~~favorable ~~non-overlapping~~safety ~~sites~~profiles, meaningfully differentiated PK profiles supporting potential quarterly or twice annual maintenance dosing, and complete suppression of ~~action~~free TL1A through up to 20-24 weeks at single 100mg doses. WeBased ~~are~~on ~~currently~~these ~~evaluating~~results, ~~SPY130~~SPY002 inhas advanced to the SKYLINE Phase 2 platform trial and SPY072 has advanced to the SKYWAY Phase 2 basket trial.

SPY003 – anti-IL-23 mAb

SPY003 is a clinical-stage program designed to bind to interleukin 23 (“IL-23”) and incorporates half-life extending modifications. IL-23 is a cytokine that is produced by immune cells and is involved in immune response regulation. IL-23 promotes the survival, expansion, and activity of Th17 cells. Th17 cells produce inflammatory cytokines, such as IL-17, which contribute to the inflammation seen in IBD. IL-23 also helps in the recruitment and activation of other immune cells, such as neutrophils, which further contribute to tissue damage in the gut.

SPY003 binds to the p19 subunit of IL-23 with subnanomolar potency in cellular assays. SPY003 also exhibited extended PK half-life of greater than three-fold relative to a synthesized risankizumab comparator that does not incorporate half-life extending modifications, based on head-to-head preclinical studies in non-human primates ("NHPs").

We initiated a FIH trial in March 2025. The SPY003 Phase 1 trial is a double blind, placebo-controlled trial in healthy volunteers trial that enrolled 59 healthy adult participants into five SAD cohorts, one multiple dose (MD) cohort, and one Chinese ethnobridging cohort. The primary endpoint is safety, with PK and ADAs serving as secondary endpoints. Phase 1 trial enrollment is now complete.

Interim Phase 1 data were disclosed in November 2025, and additional data were presented in February 2026 with up to 20 weeks of follow-up, demonstrating that SPY003 exhibited a favorable safety profile

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~~nonclinical~~and ~~studies~~a ~~and~~meaningfully ~~initiated~~differentiated ~~combination~~PK ~~toxicology~~profile ~~studies~~supporting inquarterly ~~2024.~~or ~~Subject~~twice toannual ~~regulatory~~maintenance ~~feedback,~~dosing. weBased ~~intend~~on tothese ~~initiate~~results, ~~clinical~~SPY003 ~~trials~~was inadvanced ~~2025~~to ~~that~~the ~~will~~SKYLINE ~~include~~Phase ~~SPY130~~2 platform trial.

InSPY120 ~~October 2024, the Company presented new preclinical data, demonstrating in a T~~-~~cell~~ ~~transfer model of IBD~~combination, ~~that combination therapy with~~ anti-~~IL-23~~α4β7 and anti-~~α4ß7~~TL1A ~~improved body weight and reduced colonic CD4+ infiltration and IL-17 levels relative to monotherapy (Figure 11).~~ mAbs

~~Figure~~SPY120 ~~11.~~combines ~~Combination~~SPY001 ~~of anti-ß7~~ (anti-α4β7 ~~murine surrogate~~) and SPY002 (anti-~~IL-23~~TL1A) ~~increases~~antibodies, ~~efficacy~~pairing ~~and~~two PDcomplementary mechanisms studied in Tthird-~~cell~~party ~~transfer~~clinical ~~colitis~~trials ~~model~~targeting non-overlapping sites of action.

In February and May 2025, we presented preclinical data demonstrating that combinations resulted in additive or greater than additive in vivo biological activity relative to either monotherapy in mouse hapten reagent 2,4,6-trinitrobenzene sulfonic acid ("TNBS") and anti-CD40 colitis models. In October 2025, we presented preclinical data further demonstrating that combined inhibition resulted in superior efficacy relative to constituent monotherapies in a mouse TNBS-induced colitis model. In addition, combination toxicology studies have been completed with no drug-related adverse findings observed.

These preclinical data, in addition to our positive interim Phase 1 results for SPY001 and SPY002, support the advancement of SPY120 into Part B of the SKYLINE Phase 2 platform trial.

SPY130 - combination anti-α4β7 and anti-IL-23 mAbs

SPY130 combines SPY001 (anti-α4β7) and SPY003 (anti-IL-23) antibodies, pairing two commercially validated mechanisms targeting non-overlapping sites of action.

In October 2024, we presented preclinical data, demonstrating in a T-cell transfer model of IBD, that combinations with anti-IL-23 and anti-α4ß7 improved body weight and reduced colonic CD4+ infiltration and IL-17 levels relative to monotherapy. In March and October 2025, we presented additional preclinical data, demonstrating that combinations resulted in superior in vivo biological activity relative to either monotherapy in mouse TNBS model. In addition, combination toxicology studies have been completed with no drug-related adverse findings observed.

These preclinical data, in addition to our positive interim Phase 1 results for SPY001 and SPY003, support SPY130 being advanced in Part B of the SKYLINE Phase 2 platform trial.

SPY230 – combination anti-TL1A and anti-IL-23 mAbs

SPY230 combines SPY002 (anti-TL1A) and SPY003 (anti-IL-23) antibodies, pairing two complementary mechanisms of action with potential to address overlapping and non-overlapping triggers of inflammation. We are currently evaluating SPY230 in nonclinical studies and initiated combination toxicology studies in 2024. Subject to regulatory feedback, we intend to initiate clinical trials in 2025 that will include SPY230.

In October 2024, ~~the~~we ~~Company~~ presented ~~new~~ preclinical data, demonstrating that anti-IL-23 and anti-TL1A have a synergistic effect on promoting IL-17 secretion from human and mouse cells, and that the combination of anti-IL-23 and anti-TL1A suppressed IL-17 secretion more effectively than either agent alone. ~~(Figure~~In ~~12)~~March and October 2025, we presented additional preclinical data, demonstrating that combinations resulted in superior in vivo biological activity relative to either monotherapy in mouse TNBS model. In addition, combination toxicology studies have been completed with no drug-related adverse findings observed.

~~Figure~~These ~~12.~~preclinical ~~Combination~~data, ofin ~~anti-TL1A~~addition to our positive interim Phase 1 results for SPY002 and ~~anti-IL-23~~SPY003, ~~offers~~support ~~superior~~SPY230 ~~inhibition~~being advanced in Part B of ~~IL-17~~the ~~release~~SKYLINE inPhase ~~vitro~~2 platform trial.

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Employees and Human Capital Resources

As of December 31, ~~2024~~2025, we had 65102 employees, all of whom were employed full time. We also engage temporary employees and consultants to augment our existing workforce. None of our employees are represented by a labor union or covered under a collective bargaining agreement. We consider our relationship with our employees to be good.

We recognize that attracting, motivating, and retaining talent at all levels is vital to continuing our success. We invest in our employees through high-quality benefits, professional development opportunities, and various health and wellness initiatives and offer competitive compensation packages (base salary and incentive plans), ensuring fairness in internal compensation practices. The principal purposes of our incentive plans (bonus and equity) are to align with the long-term interests of our stakeholders and stockholders.

Commercial

Should any of our product candidates be approved for commercialization, we intend to develop a plan to commercialize them in the United States and other key markets, through internal infrastructure and/or external partnerships in a manner that will enable us to realize the full commercial value of our product candidates. ~~Given~~In January 2026 we hired our first Chief Commercial Officer, but given our stage of development, we have not yet established a robust commercial organization or distribution capabilities.

Manufacturing and Supply

We do not currently own or operate facilities for product manufacturing, testing, storage, and distribution. All of our nonclinical and clinical drug supply development, manufacturing, storage, distribution and testing are outsourced to third-party manufacturers and facilities. Our manufacturing strategy enables us to more efficiently direct financial resources to the research, development and commercialization of programs rather than diverting resources to internally develop and maintain manufacturing facilities. As our programs advance through development, we expect to enter into longer-term commercial supply agreements with key suppliers and manufacturers to fulfill and secure our supply needs.

Pursuant to a Novation Agreement dated September 19, 2023 (the “Novation Agreement”), by and between us, Paragon and WuXi Biologics (Hong Kong) Limited (“WuXi Biologics”), we novated (i) a Biologics Master Services Agreement (the “WuXi Biologics MSA”) and (ii) a Cell Line License Agreement (the “Cell Line License Agreement”).

InOn ~~light~~December of18, 2025, President Trump signed the ~~BIOSECURE~~Fiscal ~~Act~~Year ~~potentially~~2026 ~~being~~National ~~passed~~Defense Authorization Act, which ~~would~~includes ~~prohibit~~the BIOSECURE Act. The BIOSECURE Act prohibits federal departments and agencies from ~~entering~~contracting ~~into~~with ~~procurement~~or ~~contracts~~providing ~~with~~loans anor grants to any entity ~~that~~where ~~uses~~the biotechnology equipment or services ~~from~~of a designated "biotechnology company of concern" ("BCOC") would be used in the performance of that contract, wegrant, or loan. Generally, a BCOC is a biotechnology company that is subject to the jurisdiction, direction, control, or operates on behalf of a foreign adversary's government and poses a risk to the national security of the U.S. BCOCs include entities listed on the Department of Defense Section 1260H list of "Chinese military companies" and additional entities to be designated through an interagency process led by the Office of Management and Budget ("OMB"). OMB has not yet identified any BCOCs. We are in the process of creating manufacturing capabilities with third parties outside of China, including within the United States, and have taken several measures to strengthen our supply chain in the event that ~~WuXi Biologics or one of~~ our ~~other~~ manufacturers isare impacted. WeAmong other things, we intend to establish domestic inventory of key materials and are accelerating our clinical resupply campaigns to ensure we have a sufficient stockpile of drug substance. We will also continue to closely monitor geopolitical risk and implement additional mitigations and supply chain redundancies, as needed. See the risk ~~factor~~factors entitled “We may be negatively impacted by changes in law or other policy, including healthcare reform initiatives,” and “We currently rely, and plan to rely in the future, on third parties to conduct and support our preclinical studies and clinical trials. If these third parties do not properly and successfully carry out their contractual duties or meet expected deadlines, we may not be able to obtain regulatory approval of or commercialize our product candidates.”

Biologics Master Services Agreement

In April 2023, Paragon and WuXi Biologics entered into the WuXi Biologics MSA, which was subsequently novated to us by Paragon on September 19, 2023 pursuant to the Novation Agreement. The WuXi Biologics MSA was subsequently amended and restated in October 2024. The WuXi Biologics MSA governs certain development activities and Good Manufacturing Practice ("GMP") manufacturing and testing for the SPY001, SPY002, and SPY003 programs, as well as potential future programs, on a work order basis. Under the WuXi Biologics MSA, we are obligated to pay WuXi Biologics a service fee and all non-cancellable obligations in the amount specified in each work order associated with the agreement for the provision of services.

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The WuXi Biologics MSA terminates on the later of (i) October 14, 2029 or (ii) the completion of services under all work orders executed by the parties prior to October 14, 2029, unless terminated earlier. The term of each work order terminates upon completion of the services under such work order, unless terminated earlier. We can terminate the WuXi Biologics MSA or any work order at any time upon 30 days’ prior written notice and immediately upon written notice if WuXi Biologics fails to obtain or maintain required material governmental licenses or approvals. We can also terminate the WuXi Biologics MSA, or any work order, in the event that any law is enacted that has, or could be reasonably expected to have, a material adverse effect on us or any of our products that is the subject of the WuXi Biologics MSA, in each case, as a result of WuXi Biologics providing services under the WuXi Biologics MSA or us being a party to the WuXi Biologics MSA. Either party may terminate a work order (i) at any time upon six months’ prior notice with reasonable cause, provided however that if WuXi Biologics terminates a work order in such manner, no termination or cancellation fees shall be paid by us and (ii) immediately for cause upon (a) the other party’s material breach that remains uncured for 30 days after notice of such breach, (b) the other party’s bankruptcy or (c) a force majeure event that prevents performance for a period of at least 90 days.

Cell Line License Agreement

In April 2023, Paragon and WuXi Biologics entered into the Cell Line License Agreement, which was subsequently novated to us by Paragon pursuant to the Novation Agreement. The Cell Line License Agreement was subsequently amended and restated in October 2024. Under the Cell Line License Agreement, we received a non-exclusive, worldwide, sublicensable license to certain of WuXi Biologics’s know-how, cell line, biological materials (the “WuXi Biologics Licensed Technology”) and media and feeds to make, have made, use, sell and import certain therapeutic products produced through the use of the cell line licensed by WuXi Biologics under the Cell Line License Agreement (the “WuXi Biologics Licensed Products”). Specifically, the WuXi Biologics Licensed Technology is used in certain manufacturing activities in support of the SPY001, SPY002, and SPY003 programs.

In consideration for the license, we agreed to pay WuXi Biologics a non-refundable license fee of $150,000. Additionally, if we manufacture all of our commercial supplies of bulk drug product with a manufacturer other than WuXi Biologics or its affiliates, we are required to make royalty payments to WuXi Biologics in an amount equal to a less than one percent of global net sales of WuXi Biologics Licensed Products manufactured by a third-party manufacturer (the “Royalty”). If we manufacture part of our commercial supplies of the WuXi Biologics Licensed Products with WuXi Biologics or its affiliates, then the Royalty will be reduced accordingly on a pro rata basis. Subject to the terms of the Cell Line License Agreement, royalties owed under the Cell Line License Agreement may be bought out on a product-by-product basis for a lump-sum payment.

The Cell Line License Agreement will continue indefinitely unless terminated (i) by us upon six months’ prior written notice and our payment of all undisputed amounts due to WuXi Biologics through the effective date of termination, (ii) by WuXi Biologics for a material breach by us that remains uncured for 60 days after written notice, (iii) by WuXi Biologics if we fail to make a payment and such failure continues for 30 days after receiving notice of such failure, or (iv) by either party upon the other party’s bankruptcy.

~~Paragon~~Intellectual ~~Agreement~~Property

In May 2023, Pre-Merger Spyre entered into the Paragon Agreement with Paragon and Parapyre. Pursuant to the Paragon Agreement, the Option provided for the right to acquire the intellectual property rights related to four research programs from Paragon in accordance with a license agreement to be entered into following each exercise of the Option. Overview

OnWe ~~July~~strive ~~12,~~to ~~2023,~~protect ~~December 14, 2023 and June 5, 2024, we exercised our Option available under~~ the ~~Paragon~~proprietary ~~Agreement~~programs ~~with respect to the SPY001, SPY002~~ and ~~SPY003~~technologies ~~research~~that ~~programs, respectively. In May 2024,~~ we ~~signed~~believe ~~license~~are ~~agreements~~important ~~with Paragon for rights~~ to ~~royalty-bearing,~~our ~~world-wide~~business, ~~exclusive~~including ~~licenses~~seeking ~~to develop, manufacture, commercialize or otherwise exploit certain antibodies~~ and ~~products~~maintaining ~~targeting~~patent ~~ɑ4β7~~protection ~~integrin~~intended ~~(SPY001~~to ~~program)~~cover ~~and~~the ~~TL1A~~composition ~~(SPY002~~of ~~program)~~matter ~~and,~~of inour ~~October 2024~~programs, wetheir ~~signed~~methods aof ~~license agreement for rights to a royalty-bearing~~use, ~~world-wide,~~related ~~exclusive license to develop~~technologies, ~~manufacture~~diagnostics, ~~commercialize or otherwise exploit certain antibodies~~ and ~~products targeting IL-23 (SPY003 program) in the field of IBD. The SPY003 License Agreement was subsequently amended and restated in February 2025 to, among~~ other ~~things, clarify each party's rights and obligations with respect to license exclusivity and patent prosecution and correct~~ inventions.

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~~certain~~Patent ~~clerical~~Rights ~~errors.~~Relating ~~Our Option available under the Paragon Agreement with respect~~ to ~~the~~Our ~~SPY004~~Anti-α4β7 ~~program remains unexercised.~~Program

~~Under~~As ~~the terms~~ of ~~each~~January ~~License~~31, ~~Agreement~~2026, we ~~are~~exclusively ~~obligated~~license toor ~~pay~~owned ~~Paragon~~four uppatent families directed to ~~$22~~antibodies that target integrin receptor α4β7, including SPY001, pharmaceutical formulations and compositions, and methods of using those antibodies.0 ~~million~~The ~~upon~~first ~~the~~patent ~~achievement~~family is directed to compositions of ~~specific~~matter ~~development~~including SPY001, ~~regulatory~~method of treatment and ~~clinical~~dosing ~~milestones~~regimen ~~for~~and includes 2 U.S granted patents and patent applications filed in the ~~first~~U.S. ~~product~~and ~~under~~in ~~each~~foreign ~~agreement~~jurisdictions including Europe, ~~respectively~~Japan, ~~that~~and ~~achieves~~China. ~~such~~We ~~specified~~would ~~milestones~~expect these patents upon issuance to expire in 2044, ~~including~~absent aany ~~milestone~~applicable ~~payment~~patent ofterm $3extensions. ~~million~~The ~~upon~~second ~~the~~patent ~~first~~family ~~dosing~~is directed to methods of ausing ~~human~~SPY001 ~~patient~~and inincludes aan ~~Phase~~international 2(PCT) ~~trial~~patent application. ~~With~~If ~~respect~~the toPCT patent application is pursued in the ~~SPY002~~U.S. ~~License~~or ~~Agreement~~any ~~only,~~foreign onjurisdictions aand ~~product~~matures byinto ~~product~~one ~~basis~~or more issued patents, we ~~are~~would ~~obligated~~expect those patents to ~~pay~~expire ~~sublicensing~~in ~~fees~~2045, ofabsent upany applicable patent term extensions. The third patent family is directed to ~~approximately~~pharmaceutical ~~$20~~formulations ~~million~~containing ~~upon~~SPY001 ~~the~~and ~~achievement~~includes ofa ~~mostly~~PCT ~~commercial~~patent ~~milestones~~application. ~~Subject~~If to the ~~execution~~PCT ofpatent application is pursued in the ~~Option~~U.S. ~~with~~or ~~respect~~any toforeign ~~the~~jurisdictions ~~SPY004~~and ~~research~~matures ~~program~~into one or more issued patents, we would expect those patents to beexpire ~~obligated~~in 2045, absent any applicable patent term extensions. The fourth patent family is directed to ~~make~~other ~~similar~~α4β7 ~~payments~~antibody ~~upon~~compositions and ~~following~~includes a U.S. patent application and a PCT patent application. If the ~~execution~~PCT ofpatent application is pursued in any foreign jurisdictions and matures into one or more issued patents, and if the US patent application matures into a ~~license~~U.S. ~~agreement~~patent, ~~with~~we ~~respect~~would expect those patents upon issuance to ~~such~~expire ~~research~~in ~~program~~2044, absent any applicable patent term extensions.

Patent Rights Relating to Our Anti-Tl1A Program

As of January 31, 2026, we exclusively license or own ten patent families directed to antibodies that target TL1A, including SPY002 and SPY072, and methods of using those antibodies. The first patent family is directed to SPY002 and SPY072 compositions of matter and includes 2 U.S. granted patents, and a PCT patent application. If the PCT application is pursued in any foreign jurisdictions and matures into one or more issued patents, we would expect those patents upon issuance to expire in 2044, absent any applicable patent term extensions. The second patent family is directed to composition comprising other anti-TL1A antibody compositions and includes applications filed in the U.S., Europe, Japan, and China. If Spyre pursues the U.S. or any foreign jurisdictions and it matures into one or more issued patents, we would expect those patents upon issuance to expire in 2044, absent any applicable patent term extensions. The next six patent families are directed to methods of using SPY002 and SPY072 and includes six PCT patent applications. If these PCT patent applications are pursued in the U.S. and any foreign jurisdictions and mature into one or more issued patents, we would expect those patents upon issuance to expire in 2046, absent any applicable patent term extensions. The remaining two patent families are directed to SPY002 and SPY072 compositions and as of January 31, 2026, each family includes two provisional patent applications. If these provisional applications are pursued non-provisionally and mature into one or more issued patents, we would expect those patents upon issuance to expire in 2046, absent any applicable patent term extensions.

Patent Rights Relating to Our Anti-IL-23 Program

As of January 31, 2026, we exclusively license or own two patent families directed to antibodies that target IL-23, including SPY003, and methods of using those antibodies and formulations thereof. The first patent family is directed to compositions of matter including SPY003 and includes a U.S. patent application and a PCT patent application. If the PCT patent application is pursued in any foreign jurisdictions and matures into an issued patent or the Argentina or Taiwan applications are pursued and mature into one or more issued patents, we would expect those patents upon issuance to expire in 2045, absent any applicable patent term extensions. The second patent family is directed to pharmaceutical formulations and compositions including SPY003 and as of January 31, 2026, includes one provisional application. If the provisional application is pursued non-provisionally and matures into one or more issued patents, we would expect those patents upon issuance to expire in 2046, absent any applicable patent term extensions.

Patent Rights Relating to Our Combination Programs

As of January 31, 2026, we own four patent families directed to combinations of SPY001, SPY002, and SPY003. The first patent family is directed to methods of treatment with a combination of SPY001 and SPY002 (SPY120) and includes a PCT patent application. If the PCT application is pursued in the U.S. or any foreign jurisdictions and matures into one or more issued patents, we would expect those patents upon issuance to expire in 2045, absent any applicable patent term extensions. The second patent family is directed to methods of treatment with a combination of SPY001 and SPY003 (SPY130) and includes, as of January 31, 2026, one

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provisional application. If this provisional application is pursued non-provisionally and matures into one or more issued patents, we would expect those patents upon issuance to expire in 2046, absent any applicable patent term extensions. The remaining two patent families are directed to methods of treatment with a combination of SPY002 and SPY072 and SPY003 (SPY230) and as of January 31, 2026, each family includes two provisional patent applications. If these provisional applications are pursued non-provisionally and mature into one or more issued patents, we would expect those patents upon issuance to expire in 2046, absent any applicable patent term extensions.

Other IP Rights

In addition to patents, we rely upon unpatented trade secrets, know-how and continuing technological innovation to develop and maintain our competitive position. However, trade secrets and know-how can be difficult to protect. We seek to protect our proprietary information, in part by executing confidentiality agreements with our collaborators and scientific advisors, and non-competition, non-solicitation, confidentiality and invention assignment agreements with our employees and consultants. We have also executed agreements requiring assignment of inventions with selected scientific advisors and collaborators. The confidentiality agreements we enter into are designed to protect our proprietary information and the agreements or clauses requiring assignment of inventions to us are designed to grant us ownership of technologies that are developed through our relationship with the respective counterparty. We cannot guarantee, however, that we have executed such agreements with all applicable counterparties, that such agreements will not be breached, or that these agreements will afford us adequate protection of our intellectual property and proprietary rights. For more information, see the section entitled “Risk Factors - Risks Related to Our Intellectual Property”.

Trademark Rights Relating to the Spyre Therapeutics Name and Logo

As of January 31, 2026, we own trademark registrations for the Spyre name and name plus logo for research and development services of new pharmaceutical products in Australia, China, Europe, and the UK.

Paragon Agreement

In May 2023, Pre-Merger Spyre entered into the Paragon Agreement with Paragon and Parapyre. Pursuant to the Paragon Agreement, we received the option to license the intellectual property rights related to four research programs (collectively, the "Option") from Paragon in accordance with a license agreement to be entered into following each exercise of the Option.

On July 12, 2023, December 14, 2023 and June 5, 2024, we exercised our Option available under the Paragon Agreement with respect to the SPY001, SPY002 and SPY003 research programs, respectively. In May 2024, we signed license agreements with Paragon for rights to royalty-bearing, world-wide, exclusive licenses to develop, manufacture, commercialize or otherwise exploit certain antibodies and products targeting ɑ4β7 integrin (SPY001 program) (the "SPY001 License Agreement") and TL1A (SPY002 program) (the "SPY002 License Agreement") and, in October 2024, we signed a license agreement for rights to a royalty-bearing, world-wide, exclusive license to develop, manufacture, commercialize or otherwise exploit certain antibodies and products targeting IL-23 (SPY003 program) (the "SPY003 License Agreement" and, together with the SPY001 License Agreement and the SPY002 License Agreement, the "License Agreements") in the field of IBD. The SPY003 License Agreement was subsequently amended and restated in February 2025 to, among other things, clarify each party's rights and obligations with respect to license exclusivity and patent prosecution and correct certain clerical errors. The Option with respect to one additional program remains unexercised under the Paragon Agreement.

Under the terms of each License Agreement, we are obligated to pay Paragon up to $22.0 million upon the achievement of specific development, regulatory and clinical milestones for the first product under each agreement, respectively, that achieves such specified milestones, including a milestone payment of $5 million upon the first dosing of a human patient in a Phase 3 trial. With respect to the SPY002 License Agreement only, on a product by product basis, we are obligated to pay sublicensing fees of up to approximately $20 million upon the achievement of mostly commercial milestones. Subject to the execution of the Option with respect to the remaining research program, we expect to be obligated to make similar payments upon and following the execution of a license agreement with respect to such research program.

Competition

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We expect to face intense competition from other biopharmaceutical companies that are developing agents for the treatment of inflammatory diseases. If approved for the treatment of patients with moderate-to-severe IBD, our portfolio of products would compete with TNF antibodies including Humira (AbbVie), Remicade (Johnson & Johnson), and Simponi (Johnson & Johnson); IL-12/23 and IL-23 antibodies including Stelara (Johnson & Johnson), Skyrizi (AbbVie), Omvoh (Lilly), and Tremfya (Johnson & Johnson); α4ß7 antibody Entyvio (Takeda); JAK inhibitors including Xeljanz (Pfizer) and Rinvoq (AbbVie); and S1P1 receptor modulating therapies including Zeposia (Bristol Myers Squibb) and Velsipity (Pfizer). Our products would also compete with biosimilars or generics, either currently approved or in development, to many of these products.

We are aware of several companies with product candidates in development for the treatment of patients with IBD, including Merck’s tulisokibart, Roche/Roivant’s ~~RO7790121~~afimkibart, and Sanofi/Teva’s duvakitug TL1A antibodies; additional IL-23/IL-23Rs including icotrokinra (Johnson & Johnson) and picankibart (Innovent); oral anti-integrin agents including Lilly’s MORF-057, and Gilead’s GS-1427; PDE4 inhibitor PALI-2108 (Palisade Bio); multispecifics including PF-07261271 targeting TL1A and IL-12/23 (Pfizer and Roche), ~~and~~ SOR102 targeting TNF and IL-23 (Sorriso), HXN-1002 targeting α4β7 and TL1A (Sanofi/Earendil), HXN-1003 targeting TL1A and IL-23 (Sanofi/Earendil), SIM0709 targeting TL1A and IL-23 (Simcere and Boehringer Ingelheim) and XmAb412 targeting TL1A and IL-23 (Xencor).

If approved for the treatment of patients with moderate-to-severe ~~rheumatoid arthritis~~RA, ~~SPY002~~SPY072 would compete with TNF antibodies including Humira (AbbVie), Cimzia (UCB), Enbrel (Amgen), Remicade (Johnson & Johnson), and Simponi (Johnson & Johnson); T-cell activation inhibitor Orencia (Bristol Myers Squibb); IL-6R antibodies Actemra (Roche) and Kevzara (Sanofi); CD20 antibody Rituxan (Roche); IL-1R antibody Kineret (Sobi); and JAK inhibitors including Xeljanz (Pfizer), Rinvoq (AbbVie), and Olumiant (Lilly). Our products would also compete with biosimilars or generics, either currently approved or in development, to many of these products.

We are aware of several companies with product candidates in development for the treatment of patients with RA, including Merck’s tulisokibart and Roche/Roivant’s afimkibart TL1A antibodies; Anaptys’ rosnilimab, Johnson and Johnson’s JNJ-4703, and Gilead’s GS-0151 PD-1 agonists; ~~FcRn inhibitors including IMVT-1402 (Immunovant), a nipocalimab and certolizumab combination (Johnson and Johnson);~~ RIPK1 inhibitors including Lilly’s ocadusertib; additional TNF inhibitors including Zenas’ ZB002 half-life extended antibody and Sanofi’s oral small molecule ~~SAR441566~~balinatunfib; BTLA agonist GS-0272 (Gilead); Treg cell therapy SBT-77-7101 (Sonoma Biotherapeutics); ~~IgG~~MC1/3 ~~degrader~~agonist ~~BHV-1300~~resomelagon/AP1189 (~~Biohaven~~Synact Pharma); ~~and~~ bispecific fusion proteins including plamotamab/XmAb-13676 (Xencor); and IL-1α/β inhibitors including a lutikizumab and ravagalimab combination (AbbVie).

~~Government~~If ~~Regulation~~approved for the treatment of patients with moderate-to-severe PsA, SPY072 would compete with TNF antibodies including Humira (AbbVie), Cimzia (UCB), Enbrel (Amgen), Remicade (Johnson & Johnson), and Simponi (Johnson & Johnson); T-cell activation inhibitor Orencia (Bristol Myers Squibb); IL-17 antibodies Cosentyx (Novartis), Taltz (Lilly), and Bimzelx (UCB); CD20 antibody Rituxan (Roche); IL-12/23 antibody Stelara (Johnson & Johnson); IL-23 antibodies Skyrizi (AbbVie) and Tremfya (Johnson & Johnson); PDE4 antibody Otezla (Amgen); and JAK inhibitors including Xeljanz (Pfizer) and Rinvoq (AbbVie). Our products would also compete with biosimilars or generics, either currently approved or in development, to many of these products.

~~The~~We ~~FDA~~are ~~and~~aware ~~other~~of ~~regulatory~~several ~~authorities~~companies atwith ~~federal,~~product ~~state~~candidates ~~and local levels, as well as~~ in ~~foreign~~development ~~countries,~~for ~~extensively regulate, among other things,~~ the ~~research,~~treatment ~~development,~~of ~~testing,~~patients ~~manufacture,~~with ~~quality control~~PsA, ~~import,~~including ~~export,~~TYK2 ~~safety,~~inhibitor ~~effectiveness,~~Sotyktu ~~labeling,~~(Bristol ~~packaging,~~Myers ~~storage,~~Squibb); ~~distribution,~~IL-23 ~~record~~antibodies ~~keeping,~~including ~~approval,~~icotrokinra ~~advertising,~~(Johnson ~~promotion,~~& ~~marketing,~~Johnson) ~~post-approval monitoring~~ and ~~post-approval~~tildrakizumab ~~reporting~~(Sun ofPharma); ~~biologics~~IL-17A/F ~~such~~nanobody assonelokimab ~~those~~(MoonLake); weand ~~are~~multiple ~~developing.~~combination ~~We,~~trials ~~along~~including ~~with~~a ~~our~~Tremfya ~~third~~(IL-~~party~~23) ~~contractors, will be required to navigate the various preclinical, clinical~~ and ~~commercial~~Simponi ~~approval~~(TNF) ~~requirements~~combination of(Johnson ~~the~~& ~~governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidates. Generally~~Johnson), ~~before~~ a ~~new~~lutikizumab ~~therapeutic~~(IL-1α/β) ~~product~~and ~~can~~Skyrizi be(IL-23) ~~marketed,~~combination ~~considerable data demonstrating a biological product candidate’s quality~~(AbbVie), ~~safety, purity~~ and ~~potency, or~~ a ~~small~~Taltz ~~molecule~~(IL-17) ~~drug candidate’s quality, safety~~ and ~~efficacy,~~Zepbound ~~must~~(GIP/GLP-1 bereceptor ~~obtained,~~agonist) ~~organized~~combination ~~into a format specific for each regulatory authority, submitted for review and approved by~~ (Lilly).

13If approved for the treatment of patients with moderate-to-severe axSpA, SPY072 would compete with TNF antibodies including Humira (AbbVie), Cimzia (UCB), Enbrel (Amgen), Remicade (Johnson & Johnson), and Simponi (Johnson & Johnson); IL-17 antibodies Cosentyx (Novartis), Taltz (Lilly), and Bimzelx (UCB); and JAK inhibitors including Xeljanz (Pfizer) and Rinvoq (AbbVie). Our products would also compete with biosimilars or generics, either currently approved or in development, to many of these products.

We are aware of several companies with product candidates in development for the treatment of patients with axSpA, including TL1A inhibitor tulisokibart (Merck); IL-17A inhibitor gumokimab (Akesobio) and IL-17A/F nanobody sonelokimab (MoonLake); and PDE4 inhibtior mufemilast (Hemay).

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~~the~~Government regulatory authority. For biological product candidates, potency is similar to efficacy and is interpreted to mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.Regulation

The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of biologics such as those we are developing. We, along with our third-party contractors, will be required to navigate the various preclinical, clinical and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidates. Generally, before a new therapeutic product can be marketed, considerable data demonstrating a biological product candidate’s quality, safety, purity and potency, or a small molecule drug candidate’s quality, safety and efficacy, must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority. For biological product candidates, potency is similar to efficacy and is interpreted to mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.

Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or post-marketing may subject an applicant to administrative or judicial sanctions. These sanctions could include, among other actions, the FDA’s refusal to approve pending applications from the sponsor, withdrawal of an approval, a clinical hold, untitled or warning letters, product recalls or market withdrawals, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement and civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on our company and our products or product candidates.

United States Biologics Regulation

In the United States, biological products are subject to regulation under the Federal Food, Drug, and Cosmetic Act (“FDCA”), the Public Health Service Act (“PHSA”) and other federal, state, local, and foreign statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, and local statutes and regulations requires the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or following approval may subject an applicant to administrative action and judicial sanctions. The process required by the FDA before biologic product candidates may be marketed in the United States generally involves the following:

•completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s current Good Laboratory Practices ("~~GLP~~GLPs") regulation;

•submission to the FDA of an IND, which must become effective before clinical trials may begin and must be updated annually or when significant changes are made;

•approval by an independent institutional review board (“IRB”), or ethics committee at each clinical site before the trial is commenced;

•manufacture of the proposed biologic candidate in accordance with current Good Manufacturing Practices (“cGMPs”);

•performance of adequate and well-controlled human clinical trials in accordance with current Good Clinical Practice (“GCP”) requirements to establish the safety, purity and potency of the proposed biologic product candidate for its intended purpose;

•preparation of and submission to the FDA of a Biologics License Application ("BLA"), after completion of all pivotal clinical trials;

•satisfactory completion of an FDA Advisory Committee review, if applicable;

•a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;

•satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMPs, and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency, and of selected clinical investigation sites to assess compliance with GCPs; and

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facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency, and of selected clinical investigation sites to assess compliance with GCP; and

•FDA review and approval of a BLA to permit commercial marketing of the product for particular indications for use in the United States.

Preclinical and Clinical Development

~~Prior~~Once ~~to beginning any clinical trial with~~ a therapeutic product candidate inis ~~the~~identified ~~United~~for ~~States~~development, weit must ~~submit~~undergo anpreclinical ~~IND~~studies tobefore ~~the~~commencing ~~FDA.~~any Antesting ~~IND~~in ishumans. aPreclinical ~~request~~studies ~~for~~include ~~authorization~~laboratory ~~from~~evaluations ~~the~~of ~~FDA to administer an investigational new drug~~ product tochemistry, ~~humans.~~formulation ~~The~~and ~~central~~stability, ~~focus~~as ofwell anas ~~IND~~studies ~~submission~~to isevaluate on the ~~general~~candidate's ~~investigational~~potential ~~plan~~for efficacy and ~~the~~toxicity ~~protocol~~in oranimals. ~~protocols~~The ~~for~~conduct of preclinical ~~studies~~tests and ~~clinical~~formulation ~~trials.~~of ~~The~~the ~~IND~~compounds ~~also~~for ~~includes~~testing ~~results~~must ofcomply ~~animal~~with federal regulations and inrequirements, ~~vitro~~including current GLPs.

14Prior to beginning any clinical trial with a product candidate in the United States, we must submit an IND application to the FDA. An IND application is a request for authorization from the FDA to administer an investigational new drug product to humans. The central focus of an IND application is on the general investigational plan, supportive nonclinical evaluations, and the protocol or protocols for clinical trials. The IND includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology and pharmacodynamic characteristics of the product, chemistry, manufacturing and controls information, and any available human data or literature to support the use of the investigational product. An IND must become effective before human clinical trials may begin. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day period, raises safety concerns or questions about the proposed clinical trial. In such a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin. Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.

~~Table~~Clinical trials involve the administration of ~~Contents~~the investigational product to human subjects under the supervision of qualified investigators in accordance with current GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated. A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments. Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site and must monitor the trial until completed.

~~studies~~Regulatory ~~assessing~~authorities, the ~~toxicology,~~IRB ~~pharmacokinetics,~~or ~~pharmacology~~the ~~and~~sponsor ~~pharmacodynamic~~may ~~characteristics~~suspend ofa ~~the~~clinical ~~product,~~trial ~~chemistry,~~at ~~manufacturing~~any ~~and~~time ~~controls~~on ~~information~~various grounds, ~~and~~including ~~any~~a ~~available~~finding ~~human~~that ~~data~~the orsubjects ~~literature~~are being exposed to ~~support~~an ~~the~~unacceptable ~~use~~health ofrisk ~~the~~or ~~investigational~~that ~~product.~~the Antrial ~~IND~~is ~~must~~unlikely ~~become~~to ~~effective~~meet ~~before~~its ~~human~~stated ~~clinical~~objectives. Some trials ~~may~~also ~~begin.~~include ~~The~~oversight ~~IND~~by ~~automatically~~an ~~becomes~~independent ~~effective~~group 30of ~~days~~qualified ~~after~~experts ~~receipt~~organized by the ~~FDA,~~clinical ~~unless~~trial ~~the FDA~~sponsor, ~~within~~known ~~the~~as ~~30-day~~a ~~period,~~data ~~raises~~ safety ~~concerns~~monitoring board or ~~questions~~data ~~about~~monitoring ~~the~~committee, ~~proposed~~which ~~clinical~~provides ~~trial.~~authorization Infor ~~such~~whether aor ~~case,~~not ~~the~~a ~~IND~~trial may bemove ~~placed~~forward onat ~~clinical~~designated ~~hold~~check ~~and~~points ~~the~~based ~~IND~~on ~~sponsor~~access ~~and~~to ~~the~~certain ~~FDA~~data ~~must~~from ~~resolve~~the ~~any~~trial ~~outstanding~~and ~~concerns~~may orhalt ~~questions before~~ the clinical trial ~~can~~if ~~begin.~~it ~~Submission~~determines ofthat there is an ~~IND~~unacceptable ~~therefore~~safety ~~may~~risk for subjects or ~~may~~other ~~not~~grounds, ~~result~~such inas ~~FDA~~no ~~authorization~~demonstration toof ~~begin~~efficacy. aThere are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.

InHuman ~~addition~~clinical ~~to the IND submission process, supervision of human gene transfer~~ trials ~~includes~~are ~~evaluation~~typically ~~and~~conducted ~~assessment~~in bythree ansequential ~~institutional~~phases ~~biosafety committee (“IBC”), a local institutional committee~~ that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution. The IBC assesses the safety of the research and identifies any potential risk to public health or the environment and such review may ~~result in some delay before initiation of a clinical trial~~overlap.

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical study. Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated. A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments. Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the study until completed.

Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives. Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy. There are also requirements governing the reporting of ongoing preclinical studies and clinical trials and clinical study results to public registries.

For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap.

•Phase 1. The investigational product is initially introduced into healthy human subjects or patients with the target disease or condition. These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

•Phase 2. The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks. Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.

•Phase 3. The investigational product is administered to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval.17

In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product. These so-called Phase 4 studies may be made a condition to approval of the BLA. Concurrent with clinical trials, companies may complete additional animal studies and develop additional information about the biological characteristics of the product candidate and must finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the

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~~product~~•Phase ~~candidate~~3. ~~and,~~The ~~among~~investigational ~~other~~product ~~things,~~is ~~must~~administered ~~develop~~to ~~methods~~an ~~for~~expanded ~~testing~~patient ~~the~~population ~~identity,~~to ~~strength~~further evaluate dosage, ~~quality~~to ~~and~~provide ~~purity~~statistically significant evidence of ~~the~~clinical ~~final~~efficacy ~~product,~~and orto ~~for~~further ~~biologics,~~test ~~the~~for safety, ~~purity~~generally ~~and~~at ~~potency.~~multiple ~~Additionally,~~geographically ~~appropriate~~dispersed ~~packaging~~clinical ~~must~~trial besites. ~~selected~~These ~~and~~clinical ~~tested,~~trials ~~and~~are ~~stability~~intended ~~studies~~to ~~must~~establish bethe ~~conducted~~overall torisk/benefit ~~demonstrate~~ratio ~~that~~of the investigational product ~~candidate~~and ~~does~~to ~~not~~provide ~~undergo~~an ~~unacceptable~~adequate ~~deterioration~~basis ~~over~~for ~~its~~product ~~shelf life~~approval.

AIn ~~sponsor~~some ~~may choose~~cases, ~~but~~the isFDA ~~not~~may ~~required~~require, toor ~~conduct~~companies amay ~~foreign~~voluntarily ~~clinical~~pursue, ~~study~~additional ~~under~~clinical antrials ~~IND.~~after ~~When~~ a ~~foreign~~product ~~clinical study~~ is ~~conducted~~approved ~~under~~to angain ~~IND,~~more ~~all~~information ~~IND~~about ~~requirements~~the ~~must~~product. beThese ~~met~~so-called ~~unless~~Phase ~~waived.~~4 ~~When~~studies ~~the~~may ~~foreign~~be ~~clinical~~made ~~study~~a iscondition ~~not~~to ~~conducted~~approval ~~under~~of ~~an IND,~~ the ~~sponsor~~BLA. ~~must~~Concurrent ~~ensure~~with ~~that~~clinical ~~the~~trials, ~~study~~companies ~~complies~~may ~~with~~complete ~~certain~~additional ~~FDA~~animal ~~regulatory~~studies ~~requirements~~and indevelop ~~order~~additional toinformation ~~use~~about the ~~study~~biological ascharacteristics ~~support~~of ~~for~~the anproduct ~~IND~~candidate orand ~~application~~must ~~for~~finalize ~~marketing~~a ~~approval~~process orfor ~~licensure,~~manufacturing ~~including that~~ the ~~study~~product ~~was~~in ~~conducted~~commercial quantities in accordance with ~~GCP,~~cGMP ~~including~~requirements. ~~review~~The ~~and~~manufacturing ~~approval~~process bymust anbe ~~independent~~capable ~~ethics~~of ~~committee~~consistently ~~and~~producing ~~use~~quality batches of ~~proper~~the ~~procedures~~product ~~for~~candidate ~~obtaining~~and, ~~informed~~among ~~consent~~other ~~from subjects~~things, ~~and~~methods must be developed for testing the ~~FDA~~safety, ispurity ~~able~~and topotency ~~validate~~of the ~~data~~biologic. ~~from~~Additionally, ~~the~~appropriate ~~study~~packaging ~~through~~must anbe ~~onsite~~selected ~~inspection~~and iftested, ~~the~~and ~~FDA~~stability ~~deems~~studies ~~such~~must ~~inspection~~be ~~necessary.~~conducted ~~The~~to ~~GCP~~demonstrate ~~requirements~~that ~~encompass~~the ~~both~~product ~~ethical~~candidate ~~and~~does ~~data~~not ~~integrity~~undergo ~~standards~~unacceptable ~~for~~deterioration ~~clinical~~over ~~studies~~its claimed shelf life.

A sponsor may choose, but is not required, to conduct a foreign clinical trial under an IND. When a foreign clinical trial is conducted under an IND, all IND requirements must be met unless waived. When the foreign clinical trial is not conducted under an IND, the sponsor must ensure that the trial complies with certain FDA regulatory requirements in order to use the trial in support of a BLA, including that the trial was conducted in accordance with GCP, review and approval by an independent ethics committee, use of proper procedures for obtaining informed consent from subjects, and the FDA is able to validate the data from the trial through an onsite inspection if the FDA deems such inspection necessary. The GCP requirements encompass both ethical and data integrity standards for clinical studies.

BLA Submission and Review

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies and clinical trials are submitted to the FDA as part of a BLA requesting approval to market the product for one or more indications. The BLA must include all relevant data available from pertinent preclinical studies and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things. Data can come from company-sponsored clinical studies intended to test the safety and effectiveness of the product, or from a number of alternative sources, including studies initiated and sponsored by investigators. The submission of a BLA requires payment of a substantial application user fee to the FDA, unless a waiver or exemption applies.

In addition, under the Pediatric Research Equity Act (“PREA”), a BLA or supplement to a BLA must contain data to assess the safety and effectiveness of the biological product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective, unless a different timeline has been previously agreed upon by the FDA, through approval of a pediatric study plan, described below. The Food and Drug Administration Safety and Innovation Act requires that a sponsor who is planning to submit a marketing application for a biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial pediatric study plan (“PSP”) within sixty days after an end-of-Phase 2 meeting or as may be agreed between the sponsor and FDA. Unless otherwise required by regulation, PREA does not apply to any biological product for an indication for which orphan designation has been granted.

Within 60 days following submission of the application, the FDA reviews a BLA submitted to determine if it is substantially complete before the agency accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA must be resubmitted with the additional information. Once a BLA has been accepted for filing, the FDA’s goal is to review standard applications within ten months after the ~~filing~~FDA ~~date~~accepts the application for filing, or, if the application qualifies for priority review, six months after the FDA accepts the application for filing. In both standard and priority reviews, the review process may also be extended by FDA requests for additional information or clarification. The FDA reviews a BLA to determine, among other things, whether a product is safe, pure and potent and the facility in which it is manufactured, processed, packed or held meets standards designed to assure the product’s continued safety, purity and potency. The FDA may convene an advisory committee to provide clinical insight on application review questions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving a BLA, the FDA will typically inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCPs. If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information. Notwithstanding the submission of any requested additional 18

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~~information~~product is safe, pure and potent and the ~~FDA~~facility ~~ultimately~~in ~~may~~which ~~decide~~it ~~that~~is manufactured, processed, packed or held meets standards designed to assure the product’s continued safety, purity and potency. The FDA may convene an advisory committee to provide clinical insight on application ~~does~~review questions. The FDA is not ~~satisfy~~bound by the ~~regulatory~~recommendations ~~criteria~~of ~~for~~an ~~approval~~advisory committee, but it considers such recommendations carefully when making decisions.

Before approving a BLA, the FDA will typically inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCPs and data integrity of the submitted clinical trial data. If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information. Notwithstanding the submission of any requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

After the FDA evaluates a BLA and conducts inspections of manufacturing facilities where the investigational product and/or its drug substance will be produced, the FDA may issue an approval letter or a Complete Response letter. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications. A Complete Response letter will describe all of the deficiencies that the FDA has identified in the BLA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the Complete Response letter without first conducting required inspections, testing submitted product lots and/or reviewing proposed labeling. In issuing the Complete Response letter, the FDA may recommend actions that the applicant might take to place the BLA in condition for approval, including requests for additional information or clarification. The FDA may delay or refuse approval of a BLA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.

If regulatory approval of a product is granted, such approval will be granted for particular indications and may entail limitations on the indicated uses for which such product may be marketed. For example, the FDA may approve the BLA with a Risk Evaluation and Mitigation Strategy (“REMS”) to ensure the benefits of the product outweigh its risks. A REMS is a safety strategy to manage a known or potential serious risk associated with a product and to enable patients to have continued access to such medicines by managing their safe use, and could include requirements for medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls and specifications. Once approved, the FDA may withdraw the product approval if compliance with pre- and post-marketing requirements is not maintained or if problems occur after the product reaches the marketplace. The FDA may require one or more Phase 4 post-~~market~~marketing studies and/or surveillance in addition to that required of every approved product to further assess and monitor the product’s safety and effectiveness after commercialization, and may limit further marketing of the product based on the results of these post-marketing studies.

Expedited Development and Review Programs

The FDA offers a number of expedited development and review programs for qualifying product candidates. The fast track program is intended to expedite or facilitate the process for reviewing new products that meet certain criteria. Specifically, new products are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and data demonstrate the potential to address unmet medical needs for the disease or condition. Fast track designation applies to the combination of the product and the specific indication for which it is being studied. A fast track product may also be eligible for rolling review, where the FDA may consider for review sections of the BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the BLA, the FDA agrees to accept sections of the BLA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the BLA.

Additionally, products studied for their safety and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. As a condition of accelerated approval, the FDA will generally require the sponsor to perform adequate and well-controlled post-marketing clinical studies to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit. Under the Food and Drug Omnibus Reform Act of 2022 the FDA may require, as appropriate, that such studies be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval. Products receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required post-marketing studies or if such studies fail to verify the predicted clinical benefit. In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

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Aa ~~product~~surrogate ~~intended~~endpoint that is reasonably likely to ~~treat~~predict aclinical ~~serious~~benefit, or ~~life-threatening~~on ~~disease~~a orclinical ~~condition~~endpoint ~~may~~that ~~also~~can be ~~eligible~~measured ~~for~~earlier ~~breakthrough~~than ~~therapy~~irreversible ~~designation~~morbidity toor ~~expedite~~mortality, ~~its~~that ~~development~~is ~~and~~reasonably ~~review.~~likely Ato ~~product~~predict ~~can~~an ~~receive~~effect ~~breakthrough~~on ~~therapy~~irreversible ~~designation~~morbidity ifor ~~preliminary~~mortality or other clinical ~~evidence~~benefit, ~~indicates~~taking ~~that~~into account the ~~product~~severity, ~~alone~~rarity, or inprevalence ~~combination~~of ~~with~~the ~~one~~condition and the availability or ~~more~~lack ~~other~~of ~~drugs~~alternative ortreatments. ~~biologics~~As a condition of accelerated approval, ~~may~~the ~~demonstrate~~FDA ~~substantial~~will ~~improvement~~generally ~~over~~require ~~existing~~the ~~therapies~~sponsor onto ~~one~~perform oradequate ~~more~~and ~~clinically~~well-controlled ~~significant~~post-marketing ~~endpoints,~~clinical ~~such~~studies asto ~~substantial~~verify ~~treatment~~and ~~effects~~describe ~~observed~~the ~~early~~anticipated ineffect on irreversible morbidity or mortality or other clinical ~~development~~benefit measure. ~~The~~Under ~~designation~~the ~~includes~~Food ~~all~~and Drug Omnibus Reform Act of 2022 the ~~fast~~FDA ~~track~~may ~~program features~~require, as ~~well~~appropriate, asthat ~~more~~such ~~intensive~~studies ~~FDA~~be ~~interaction~~underway ~~and~~prior ~~guidance~~to ~~beginning~~approval asor ~~early~~within asa ~~Phase~~specific 1time ~~and~~period anafter ~~organizational~~the ~~commitment~~date of approval for a product granted accelerated approval. Products receiving accelerated approval may be subject to ~~expedite~~expedited withdrawal procedures if the ~~development~~sponsor ~~and~~fails ~~review~~to ofconduct the ~~product~~required post-marketing studies or if such studies fail to verify the predicted clinical benefit. In addition, ~~including~~the ~~involvement~~FDA currently requires as a condition for accelerated approval pre-approval of ~~senior~~promotional ~~managers~~materials, which could adversely impact the timing of the commercial launch of the product.

~~Any~~A ~~marketing~~product ~~application~~intended ~~for~~to treat a ~~biologic~~serious ~~submitted~~or tolife-threatening ~~the~~disease ~~FDA~~or ~~for~~condition ~~approval,~~may ~~including~~also abe ~~product~~eligible ~~with~~for aBreakthrough ~~fast~~Therapy ~~track~~Designation ~~designation~~to ~~and/or~~expedite ~~breakthrough~~its ~~therapy~~development ~~designation,~~and ~~may~~review. beA ~~eligible~~product ~~for~~can ~~other~~receive ~~types~~Breakthrough ofTherapy ~~FDA~~Designation ~~programs~~if ~~intended~~preliminary toclinical ~~expedite~~evidence indicates that the ~~FDA~~product, ~~review~~alone ~~and~~or ~~approval~~in ~~process,~~combination ~~such~~with asone ~~priority~~or ~~review~~more ~~and~~other ~~accelerated~~drugs ~~approval.~~or Abiologics, ~~product~~may isdemonstrate ~~eligible~~substantial ~~for~~improvement ~~priority~~over ~~review~~existing iftherapies ~~there~~on isone ~~evidence~~or itmore ~~has~~clinically ~~the~~significant ~~potential~~endpoints, tosuch ~~provide~~as asubstantial ~~significant~~treatment ~~improvement~~effects inobserved ~~the~~early ~~treatment,~~in ~~diagnosis~~clinical ordevelopment. ~~prevention~~The ofdesignation aincludes ~~serious~~all ~~disease~~of orthe ~~condition.~~Fast ~~For~~Track ~~original~~program ~~BLAs~~features, ~~priority~~as ~~review~~well ~~designation~~as ~~means~~more ~~the~~intensive FDA’s ~~goal~~interaction isand toguidance ~~take~~beginning ~~action~~as onearly ~~the~~as ~~marketing~~Phase ~~application~~1 ~~within~~and ~~six~~an ~~months~~organizational ofcommitment to expedite the ~~60-day~~development ~~filing~~and ~~date~~review ~~(as~~of ~~compared~~the toproduct, ~~ten~~including ~~months~~involvement ~~under~~of ~~standard~~senior ~~review)~~managers.

Any marketing application for a biologic submitted to the FDA for approval, including a product with a Fast Track Designation and/or Breakthrough Therapy Designation, may be eligible for other types of FDA programs intended to expedite the FDA review and approval process, such as priority review and accelerated approval. A product is eligible for priority review if there is evidence it has the potential to provide a significant improvement in the treatment, diagnosis or prevention of a serious disease or condition. For original BLAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing acceptance date (as compared to ten months under standard review).

Fast track designation, breakthrough therapy designation and priority review do not change the standards for approval but may expedite the development or approval process. Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Combination Therapy

Combination therapy is a treatment modality that involves the use of two or more drugs to be used in combination to treat a disease or condition. If those drugs are combined in one dosage form, such as ~~one~~a ~~pill~~single injection, that is known as a fixed dose combination product, and it is reviewed pursuant to the FDA’s Combination Rule at 21 CFR 300.50. The rule provides that two or more drugs may be combined in a single dosage form when each component contributes to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy, as defined in the labeling for the drug.

~~But~~However, not all combination therapy falls under the category of a fixed dose combination. For example, the FDA recognizes that two drugs in separate dosage forms and in separate packaging, that otherwise might be administered as monotherapy for an indication, also may be used in combination for the same indication. In 2013, the FDA issued guidance to assist sponsors that were developing the range of combination therapies that fall outside the category of fixed dose combinations. That guidance provides recommendations and advice on such topics as: (1) assessment at the outset whether two or more therapies are appropriate for use in combination; (2) guiding principles for nonclinical and clinical development of the combination; (3) options for regulatory pathways to seek marketing approval of the combination; and (4) post-marketing safety monitoring and reporting obligations. Given the wide range of potential combination therapy variations, the FDA indicated it intends to assess each potential combination on a case-by case basis and encouraged sponsors to engage in early and regular consultation with the relevant review division at the agency throughout the development process for its proposed combination.

~~Regulation of Combination Products~~20

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~~guidance~~Regulation ~~and regulations to clarify the regulation~~ of ~~combination~~Combination products, and for assignment of the FDA center that has primary jurisdiction for review of combination products where the jurisdiction is unclear or in dispute. A combination product with a primary mode of action attributable to the drug or biologic component generally would be reviewed and approved pursuant to the drug or biologic approval processes set forth in the FDCA. In reviewing the new drug application (NDA) or BLA for such a product, however, FDA reviewers would consult with their counterparts in the FDA’s Center for Devices and Radiological Health to ensure that the device component of the combination product met applicable requirements regarding safety, effectiveness, durability and performance. In addition, under FDA regulations, combination products are subject to cGMP requirements applicable to both drugs and devices, including the Quality System Regulation applicable to medical devices.Products

Certain therapeutic products are comprised of multiple components, such as drug components, biologic components, and device components, that would normally be subject to different regulatory frameworks by the FDA and frequently regulated by different centers at the FDA. These products are known as combination products. Under the FDCA, the FDA is charged with assigning a center with primary jurisdiction, or a lead center, for review of a combination product. The determination of which center will be the lead center is based on the “primary mode of action” of the combination product. Thus, if the primary mode of action of a drug/biologic-device combination product is attributable to the drug or biological product, the FDA center responsible for premarket review of the drug or biological product would have primary jurisdiction for the combination product. The FDA has also established the Office of Combination Products to address issues surrounding combination products and provide more certainty to the regulatory review process. That office serves as a focal point for combination product issues for agency reviewers and industry. It is also responsible for developing guidance and regulations to clarify the regulation of combination products, and for assignment of the FDA center that has primary jurisdiction for review of combination products where the jurisdiction is unclear or in dispute. A combination product with a primary mode of action attributable to the drug or biologic component generally would be reviewed and approved pursuant to the drug or biologic approval processes set forth in the FDCA. In reviewing the new drug application (NDA) or BLA for such a product, however, FDA reviewers would consult with their counterparts in the FDA’s Center for Devices and Radiological Health to ensure that the device component of the combination product met applicable requirements regarding safety, effectiveness, durability and performance. In addition, under FDA regulations, combination products are subject to cGMP requirements applicable to both drugs and devices, including the Quality System Regulation applicable to medical devices.

Post-Approval Requirements

Any products manufactured or distributed by us pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product. As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution. After a BLA is approved for a biological product, the product also may be subject to official lot release. If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of product to the FDA together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer’s tests performed on the lot. The FDA also may perform certain confirmatory tests on lots of some products before releasing the lots for distribution by the manufacturer. In addition, the FDA conducts laboratory research related to the regulatory standards on the safety, purity, and potency or effectiveness of biologics. After approval, ~~most~~ changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing user fee requirements, under which the FDA assesses an annual program fee for each product identified in an approved BLA. Biologic manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMPs, which impose certain procedural and documentation requirements upon us and our third-party manufacturers. Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA review and approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMPs and impose reporting requirements upon us and any third-party manufacturers that we may decide to use. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMPs and other aspects of regulatory compliance.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-~~market~~marketing studies or clinical studies to assess new safety risks; or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

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•restrictions on the marketing or manufacturing of a product, complete withdrawal of the product from the market or product recalls;

•fines, warning letters or holds on post-approval clinical studies;

•refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of existing product approvals;

•product seizure or detention, or refusal of the FDA to permit the import or export of products;

•consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs;

•mandated modification of promotional materials and labeling and the issuance of corrective information;

•the issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other safety information about the product; or

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•injunctions or the imposition of civil or criminal penalties.

The FDA closely regulates the marketing, labeling, advertising and promotion of biologics. A company can make only those claims relating to safety and efficacy, purity and potency that are approved by the FDA and inconsistent ~~accordance~~ with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses. Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties. Physicians may prescribe legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. Such off-label uses are common across medical specialties. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications on the subject of off-label ~~use~~uses of their products. Additionally, promotional materials for approved biologic products must be submitted to the FDA in conjunction with their first use.

Biosimilars and Reference Product Exclusivity

The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively, the “ACA”), includes a subtitle called the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which created an abbreviated approval pathway for biological products that are highly similar, or “biosimilar,” to or interchangeable with an FDA-approved reference biological product. The FDA has issued several guidance documents outlining an approach to review and approval of biosimilars.

Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency, is generally shown through analytical studies, animal studies, and a clinical ~~study~~trial or ~~studies~~trials. Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic. A product shown to be biosimilar or interchangeable with an FDA-approved reference biological product may rely in part on the FDA’s previous determination of safety and effectiveness for the reference product for approval, which can potentially reduce the cost and time required to obtain approval to market the product. Complexities associated with the larger, and often more complex, structures of biological products, as well as the processes by which such products are manufactured, pose significant hurdles to implementation ofand the ~~abbreviated approval pathway that are still being worked out by the~~ FDA. ~~The FDA~~ has issued guidance documents intended to inform prospective applicants and facilitate the development of proposed biosimilars and interchangeable biosimilars, as well as to describe the FDA’s interpretation of certain statutory requirements added by the BPCIA.

Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA. In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed. During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product. The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products. At this juncture, it is unclear whether products deemed “interchangeable” by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law.

A reference biologic is granted twelve years of exclusivity from the time of first licensure of the reference product. The first biologic product submitted under the abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against other biologics submitted under the abbreviated approval pathway for the lesser of (i) one year after the first commercial marketing, (ii) 18 months after approval if there is no legal challenge, (iii) 18 months after the resolution in the applicant’s favor of a lawsuit challenging the biologics’ patents if an application has been submitted, or (iv) 42 months after the application has been approved if a lawsuit is ongoing within the 42-month period.22

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that applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product. The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products. Additionally, many states have passed laws concerning the ability of pharmacies to substitute biosimilar and interchangeable products for the reference product.

A reference biologic is granted twelve years of exclusivity from the time of first licensure (BLA approval) of the reference product. The first biologic product submitted under the abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against other biologics submitted under the abbreviated approval pathway for the lesser of (i) one year after the first commercial marketing, (ii) 18 months after approval if there is no legal challenge, (iii) 18 months after the resolution in the applicant’s favor of a lawsuit challenging the biologics’ patents if an application has been submitted, or (iv) 42 months after the application has been approved if a lawsuit is ongoing within the 42-month period.

A biological product can also obtain pediatric market exclusivity in the United States. Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms. This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.

The BPCIA is complex and continues to be interpreted and implemented by the FDA. In July 2018, the FDA announced an action plan to encourage the development and efficient review of biosimilars, including the establishment of a new office within the agency that will focus on therapeutic biologics and biosimilars. On December 20, 2020, Congress amended the PHSA as part of the COVID-19 relief bill to further simplify the biosimilar review process by making it optional to show that conditions of use proposed in labeling have been previously approved for the reference product, which used to be a requirement of the application. In addition, government proposals have sought to reduce the 12-year reference product exclusivity period. Other aspects of the BPCIA, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent litigation. As a result, the ultimate impact, implementation, and impact of the BPCIA is subject to significant uncertainty.

As discussed below, the Inflation Reduction Act of 2022 (“IRA”) is a significant new law that intends to foster generic and biosimilar competition and to lower drug and biologic costs.

Patent Term Extension

In the United States, after a BLA is approved, owners of relevant drug patents may apply for up to a five-year patent extension, which permits patent term restoration as compensation for the patent term lost during the FDA regulatory process. The allowable patent term extension is typically calculated as one-half the time between, the latter of the effective date of an IND and issue date of the patent for which extension is sought, and the submission date of a BLA, plus the time between BLA submission date and the BLA approval date up to a maximum of five years. The time can be shortened if the FDA determines that the applicant did not pursue licensure with due diligence. The total patent term after the extension may not exceed 14 years from the date of product licensure. Only one patent applicable to a licensed biological product is eligible for extension and only those claims covering the product, a method for using it, or a method for manufacturing it may be extended and the application for the extension must be submitted prior to the expiration of the patent in question. However, we may not be granted an extension because of, for example, failing to exercise due diligence during the testing phase or regulatory review process, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents or otherwise failing to satisfy applicable requirements. Some, but not all, foreign jurisdictions possess patent term extension or other additional patent exclusivity mechanisms that may be more or less stringent and comprehensive than those of the United States.

Other Healthcare Laws and Compliance Requirements

~~Pharmaceutical~~Biopharmaceutical ~~companies~~manufacturers, particularly manufacturers of marketed products, are subject to ~~additional~~wide-ranging healthcare regulation and enforcement by ~~the~~ federal, ~~government~~state and bylocal government authorities in the ~~states~~U.S. ~~and~~as ~~foreign~~well ~~jurisdictions~~as inby ~~which~~foreign ~~they conduct their business~~jurisdictions. ~~Such~~Biopharmaceutical ~~laws~~manufacturers ~~include,~~must ~~without~~comply ~~limitation:~~with ~~the~~various federal, ~~Anti-Kickback~~state ~~Statute (“AKS”); the federal False Claims Act (“FCA”); the Health Insurance Portability~~ and ~~Accountability~~local ~~Act~~laws oftargeting ~~1996~~fraud ~~(“HIPAA”)~~ and ~~similar~~abuse ~~foreign,~~in ~~federal~~the ~~and~~healthcare ~~state fraud~~industry, ~~abuse~~including anti-kickback and ~~transparency~~false claims laws.

The ~~AKS~~federal Anti-Kickback Statute generally prohibits, among other things, ~~persons~~a ~~and~~pharmaceutical ~~entities~~manufacturer from ~~knowingly~~directly ~~and~~or ~~willfully~~indirectly soliciting, offering, receiving, ~~offering~~ or paying any remuneration, toin ~~induce,~~cash or in ~~return~~kind ~~for,~~where one purpose is either to induce the referral of an individual for, or the purchase or ~~recommendation~~prescription of, ana ~~item~~particular ordrug ~~service~~that ~~for~~is ~~which~~payable ~~payment~~by ~~may~~a ~~be made under any~~ federal ~~healthcare~~health care program., ~~The~~including ~~term~~Medicare ~~remuneration~~or ~~has been interpreted broadly to include anything of value~~Medicaid. ~~The~~A ~~AKS~~person ~~has~~or ~~been~~entity ~~interpreted~~does tonot ~~apply~~need to ~~arrangements~~have ~~between~~actual ~~pharmaceutical~~knowledge ~~manufacturers~~of ~~on one hand, and prescribers and purchasers on~~ the ~~other.~~statute ~~The~~or ~~government~~a ~~often~~specific ~~takes~~intent ~~the position that~~ to violate the ~~AKS, only one purpose of the remuneration need be to induce referrals, even if there are other legitimate purposes for the remuneration~~statute. There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from ~~AKS~~ prosecution, but ~~they~~protection ~~are~~is ~~drawn~~available ~~narrowly~~only ~~and~~if ~~practices~~all ~~that~~requirements ~~involve~~are ~~remuneration~~met. Our practices, such as paying physicians for consulting ~~agreements~~services, ~~that~~ may benot ~~alleged~~in toall becases ~~intended~~meet toall ~~induce~~of ~~prescribing,~~the ~~purchasing~~criteria for protection under a statutory exception or ~~recommending~~regulatory ~~may~~safe beharbor. ~~subject~~Failure to ~~scrutiny~~meet ifall ~~they~~of dothe ~~not~~requirements ~~qualify~~of ~~for~~a anparticular applicable statutory exception or regulatory safe harbor. ~~Our~~does ~~practices~~not ~~may~~make ~~not~~the inconduct ~~all~~per ~~cases~~se ~~meet~~illegal ~~all~~under the statute. Instead, the legality of the ~~criteria~~arrangement ~~for~~will ~~protection~~be ~~under~~evaluated on a ~~statutory~~case-by-case ~~exception~~basis orbased ~~regulatory~~on ~~safe~~a ~~harbor.~~cumulative ~~Failure~~review toof ~~meet~~ all of ~~the~~its ~~requirements~~facts ofand circumstances. A claim arising from a ~~particular~~violation ~~applicable~~of ~~statutory~~the ~~exception~~federal orAnti-Kickback ~~regulatory~~Statute ~~safe~~also ~~harbor~~constitutes a

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~~does~~false ~~not~~or ~~make~~fraudulent ~~the~~claim ~~conduct~~for ~~per~~purposes seof ~~illegal under~~ the ~~AKS~~FCA. ~~Instead,~~Other ~~the~~federal ~~legality~~and ofstate ~~the~~anti-kickback ~~arrangement~~statutes ~~will~~exist. beFor ~~evaluated~~example, onanother ahealthcare ~~case~~anti-~~by-case~~kickback ~~basis~~statute ~~based~~prohibits oncertain apayments ~~cumulative~~related ~~review~~to ofreferrals ~~all~~ of ~~its~~patients ~~facts~~to ~~and~~certain ~~circumstances.~~providers A(such ~~person~~as orclinical ~~entity~~laboratories) ~~does~~and ~~not~~applies ~~need~~ to ~~have~~services ~~actual~~reimbursed ~~knowledge~~by ofprivate ~~the~~health ~~statute~~plans oras ~~specific~~well ~~intent~~as togovernment ~~violate~~health itcare ~~in order to have committed a violation~~programs.

~~Civil~~Federal and ~~criminal~~state false claims laws, ~~including~~such as the ~~FCA,~~federal ~~and~~ civil ~~monetary~~False ~~penalty~~Claims ~~laws~~Act (“FCA”), ~~which~~generally ~~can~~prohibit beanyone ~~enforced~~from ~~through~~knowingly ~~civil~~and ~~whistleblower or qui tam actions~~willfully, ~~prohibit,~~ among other ~~things~~activities, ~~individuals or entities from knowingly~~ presenting, or causing to be presented, ~~claims~~ for payment ofto ~~federal~~third ~~government~~party ~~funds,~~payors (including inMedicare ~~federal~~and ~~healthcare~~Medicaid) ~~programs,~~claims for drugs or services that are false or fraudulent. Pharmaceutical and other healthcare companies have been prosecuted under these laws for engaging in a variety of different types of conduct that “caused” the submission of false claims to federal healthcare programs. ~~Under~~Such laws are not always limited to activities involving government programs or payors. For example, a federal healthcare fraud statute prohibits the ~~AKS~~knowing and willful execution, ~~for~~or ~~example~~attempt to execute, a ~~claim~~scheme ~~resulting~~to ~~from~~defraud a ~~violation~~health care benefit program, including private health plans, or obtain, through false or fraudulent pretenses, money or property owned by, or under the custody or control of, such a health care benefit program. Laws and regulations have also been enacted by the ~~AKS~~federal isgovernment ~~deemed~~and various states to beregulate athe ~~false~~sales and marketing practices of pharmaceutical manufacturers. The laws and regulations generally limit financial interactions between manufacturers and health care providers; require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the U.S. federal government; and/or ~~fraudulent~~require ~~claim~~disclosure ~~for~~to ~~purposes~~the government and/or public of financial interactions (so-called “sunshine laws” and "sunshine reporting"). State and local laws may also require disclosure of pharmaceutical pricing information and marketing expenditures or licensure of sales representatives. Manufacturers must also submit information to the ~~FCA~~FDA on the identity and quantity of drug samples requested and distributed by a manufacturer during each year.

~~HIPAA~~Biopharmaceutical ~~created~~manufacturers ~~additional~~are ~~federal~~also ~~criminal~~subject ~~statutes~~to ~~that~~federal ~~prohibit,~~pricing ~~among~~and ~~other~~price ~~things,~~reporting ~~executing~~laws. aSuch ~~scheme~~laws require manufacturers to ~~defraud~~calculate ~~any~~and ~~healthcare~~report ~~benefit~~complex ~~program,~~pricing ~~including~~metrics ~~private~~to ~~third-party~~government ~~payors~~programs, ~~and~~where ~~making~~such ~~false~~reported ~~statements~~prices ~~relating~~may tobe ~~healthcare~~used ~~matters.~~in Athe ~~person~~calculation of reimbursement and/or ~~entity~~discounts ~~does~~on ~~not~~approved ~~need~~products. The tolaws ~~have~~may ~~actual~~also ~~knowledge~~require ofbiopharmaceutical ~~the~~manufacturers ~~healthcare~~to ~~fraud~~offer ~~statute~~products ~~implemented~~at ~~under~~discounted ~~HIPAA~~prices to specific government programs or specific ~~intent~~purchasers toas ~~violate~~a ~~the~~condition ~~statute~~for participation in ~~order~~certain togovernment ~~have~~health ~~committed~~benefit aprograms. ~~violation~~Federal consumer protection and unfair competition laws broadly regulate our marketplace activities and activities that potentially harm consumers.

The ~~FDCA~~distribution ~~addresses,~~of ~~among~~biological ~~other~~products ~~things,~~is ~~the~~subject ~~design,~~to ~~production,~~additional ~~labeling,~~requirements ~~promotion,~~and ~~manufacturing~~regulations, ~~and~~including ~~testing~~extensive ofrecord-keeping, ~~drugs~~licensing, ~~biologics and medical devices~~storage, and ~~prohibits~~security ~~such~~requirements ~~acts~~intended asto ~~the~~prevent ~~introduction into interstate commerce of adulterated or misbranded drugs or devices. The PHSA also prohibits~~ the ~~introduction~~unauthorized ~~into~~sale ~~interstate commerce~~ of ~~unlicensed~~such ~~or mislabeled biological~~ products.

~~The~~Sanctions ~~U.S.~~for ~~federal~~the ~~Physician~~violation ~~Payments~~of ~~Sunshine~~healthcare ~~Act~~laws ~~requires~~vary ~~certain~~by ~~manufacturers~~law ofbut ~~drugs~~may be significant and compliance is challenging. For example, ~~devices~~violations of fraud and abuse laws may be punishable by criminal or civil sanctions, ~~biologics~~including fines and ~~medical~~civil ~~supplies~~monetary ~~for~~penalties, ~~which~~and/or ~~payment~~exclusion isfrom ~~available~~federal ~~under~~health care programs (including Medicare, and Medicaid). orThe scope of the ~~Children’s~~federal ~~Health~~and ~~Insurance~~the ~~Program~~various analogous state anti-kickback, ~~with~~false ~~specific~~claims, ~~exceptions~~and similar fraud and abuse laws vary, tobut ~~annually~~is ~~report~~generally tobroad. ~~the~~Many ~~Centers~~of ~~for~~the ~~Medicaid~~fraud &and ~~Medicare~~abuse ~~Services~~laws ~~("CMS")~~and ~~information~~regulations ~~related~~contain toambiguous ~~payments~~requirements or ~~other~~require ~~transfers~~administrative ofguidance ~~value~~for toimplementation. ~~various~~Federal ~~healthcare~~and ~~professionals~~state ~~including~~authorities ~~physicians,~~are ~~physician~~paying ~~assistants,~~increased ~~nurse~~attention ~~practitioners,~~to ~~clinical~~enforcement ~~nurse~~of ~~specialists,~~these ~~certified~~laws ~~nurse~~within ~~anesthetists,~~the ~~certified~~pharmaceutical ~~nurse-midwives~~industry, and ~~teaching~~private ~~hospitals,~~individuals ashave ~~well~~been asactive ~~ownership~~in ~~and~~alleging ~~investment~~violations ~~interests~~of ~~held~~the bylaws ~~physicians~~ and ~~their~~bringing ~~immediate~~suits ~~family~~on ~~members.~~behalf ~~Beginning~~of onthe ~~January~~government 1,under ~~2023,~~the ~~California~~FCA ~~Assembly~~as ~~Bill~~evidenced ~~1278~~by ~~requires~~numerous ~~California~~significant ~~physicians~~settlements. Violations of international fraud and ~~surgeons~~abuse tolaws ~~notify~~could ~~patients~~result ofin ~~the~~similar ~~Open~~penalties, ~~Payments~~including ~~database~~exclusion ~~established~~from ~~under~~participation ~~the~~in ~~federal~~health ~~Physician~~programs ~~Payments~~outside ~~Sunshine~~the ~~Act~~U.S.

WeGiven ~~are~~the ~~also~~scope, ~~subject~~complexity ~~to federal price reporting laws~~ and ~~federal~~lack ~~consumer~~of ~~protection~~clarity ~~and~~in ~~unfair~~healthcare ~~competition~~ laws. ~~Federal price reporting laws require manufacturers to calculate~~ and ~~report~~their ~~complex pricing metrics to government programs~~implementation, ~~where~~our ~~such~~activities ~~reported~~could ~~prices~~be ~~may~~subject beto ~~used~~scrutiny inand the ~~calculation~~imposition of ~~reimbursement~~penalties ~~and/~~under orthe ~~discounts~~laws. onIf ~~approved~~we ~~products.~~were ~~Federal~~subject ~~consumer~~to ~~protection~~allegations ~~and~~concerning, ~~unfair~~or ~~competition~~were ~~laws~~convicted ~~broadly~~of ~~regulate~~violating, ~~marketplace~~these ~~activities~~laws, ~~and~~our ~~activities~~business ~~that~~could ~~potentially~~be ~~harm consumers~~harmed.

WeData ~~are~~Privacy ~~also~~and ~~subject~~Cybersecurity toRequirements ~~additional similar~~ (U.S. state and foreign law equivalents of each of the above federal laws, which, in some cases, differ from each other in significant ways, and may not have the same effect, thus complicating compliance efforts. If our operations are found to be in violation of any of such laws or any other governmental regulations that apply, we may be subject to penalties, including, without limitation, civil, criminal and administrative penalties, damages, fines, exclusion from government-funded healthcare programs, such as Medicare and Medicaid or similar programs in other countries or jurisdictions, integrity oversight and reporting obligations to resolve allegations of non-compliance, disgorgement, individual imprisonment, contractual damages, reputational harm, diminished profits and the curtailment or restructuring of our operations.)

~~Data~~We ~~Privacy~~are subject to numerous and ~~Security~~evolving U.S. federal and state laws and regulations governing the collection, use, disclosure, transfer, and security of personal information, including health‑related information, any of which may impose operational constraints, create compliance complexity, and increase enforcement and

Numerous state, federal, and foreign laws govern the collection, dissemination, use, access to, confidentiality, and security of personal information, including health-related information. In the United States, numerous federal and state laws and regulations, including state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws and regulations, govern the collection, use, disclosure, and protection of health-related and other personal information could apply to our operations or the operations of our partners. For example, HIPAA, as amended by the Health Information Technology for 24

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~~Economic~~litigation ~~and~~exposure. ~~Clinical~~Applicable ~~Health~~federal ~~("HITECH"),~~ and ~~their~~state ~~respective~~frameworks ~~implementing~~include ~~regulations imposes data privacy~~HIPAA, ~~security,~~as ~~and~~amended ~~breach~~by ~~notification~~the ~~obligations~~Health onInformation ~~certain~~Technology ~~health~~for ~~care~~Economic ~~providers, health plans,~~ and ~~health~~Clinical ~~care~~Health ~~clearinghouses,~~Act ~~known as covered entities~~(“HITECH”), ~~as well as their business associates~~ and ~~their~~its ~~covered~~implementing ~~subcontractors~~regulations ~~that~~(including ~~perform~~the ~~certain services that involve using~~Privacy, ~~disclosing~~Security, ~~creating,~~Breach ~~receiving~~Notification, ~~maintaining,~~and orEnforcement ~~transmitting~~Rules), ~~individually~~state ~~identifiable protected~~ health information ~~("PHI")~~privacy ~~for~~laws, orstate ondata ~~behalf~~breach ofnotification ~~such~~laws, ~~covered~~a ~~entities.~~growing ~~These~~number ~~requirements~~of ~~imposed~~state bycomprehensive ~~HIPAA~~consumer ~~and~~privacy ~~the~~laws, ~~HITECH~~as ~~Act~~well onas ~~covered~~other ~~entities~~consumer ~~and~~protection ~~business~~laws ~~associates~~and ~~include~~regulations ~~entering into agreements~~ that ~~require~~could ~~business~~apply ~~associates~~to ~~protect~~our ~~PHI~~operations ~~provided by the covered entity against improper use~~ or ~~disclosure, among other things; following certain standards for~~ the ~~privacy~~operations of ~~PHI,~~our ~~which~~partners. ~~limit~~In ~~the disclosure of a patient’s past~~addition, ~~present,~~sector- orand ~~future~~data-specific ~~physical~~laws—such oras ~~mental~~those ~~health~~addressing ormarketing ~~condition or information about a patient’s receipt of health care if the information identifies~~communications, ordata ~~could reasonably be used to identify~~security, ~~the~~and ~~individual; ensuring~~ the ~~confidentiality,~~sale/transfer ~~integrity, and availability~~ of ~~all~~certain ~~PHI~~bulk ~~created,~~sensitive ~~received,~~data—may ~~maintained,~~apply ~~or transmitted in electronic form,~~ to ~~identify~~aspects ~~and~~of ~~protect~~our ~~against~~operations ~~reasonably anticipated threats~~ or ~~impermissible uses or disclosures to~~ the ~~security~~operations ~~and integrity~~ of ~~such~~our ~~PHI;~~partners. ~~and~~In ~~reporting~~addition ~~of breaches of PHI~~ to ~~individuals~~statutory ~~and~~regimes, ~~regulators.~~we ~~Entities that~~ are ~~found~~also ~~to be in violation of HIPAA may be~~ subject to ~~significant~~evolving ~~civil,~~state ~~criminal,~~tort and ~~administrative~~other ~~fines~~common ~~and~~law ~~penalties~~restrictions ~~and/or~~that ~~additional~~may ~~reporting~~govern ~~and~~privacy ~~oversight obligations if required to enter into a resolution agreement~~ and ~~corrective~~data ~~action~~security ~~plan~~practices, ~~with~~including ~~the~~potential ~~U.S.~~duties ~~Department of Health~~ and ~~Human~~liability ~~Services~~under ~~("HHS")~~theories tosuch ~~settle~~as ~~allegations~~negligence, ofinvasion ~~HIPAA non-compliance. A covered entity or business associate is also liable for civil money penalties for a violation that is based on an act or omission~~ of ~~any of its agents~~privacy, ~~which~~breach ~~may~~of ~~include a downstream business associate~~confidence, asand ~~determined~~implied ~~according to the federal common law of agency~~contract. Courts ~~HITECH also increased the civil~~ and ~~criminal~~enforcement ~~penalties~~authorities ~~applicable~~continue to ~~covered~~apply ~~entities~~ and ~~business~~test ~~associates~~these ~~and~~doctrines ~~gave state attorneys general new authority to file civil actions for damages or injunctions~~ in ~~federal~~the ~~courts~~data toprivacy ~~enforce HIPAA~~ and ~~seek~~cybersecurity ~~attorneys’~~context, ~~fees~~which ~~and~~can ~~costs~~expand ~~associated~~obligations ~~with~~and ~~pursuing~~remedies ~~federal civil actions. To the extent that we submit electronic healthcare claims~~ and ~~payment~~increase ~~transactions~~litigation ~~that~~exposure ~~do not comply with the electronic data transmission standards established under HIPAA~~ and ~~HITECH,~~compliance ~~payments to us may be delayed or denied.~~costs

InCertain ~~addition~~of our activities may be subject to HIPAA, ~~state~~which ~~health~~imposes ~~information~~standards for the privacy ~~laws,~~of ~~such~~protected ashealth ~~California’s~~information ~~Confidentiality~~(“PHI”), the security of ~~Medical~~electronic ~~Information~~PHI, ~~Act~~breach notification to individuals and ~~Washington’s~~regulators, Myand ~~Health~~enforcement. MyHIPAA ~~Data~~applies ~~Act~~directly to “covered entities” (health care providers, ~~govern~~health ~~the~~plans, ~~privacy~~and health care clearinghouses), as well as their “business associates” and ~~security~~their ofcovered ~~health-related~~subcontractors ~~information~~that perform certain services that involve using, ~~specifically~~disclosing, ~~may~~creating, ~~apply~~receiving, ~~even~~maintaining, ~~when~~or ~~HIPAA~~transmitting ~~does~~individually ~~not~~identifiable ~~and~~PHI ~~impose~~for ~~additional~~or ~~requirements~~on behalf of such covered entities.

~~Even~~Requirements ~~when~~imposed by HIPAA on covered entities and ~~state~~business ~~health~~associates ~~information~~include: ~~privacy~~(i) ~~laws~~entering dointo ~~not~~agreements ~~apply,~~that ~~according~~require business associates and their covered subcontracts to protect PHI provided by the ~~FTC~~covered entity against improper use or disclosure; (ii) complying with HIPAA privacy standards that limit the use and ~~state~~disclosure ~~Attorneys~~of ~~General~~information about a patient’s past, ~~violating~~present, ~~consumers~~or future physical or mental health or condition, or the patient’s ~~privacy~~receipt ~~rights~~of health care, where the information identifies, or ~~failing~~could reasonably be used to ~~take~~identify, ~~appropriate~~the ~~steps~~individual; (iii) implementing administrative, physical, and technical safeguards to ~~keep~~ensure ~~consumers’~~the ~~personal~~confidentiality, ~~information~~integrity, ~~secure~~and ~~may~~availability ~~constitute~~of ~~unfair~~electronic ~~acts~~PHI and to protect against reasonably anticipated threats, hazards, or ~~practices~~impermissible inuses or ~~affecting~~disclosures; ~~commerce~~and (iv) reporting of breaches of unsecured PHI to affected individuals and, where applicable, regulators. Entities found to be in violation of ~~Section~~HIPAA 5may be subject to significant civil, criminal, and administrative fines and penalties, and may be required to enter into resolution agreements and corrective action plan with the U.S. Department of Health and Human Services (a“HHS”) to resolve allegations of non-compliance. A covered entity or business associate can also be liable for civil money penalties for violations based on an act or omission of its agents, including downstream business associates. HITECH increased the ~~Federal~~civil ~~Trade~~and ~~Commission~~criminal ~~Act~~penalties applicable to covered entities and business associates and authorized state ~~consumer~~attorneys ~~protection~~general ~~laws~~to bring civil actions in federal court to enforce HIPAA and seek damages, injunctive relief, and attorneys’ fees and costs. To the extent we submit electronic healthcare claims and payment transactions that do not comply with HIPAA’s electronic data transmission standards, payments to us may be delayed or denied.

InSeveral ~~addition,~~states ~~certain~~have ~~state~~enacted ~~laws,~~or ~~such~~are asimplementing ~~the~~health-data-specific ~~California~~statutes ~~Consumer~~outside ~~Privacy~~HIPAA—such ~~Act of 2018,~~ as ~~amended~~laws byin ~~the~~Washington ~~California~~and ~~Privacy~~Nevada—that ~~Rights~~broadly ~~Act~~regulate ofthe ~~2020~~collection, ~~(“CCPA”)~~use, ~~govern the privacy~~ and ~~security~~disclosure of ~~personal~~“consumer ~~information~~health data,” including ~~health-related information in~~ certain ~~circumstances~~research, ~~some~~analytics, ofwebsite, ~~which~~and ~~are~~marketing ~~more stringent than HIPAA in various ways~~activities. ~~Numerous~~These ~~other states have passed similar~~ laws, ~~but many differ from each other in significant ways and~~ may ~~not~~impose ~~have the same effect~~consent, ~~thus complicating compliance efforts. The CCPA applies to personal data of consumers~~notice, ~~business representatives~~contract, and ~~employees,~~data ~~and~~security ~~imposes~~ obligations ~~on certain businesses that do business in California~~, ~~including~~create tolimitations ~~provide~~on ~~specific~~sharing ~~disclosures~~with inthird ~~privacy~~parties ~~notices,~~ and ~~affords rights to California residents in relation to their personal information. Health information falls under the CCPA’s definition of personal information where it identifies~~processors, ~~relates~~and ~~to,~~provide ~~describes,~~private orrights ~~is reasonably capable~~ of ~~being~~action ~~associated with~~ or ~~could~~enhanced ~~reasonably be linked~~enforcement, ~~directly~~which orcould ~~indirectly,~~affect ~~with~~aspects aof ~~particular~~our ~~consumer~~operations orthat ~~household~~are —not ~~unless it is~~ subject to HIPAA. —Even ~~and~~where isHIPAA ~~included~~and ~~under~~state ahealth ~~new category of personal~~ information, ~~“sensitive personal information,” which is offered greater protection. The numerous other comprehensive~~ privacy laws ~~that~~do ~~have~~not ~~passed or are being considered in other states~~apply, ~~as well as at~~ the ~~federal~~FTC and ~~local~~state ~~levels,~~attorneys ~~also~~general ~~exempt~~have ~~some~~asserted ~~data~~that ~~processed~~violations ~~in the context~~ of ~~clinical~~consumer ~~trials;~~privacy ~~but~~or ~~others~~failures ~~exempt~~to ~~covered~~implement ~~entities~~appropriate ~~and~~data ~~business~~security ~~associates~~measures ~~subject~~may toconstitute ~~HIPAA~~unfair ~~altogether,~~acts ~~further~~or ~~complicating~~practices ~~compliance~~in ~~efforts,~~or ~~and~~affecting ~~increasing~~commerce ~~legal~~in ~~risk~~violation ~~and~~of ~~compliance~~Section ~~costs~~5(a) ~~for~~of usthe ~~and~~Federal ~~the~~Trade ~~third~~Commission ~~parties~~Act ~~upon~~and ~~whom~~state weconsumer ~~rely~~protection laws.

~~Additionally~~In addition, ~~our~~the ~~use~~amended ofCCPA ~~artificial~~and ~~intelligence~~approximately 19 other comprehensive state privacy laws, together with their implementing regulations, establish individual rights regarding personal information, impose notice, purpose-limitation, data minimization, and ~~machine~~security ~~learning~~obligations, ~~may~~and berequire ~~subject~~specific tocontracts with service providers and other third parties. Some of these laws also require honoring opt-out signals for targeted advertising or certain profiling, restrict processing of “sensitive” personal information, and ~~evolving~~mandate ~~regulations~~assessments ~~regarding~~for higher-risk processing activities. Scope and exemptions vary by state: for example, the ~~use~~CCPA applies to personal information of ~~artificial~~consumers, ~~intelligence~~business representatives, and ~~machine learning~~employees, ~~controlling~~includes additional protections for ~~data~~“sensitive ~~bias~~personal information,” and ~~antidiscrimination.~~generally excludes PHI subject to HIPAA; other states may exempt

Failure to comply with these laws, where applicable, can result in the imposition of significant civil and/or criminal penalties and private litigation. Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts, and can result in 25

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~~investigations,~~entities ~~proceedings~~regulated by HIPAA or data processed in the context of clinical trials, or ~~actions~~neither, which complicates compliance and increases legal risk and costs. We are also subject to state data breach notification statutes, like the New York SHIELD Act, that ~~lead~~require notification to ~~significant~~affected ~~civil~~individuals and~~/or~~, ~~criminal~~in ~~penalties~~some cases, regulators and ~~restrictions~~consumer onreporting ~~data~~agencies ~~processing~~following certain security incidents.

In connection with clinical research, we also handle personal information subject to privacy and/or confidentiality obligations in informed consent documents and clinical trial agreements, as well as ethical and regulatory standards governing human subjects research. Depending on the trial and role of the parties involved, our activities may be subject to oversight by institutional review boards, and we may rely on de-identification, coding, or limited data sets, along with contractual restrictions, to manage privacy and data sharing in research contexts.

We also depend on a network of service providers and partners-including clinical sites, contract research organizations, laboratories, data hosting providers, and other vendors-to support our operations. As a result, we implement contractual and technical controls, diligence, and monitoring of third parties that create, receive, maintain, or transmit personal information on our behalf, and, where data is accessed from or transferred to locations outside the United States, we apply or rely on third parties to implement cross-border transfer mechanisms and safeguards as required by applicable law.

In addition, the U.S. Department of Justice (“DOJ”) has promulgated rules restricting the sale, transfer, or access to certain categories of bulk sensitive personal data, including health data, genetic information, and other categories deemed to present heightened risks if aggregated and transferred in large volumes. The DOJ Bulk Data Rule is designed to prevent the misuse of bulk data by foreign adversaries and to mitigate national security risks associated with the transfer of sensitive information. We are actively evaluating the applicability of these requirements to our operations and monitoring regulatory developments in this area. Should the rule apply to any aspect of our business, we may be required to implement additional due diligence, risk assessment, notification, and recordkeeping measures, particularly with respect to cross-border data transfers and transactions involving bulk sensitive data. Noncompliance may result in civil or criminal penalties, and ongoing evaluation of our obligations under the DOJ Bulk Data Rule remains a component of our broader data governance and compliance program.

Our use of artificial intelligence (“AI”) and machine learning technologies in research, analytics, and business operations is subject to a rapidly evolving legal and regulatory landscape. Federal and state authorities are increasingly focused on the responsible use of AI, including requirements for transparency, accountability, and the mitigation of algorithmic bias and discrimination. Several states have enacted or are considering laws that regulate the use of AI in processing personal information, mandate impact assessments for high-risk AI applications, and require disclosures regarding automated decision-making. We may be required to implement measures to assess and address potential biases in AI models, ensure explainability and fairness, and provide individuals with rights regarding automated processing of their data. In addition, federal agencies such as the FDA have issued guidance on the use of AI in medical device development and clinical research, which may impact our operations. As regulatory expectations continue to develop, we may need to update our policies, procedures, and technical controls to ensure compliance with applicable AI-related requirements. The requirements of these laws and regulations continue to develop, and new laws, amendments, or interpretive guidance may require us to modify our data handling practices, implement additional controls, or incur increased compliance costs. Noncompliance or perceived noncompliance could result in regulatory investigations and enforcement actions, private litigation, fines and penalties, or orders requiring changes to our business practices.

Coverage and Reimbursement

In the U.S. and markets in other countries, patients generally rely on third-party payors to reimburse all or part of the costs associated with their treatment. Adequate coverage and reimbursement from ~~governmental~~government healthcare programs, such as Medicare and Medicaid, and ~~commercial~~private payors is critical to new product acceptance. Our ability to successfully commercialize our product candidates, if and when approved, will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government ~~health~~healthcare ~~administration authorities~~programs, private health insurers and other organizations. Even if coverage is provided, the approved reimbursement amount may not be high enough to allow it to establish or maintain pricing sufficient to realize a sufficient return on its investment. Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels.

Significant uncertainty exists as to the coverage and reimbursement status of any pharmaceutical or biological product for which we obtain regulatory approval. Sales of any product, if approved, depend, in part, on the extent to which such product will be covered by third-party payors, such as federal, state, and foreign government healthcare programs, commercial insurance and managed healthcare organizations, and the level of reimbursement, if any, for such product by third-party payors. Decisions regarding whether to cover any of our product candidates, if approved, the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis. Further, no uniform policy for coverage and reimbursement exists in the United States, and coverage and reimbursement can differ significantly from payor to payor. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement rates, but also have their own methods and approval process apart from Medicare determinations. As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our product candidates to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance. Factors payors consider in determining reimbursement are based on whether the product is:26

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Within the U.S., no uniform policy for coverage and reimbursement exists in the United States, and coverage and reimbursement for drug products can differ significantly from payor to payor. One third-party payor’s decision to cover a particular drug product does not ensure that other payors will also provide coverage for the drug product. Factors payors consider in determining coverage include whether the product is:

•a covered benefit under its health plan;

•safe, effective and medically necessary;

•cost-effective; and

•neither experimental nor investigational.

~~Third-party~~Even ~~payors~~if products are ~~increasingly~~covered, ~~challenging~~third ~~the~~party ~~prices~~payors ~~charged~~may ~~for~~seek ~~medical~~to control utilization of the products ~~and~~through ~~services~~various mechanisms (e.g., ~~examining~~requiring a prescriber to obtain prior authorization from a health plan before the ~~medical~~product ~~necessity~~will ~~and~~be ~~reviewing~~covered by the ~~cost~~health ~~effectiveness~~plan or establishing patient copays and deductibles that encourage use of ~~pharmaceutical~~other orproducts ~~biological~~over our products,). ~~medical~~Coverage ~~devices~~of ~~and~~a ~~medical~~product ~~services,~~by ina ~~addition~~third-party topayor ~~questioning~~does ~~safety~~not ~~and~~mean ~~efficacy~~that reimbursement will be adequate. ~~Adoption~~Third ofparty reimbursement may not be sufficient to enable us to maintain price ~~controls~~levels ~~and~~high ~~cost-containment~~enough ~~measures,~~to ~~and~~realize ~~adoption~~an ofappropriate ~~more~~return ~~restrictive~~on ~~policies~~our investment in ~~jurisdictions~~product ~~with~~development. ~~existing~~Net ~~controls~~prices ~~and~~for ~~measures,~~drugs ~~could~~may ~~further~~be ~~limit~~reduced ~~sales~~by ofmandatory ~~any~~discounts ~~product~~or ~~that~~rebates ~~receives~~required ~~approval.~~by ~~Decreases~~government inhealthcare ~~third-party~~programs ~~reimbursement~~or requested by private payors in exchange for coverage or by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold. Our ability to commercialize our product orcandidates asuccessfully ~~decision~~may be adversely affected by adiscounts ~~third-party~~or ~~not~~rebates that we are required to ~~cover~~provide ain ~~product~~order ~~could~~to ~~reduce~~ensure ~~physician~~coverage ~~usage~~of ~~and~~our ~~patient~~products ~~demand~~and ~~for~~compete in the ~~product~~marketplace.

~~For~~Significant ~~products~~uncertainty ~~administered~~exists ~~under~~as to the ~~supervision~~coverage and reimbursement status of anew ~~physician,~~drug ~~obtaining~~products. ~~coverage~~There ~~and~~may ~~adequate~~be considerable delays in obtaining reimbursement for newly-approved drugs, and coverage may be ~~particularly~~more ~~difficult~~limited ~~because~~than of the ~~higher~~indications ~~prices~~for ~~often~~which ~~associated~~the ~~with~~drug ~~such~~is ~~drugs~~approved by the FDA. ~~Additionally~~Third-party payors may also seek, ~~separate~~with ~~reimbursement~~respect ~~for~~to ~~the~~an approved product, ~~itself~~additional orclinical evidence, including comparative effectiveness evidence, that goes beyond the ~~treatment~~data orrequired ~~procedure~~to obtain marketing approval in ~~which~~order ~~the~~to ~~product~~demonstrate isclinical ~~used~~benefits ~~may~~and ~~not~~value berelative ~~available~~to other therapies before covering new products. If so, ~~which~~we may ~~impact~~be ~~physician~~required ~~utilization.~~to conduct additional pharmacoeconomic studies beyond what is required for marketing approval.

InThird-party ~~addition,~~payors ~~the~~are ~~U.S.~~increasingly ~~government,~~challenging ~~state~~the ~~legislatures~~prices ~~and~~charged ~~foreign~~for ~~governments~~pharmaceutical ~~have~~or ~~continued~~biological ~~implementing~~products ~~cost-~~and ~~containment~~related ~~programs~~services, ~~including~~examining ~~price~~the ~~controls,~~medical ~~restrictions~~necessity ~~on coverage~~ and ~~reimbursement~~reviewing ~~and~~the ~~requirements~~cost ~~for~~effectiveness ~~substitution~~ of ~~generic~~such products. ~~The~~and ~~IRA~~services. ~~provides~~For ~~CMS~~products ~~with~~administered ~~significant~~under ~~new~~the ~~authorities~~supervision ~~intended~~of toa ~~curb~~physician, ~~drug~~inadequate ~~costs~~reimbursement ~~and~~for tothe ~~encourage~~product ~~market~~itself ~~competition.~~or ~~For~~ the ~~first~~treatment ~~time,~~or ~~CMS~~procedure ~~will~~in bewhich ~~able~~the toproduct ~~directly~~is ~~negotiate~~used ~~prescription~~may ~~drug~~adversely ~~prices~~impact ~~and~~physician toutilization. ~~cap~~Adoption ~~out-~~of~~-pocket~~ ~~costs.~~price ~~Each~~controls ~~year,~~and ~~CMS~~cost-containment ~~will~~measures, ~~select~~ and ~~negotiate~~adoption ~~a preset number~~ of ~~high-spend~~more ~~drugs~~restrictive ~~and~~policies ~~biologics~~in ~~that~~jurisdictions ~~are~~with ~~covered~~existing ~~under~~controls ~~Medicare Part B~~ and ~~Part~~measures, Dcould ~~that~~further dolimit ~~not~~sales ~~have~~of ~~generic~~any orproduct ~~biosimilar~~that ~~competition~~receives approval. OnDecreases ~~August~~in ~~29,~~third-party ~~2023,~~reimbursement ~~HHS~~for ~~announced~~any ~~the~~product ~~list~~or ofa ~~the~~decision ~~first~~by ~~ten~~a ~~drugs~~third-party ~~subject~~not to ~~price~~cover ~~negotiations.~~a ~~These~~product ~~price~~could ~~negotiations~~reduce ~~occurred~~physician inusage ~~2024.~~and Inpatient ~~January~~demand ~~2025,~~for ~~CMS~~the ~~announced a~~ product.

24We cannot be sure that adequate coverage and reimbursement will be available, or remain available, for any drug that we commercialize. Coverage and reimbursement may impact the demand for, or the price of, our products and any product candidate for which we obtain marketing approval and limits on coverage and reimbursement may adversely affect our ability to successfully commercialize any product candidate for which we obtain marketing approval.

Finally, in some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed. The requirements governing drug pricing vary widely from country to country. For example, drug pricing in the European Union is primarily a national competence, with each member state setting its own prices and reimbursement rules according to national budgets and health systems. The national rules and policies should comply with EU transparency laws to ensure that national pricing and reimbursement decisions for medicines are transparent, non-discriminatory, and timely, thereby facilitating the free movement of pharmaceuticals within the European Union. To obtain reimbursement and pricing approval, countries may require the completion of clinical trials to establish relative clinical effectiveness to guide cost effectiveness assessment of a new treatment method to currently available therapies before it can be adopted for use in the respective national health systems. A member state may approve a specific price for the medicinal product or implement a system of direct or indirect controls on the profitability of the company placing the medicinal

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~~list~~product ofon 15the ~~additional~~market. ~~Medicare~~There ~~Part~~can ~~D drugs that will~~ be ~~subject~~no toassurance ~~price negotiations. The IRA also provides a new “inflation rebate” covering Medicare patients~~ that ~~took~~any ~~effect~~country inwith ~~2023 and is intended to counter certain~~ price ~~increases~~controls inor ~~prescriptions~~reimbursement ~~drugs.~~limitations ~~The inflation rebate provision requires drug manufacturers to pay a rebate to the federal government if the price~~ for apharmaceutical ~~drug~~products orwill ~~biologic~~grant ~~under~~favorable ~~Medicare~~reimbursement ~~Part B~~ and ~~Part~~pricing Dterms ~~increases~~for ~~faster~~any ~~than~~of ~~the~~our ~~rate~~product ~~of inflation~~candidates. ~~To support biosimilar competition~~Historically, ~~beginning~~products launched in ~~October~~the ~~2022,~~European ~~qualifying~~Union ~~biosimilars~~do ~~may~~not ~~receive~~follow aprice ~~Medicare~~structures ~~Part B payment increase for a period~~ of ~~five~~the ~~years~~U.S. ~~Separately,~~and ifare agenerally ~~biologic drug for which no biosimilar exists delays a biosimilar’s market entry beyond two years, CMS will be authorized to~~ subject ~~the biologics manufacturer~~ to ~~price~~lower ~~negotiations intended to ensure fair competition~~prices. ~~Notwithstanding these provisions, the IRA’s impact on commercialization and competition remains largely uncertain.~~

In addition, net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the U.S. Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. We cannot be sure that reimbursement will be available for any product candidate that we may commercialize and, if reimbursement is available, the level of reimbursement. In addition, many pharmaceutical manufacturers must calculate and report certain price reporting metrics to the government, such as average sales price and best price. Penalties may apply in some cases when such metrics are not submitted accurately and timely. Further, these prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs.

Finally, in some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed. The requirements governing drug pricing vary widely from country to country. For example, the European Union provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost effectiveness of a particular product candidate to currently available therapies. A member state may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our product candidates. Historically, products launched in the European Union do not follow price structures of the U.S. and generally prices tend to be significantly lower.

Healthcare Reform

The United States and some foreign jurisdictions are considering or have enacted a number of reform proposals to change the healthcare system. There is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality or expanding access. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by federal and state legislative initiatives, including those designed to limit the pricing, coverage, and reimbursement of pharmaceutical and biopharmaceutical products, especially under government-funded health care programs, and increased governmental control of drug pricing.

~~The~~For ~~ACA~~example, ~~which was enacted~~ in March 2010, ~~substantially changed~~ the ~~way~~U.S. ~~healthcare~~Congress isenacted ~~financed~~the byPatient ~~both~~Protection ~~governmental~~ and ~~private~~Affordable ~~insurers~~Care inAct and the ~~United~~Health ~~States,~~Care and ~~significantly~~Education ~~affected~~Reconciliation Act (the ~~pharmaceutical~~“ACA”) ~~industry.~~which ~~The~~substantially ~~ACA~~changed ~~contains~~the away ~~number~~healthcare ofis ~~provisions~~delivered ofas ~~particular~~well ~~import~~as tofinanced ~~the~~by ~~pharmaceutical~~both governmental and ~~biotechnology~~private ~~industries,~~insurers ~~including,~~in ~~but~~the ~~not~~United ~~limited~~States. The ~~to,~~ACA ~~those~~expanded ~~governing~~health ~~enrollment~~care incoverage ~~federal~~through ~~healthcare~~the ~~programs,~~Medicaid aexpansion ~~new~~and ~~methodology~~subsidization byof ~~which~~private ~~rebates~~health ~~owed~~insurance, byimplemented ~~manufacturers~~the ~~under~~“individual ~~the~~mandate” ~~Medicaid~~for ~~Drug~~health ~~Rebate~~insurance ~~Program~~coverage ~~are~~(by ~~calculated~~imposing ~~for~~a ~~drugs~~tax ~~that~~penalty ~~are~~on ~~inhaled,~~individuals ~~infused,~~who ~~instilled,~~did ~~implanted~~not orobtain ~~injected~~insurance), and ~~annual~~changed ~~fees~~the ~~based~~coverage onand ~~pharmaceutical~~reimbursement ~~companies’ share~~ of ~~sales~~drug toproducts ~~federal~~under ~~health~~government ~~care~~healthcare programs. Since its enactment, there have been judicial and Congressional challenges to certain aspects of the ACA, and we expect there will be additional challenges and amendments to the ACA in the future. For example, the IRA, among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025. The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a new manufacturer discount program.

25In the U.S., in recent years, the pharmaceutical industry has been a particular focus of healthcare reform efforts and has been significantly affected by major legislative, administrative and executive initiatives. For example, the Inflation Reduction Act of 2022 (IRA) included a number of changes intended to address rising prescription drug prices in Medicare Parts B and D. These changes included caps on Medicare Part D out-of-pocket costs, Medicare Part B and Part D drug price inflation rebates, a new Medicare Part D manufacturer discount drug program (replacing the previous coverage gap discount program) and a drug price negotiation program for certain high-spend Medicare Part B and D drugs. The IRA has had and will likely continue to have a significant impact on the pharmaceutical industry. Beyond the IRA, changes to Medicaid effective in 2024 eliminated the Medicaid rebate cap. Additionally, changes to certain Medicare price reporting requirements for drugs beginning in 2026 will likely increase the administrative and compliance burden for manufacturers.

Recently, drug pricing and payment has been subject to a number of reform initiatives. For example, President Trump issued an Executive Order in April 2025 with multiple directives aimed at lowering drug prices, including refining the Medicare drug price negotiation program established by the IRA; accelerating competition for high-cost prescription drugs by accelerating approval of generics and biosimilars and facilitating the process for re-classifying prescription drugs as over-the-counter drugs; and increasing drug importation. In May 2025, President Trump issued another Executive Order that directed government agencies and officials to identify most-favored nation pricing targets for prescription drugs (and looked to pharmaceutical manufacturers to make significant progress towards delivering target prices to patients); prevent foreign countries from disproportionately shifting the cost of global pharmaceutical research and development to the United States; and facilitate direct-to-consumer purchasing programs for pharmaceutical manufacturers to sell their products to patients at the most-favored-nation price. In the wake of the Executive Orders and related executive initiatives, a number of pharmaceutical manufacturers have announced direct-to-consumer offerings with discounted prices and/or reached agreement with the federal government regarding pricing for drugs, including prices for Medicaid drugs and newly launched products. A website sponsored by the federal government that is anticipated to offer pharmaceutical direct-to-consumer channels has also been announced. Federal agencies are developing new drug pricing pilot programs, such as a voluntary Medicaid initiative which would authorize the federal government to negotiate Medicaid supplemental rebates with participating manufacturers on behalf of state Medicaid programs, in exchange for standardized coverage criteria for participating manufacturer drugs, and the proposed Medicare Part B and Part D pilot models that, if finalized as proposed, would replace existing inflation-based Medicare rebates with rebates determined on the basis of international prices, for drugs and patients subject to the model. Many of these reform initiatives would require additional legal and/or administrative action to implement and may be subject to legal challenge.

Other federal healthcare reform efforts or actions may affect access to healthcare coverage or the funding of health care benefits, although the full impact of such efforts or actions cannot be predicted. For example, the Congressional Budget Office has estimated that Medicaid provisions in the 2025 budget

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~~Other~~reconciliation ~~legislative~~legislation, ~~changes~~including ~~have~~restrictions ~~been~~in ~~proposed~~eligibility and ~~adopted~~funding ~~since~~for ~~the ACA was enacted~~Medicaid, ~~including~~as ~~automatic~~well ~~aggregate~~as ~~reductions~~changes ~~of Medicare payments~~ to ~~providers~~the ofhealthcare onmarketplace ~~average~~such ~~2% per fiscal year~~ as ~~part of~~ the ~~federal~~elimination ~~budget sequestration under the Budget Control Act~~ of ~~2011.~~certain ~~These reductions went into effect in April 2013 and~~subsidies, ~~due to subsequent legislative amendments,~~ will ~~remain~~increase inthe ~~effect~~number ~~until~~of ~~2032 unless additional action is taken by Congress~~uninsured.

InAt ~~addition~~the state level, ~~the~~individual ~~Bipartisan~~states ~~Budget~~are ~~Act~~increasingly ofimplementing ~~2018~~initiatives designed to control pharmaceutical and biological product pricing, ~~among~~including ~~other~~price ~~things~~or patient reimbursement constraints, ~~amended~~discounts, ~~the~~restrictions ~~Medicare~~on ~~Act~~certain ~~(as~~product ~~amended~~access byand ~~the~~marketing ~~ACA)~~cost disclosure and transparency measures, and measures to ~~increase~~encourage ~~the~~importation ~~point-of-sale~~from ~~discounts~~other ~~that~~countries ~~manufacturers~~and ~~must~~bulk ~~agree~~purchasing. toFor ~~offer~~example, ~~under~~certain ~~the~~states ~~Medicare~~have ~~Part~~formed DPrescription ~~coverage~~Drug ~~discount~~Affordability ~~program~~Boards ~~from~~that ~~50%~~assert authority to ~~70%~~set ~~off~~reimbursement ~~negotiated~~rates ~~prices~~and/or ofdrug ~~applicable~~pricing ~~brand~~in ~~drugs~~the state. States are also increasingly expanding or changing Medicaid supplemental rebate programs to ~~eligible~~secure ~~beneficiaries~~additional ~~during~~rebates ~~their~~from manufacturers in exchange for drug coverage ~~gap~~and ~~period,~~to aslimit acoverage ~~condition~~of certain drugs for ~~the~~certain ~~manufacturer’s~~Medicaid ~~outpatient~~patients ~~drugs~~or ~~being~~to ~~covered~~all ~~under~~Medicaid ~~Medicare~~patients. ~~Part~~These Dand other future state-level reform activities could negatively affect Medicaid coverage and reimbursement for our products.

~~Moreover,~~Other ~~there~~recent ~~has~~government ~~recently~~actions ~~been~~also ~~heightened~~may ~~governmental~~affect ~~scrutiny~~prices ~~over~~or ~~the~~payments ~~manner in which manufacturers set prices~~ for ~~their marketed products, which has resulted in several Congressional inquiries and proposed and enacted federal and state measures designed to, among other things, reduce the cost of~~ prescription drugs~~, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products~~. For example, ~~in May 2019, CMS adopted a final rule allowing Medicare Advantage Plans~~ the ~~option~~Trump toAdministration’s ~~use~~recently ~~step~~announced ~~therapy~~tariff ~~for~~on ~~Part~~branded Bor patented drugs, ~~permitting~~may ~~Medicare~~adversely ~~Part~~impact Dour ~~plans~~ability to ~~apply~~realize ~~certain~~an ~~utilization~~adequate ~~controls~~return toon ~~new starts of five of~~ the ~~six~~sale ~~protected class drugs, and requiring the Explanation~~ of ~~Benefits~~drug ~~for~~products ~~Part~~(if Dapproved) ~~beneficiaries~~that toare ~~disclose~~imported ~~drug~~from ~~price~~abroad ~~increases~~or ~~and~~manufactured ~~lower~~using ~~cost~~products ~~therapeutic~~or ~~alternatives,~~materials ~~which~~imported ~~went~~from ~~into effect on January 1, 2021~~abroad. InThe ~~response~~timeline ~~to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models~~ for ~~testing~~implementation ~~by the CMS Innovation Center which will be evaluated on their ability to lower the cost~~ of ~~drugs,~~this ~~promote~~tariff ~~accessibility,~~has ~~and~~not ~~improve~~yet ~~quality~~been ~~of care~~finalized. ItAs isanother ~~unclear~~example, ~~whether~~ the ~~models~~Budget ~~will~~Control beAct ~~utilized~~of ~~in any health reform measures in the future. Further~~2011, onas ~~December 7~~amended, ~~2023,~~resulted ~~the~~in ~~Biden administration announced an initiative to control~~ the ~~price~~imposition of ~~prescription~~reductions ~~drugs through the use of march-~~in ~~rights~~Medicare ~~under~~(but ~~the~~not ~~Bayh-Dole~~Medicaid) ~~Act.~~payments Onto ~~December~~providers 8,in ~~2023,~~2013 ~~the National Institute of Standards~~ and ~~Technology~~will ~~published~~remain ~~for~~in ~~comment~~effect ainto ~~Draft~~2032 ~~Interagency~~unless ~~Guidance~~additional ~~Framework~~Congressional ~~for~~action ~~Considering~~is ~~the~~taken. ~~Exercise~~Any ofsignificant ~~March-In~~spending ~~Rights~~reductions ~~which~~affecting ~~for~~Medicare, ~~the~~Medicaid ~~first~~or ~~time~~other ~~includes~~publicly ~~the~~funded ~~price~~or ofsubsidized ahealth ~~product~~programs asthat ~~one~~may ~~factor~~be animplemented ~~agency~~and/or ~~can~~any ~~use~~significant ~~when~~taxes ~~deciding~~or tofees ~~exercise~~that ~~march-in~~may ~~rights.~~be ~~While~~imposed ~~march-in~~on ~~rights~~us could have ~~not~~an ~~previously~~adverse ~~been~~impact ~~exercised,~~on itour isresults ~~uncertain~~of ~~if that will continue under the new framework~~operations.

~~Notwithstanding~~Reform ~~the~~efforts ~~IRA,~~have ~~continued~~been ~~legislative~~ and ~~enforcement~~may ~~interest~~continue ~~exists~~to inbe ~~the~~subject ~~United States with respect~~ to ~~specialty~~scrutiny ~~drug~~and ~~pricing~~legal ~~practices. Specifically~~challenge, wewhich ~~expect~~increases ~~regulators~~uncertainty. toFor ~~continue pushing for transparency to drug pricing~~example, ~~reducing~~ the ~~cost~~IRA ofdrug ~~prescription~~price ~~drugs~~negotiation ~~under~~program ~~Medicare,~~has ~~reviewing~~been ~~the~~challenged ~~relationship~~in ~~between~~litigation ~~pricing~~filed ~~and~~by ~~manufacturer~~various ~~patient~~pharmaceutical ~~programs,~~manufacturers and ~~reforming~~industry ~~government program reimbursement methodologies for drugs~~groups.

~~Individual~~Moreover, ~~states~~there inhas ~~the~~recently ~~U.S.~~been ~~have~~heightened ~~also~~governmental ~~become~~scrutiny ~~increasingly~~over ~~active~~the manner in ~~passing~~which ~~legislation~~manufacturers ~~and~~set ~~implementing~~prices ~~regulations~~for ~~designed~~their tomarketed ~~control~~products, ~~pharmaceutical~~which ~~and~~has ~~biological~~resulted ~~product~~in ~~pricing,~~several ~~including~~Congressional ~~price~~inquiries orand ~~patient~~proposed ~~reimbursement~~and ~~constraints,~~enacted ~~discounts,~~federal ~~restrictions~~and onstate ~~certain~~measures ~~drug~~designed ~~access~~to, ~~and~~among ~~marketing~~other ~~cost~~things, ~~disclosure~~reduce ~~and~~the ~~transparency~~cost ~~measures~~of prescription drugs, ~~and~~bring ~~designed~~more transparency to ~~encourage~~product ~~importation~~pricing, ~~from~~review ~~other~~the ~~countries~~relationship ~~and~~between ~~bulk~~pricing ~~purchasing.~~and ~~Legally~~manufacturer ~~mandated~~patient ~~price~~programs, ~~controls~~and onreform ~~payment~~government ~~amounts~~program byreimbursement ~~third-party~~methodologies ~~payors~~for ordrug ~~other~~products. ~~restrictions~~For ~~could~~example, ~~harm~~in ~~our~~May ~~business~~2019, ~~financial~~CMS ~~condition,~~adopted ~~results~~a offinal ~~operations~~rule ~~and~~allowing ~~prospects.~~Medicare InAdvantage ~~addition,~~Plans ~~regional~~the ~~healthcare~~option ~~authorities~~to ~~and~~use ~~individual~~step ~~hospitals~~therapy ~~are~~for ~~increasingly~~Part ~~using~~B ~~bidding~~drugs, ~~procedures~~permitting toMedicare ~~determine~~Part ~~what~~D ~~pharmaceutical~~plans ~~products~~to ~~and~~apply ~~which~~certain ~~suppliers~~utilization ~~will~~controls beto ~~included~~new instarts ~~their~~of ~~prescription~~five ~~drug~~of ~~and~~the ~~other~~six ~~healthcare~~protected ~~programs.~~class ~~This~~drugs, ~~could~~and ~~reduce~~requiring the ~~ultimate~~Explanation ~~demand~~of Benefits for ~~its~~Part ~~drugs~~D orbeneficiaries ~~put~~to ~~pressure~~disclose ~~on its~~ drug ~~pricing,~~price ~~which~~increases ~~could~~and ~~negatively~~lower ~~affect~~cost ~~our~~therapeutic ~~business~~alternatives, ~~financial~~which ~~condition,~~went ~~results~~into ofeffect ~~operations~~on ~~and~~January ~~prospects~~1, 2021.

The nature and extent of future healthcare reforms cannot be predicted. There is uncertainty regarding the nature or impact of any drug pricing or broader healthcare or other reform implemented at the federal or state level and the extent to which such action may be subject to litigation or other challenges. Ongoing efforts to contain or reduced costs of healthcare and/or impose price controls may adversely affect the demand for our product candidates, if approved, and our ability to achieve or maintain profitability.

In the EU, similar political, economic and regulatory developments may affect our, or our collaborators’, ability to profitably commercialize our current or any future products. In addition to continuing pressure on prices and cost containment measures, legislative developments at the EU or member state level may result in significant additional requirements or obstacles that may increase our operating costs. The EU is undergoing a revision of its general pharmaceutical legislation, commonly known as the ‘Pharma Package’ to help ensure, among others, fair access to safe, effective and affordable medicines across the EU. It also seeks to improve the competitiveness of the pharmaceutical industry by reducing regulatory burdens and strengthening supply chain security to prevent and manage shortages. The legislative process for the EU Pharma Package began with the European Commission’s proposal in April 2023, followed by the development of positions by the European Parliament and the Council. This culminated in Trilogue negotiations, with a political agreement reached in December 2025. The agreed text now awaits formal adoption by both the Parliament and Council, after which it will be published in the Official Journal of the EU. The new Directive and Regulation will then enter into force following a transition period of 18 to 36 months, ultimately modernizing EU pharmaceutical law to better support innovation, access, and supply. In addition, the European Commission proposed in December

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2025 the Biotech Act which seeks to strengthen the competitiveness of the biotechnology sector and facilitate the development and timely market entry of biotechnology innovations, while ensuring high standards for the protection of human health. In international markets, reimbursement and healthcare payment systems vary significantly from country to country, and many countries have instituted price ceilings on specific products and therapies. Our future products, if any, might not be considered clinically appropriate or justified for a specific indication, or cost-effective by third-party payors as reimbursement decisions typically require robust scientific evidence of effectiveness or national health systems and demonstration of therapeutic value to advance patient care. An adequate level of reimbursement might not be available for such products and third-party payors’ reimbursement policies or national health systems might adversely affect our, or our collaborators’ ability to sell any future products profitably.

Other Government Regulation Outside of the United States

In addition to regulations in the United States, we are subject to a variety of regulations in other jurisdictions governing, among other things, research and development, clinical trials, testing, manufacturing, safety, efficacy, quality control, labeling, packaging, storage, record keeping, distribution, reporting, export and import, advertising, marketing and other promotional practices involving biological products as well as authorization, approval as well as post-approval monitoring and reporting of our products. Because biologically sourced raw materials are subject to unique contamination risks, their use may be restricted in some countries.

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Whether or not we obtain FDA approval for a product, we must obtain the requisite approvals from regulatory authorities in foreign countries prior to the commencement of clinical trials or marketing of the product in those countries. Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application much like the IND prior to the commencement of human clinical trials.

The requirements and process governing the conduct of clinical trials, including requirements to conduct additional clinical trials, product licensing, safety reporting, post-authorization requirements, marketing and promotion, interactions with healthcare professionals, pricing and reimbursement may vary widely from country to country. No action can be taken to market any product in a country until an appropriate marketing approval ~~application~~ has been ~~approved~~granted by the regulatory authorities in that country. The current approval process varies from country to country, and the time spent in gaining approval ~~varies~~may vary from that required for FDA approval. In certain countries, the sales price of a product must also be agreed or approved by payors or the respective national health systems before commercial launch. The pricing review period ~~often~~typically ~~begins~~commences ~~after~~following ~~market~~marketing approval ~~is granted~~. ~~Even~~Although if a product ismay ~~approved~~receive bymarketing approval from a regulatory authority, ~~satisfactory~~the ~~prices~~price ~~may~~agreed ~~not~~upon beduring ~~approved~~the ~~for~~review ~~such~~process ~~product,~~may ~~which~~not ~~would~~be ~~make~~commercially ~~launch~~sustainable ofto ~~such~~justify ~~products~~a ~~commercially~~commercial ~~unfeasible~~launch in ~~such~~those countries.

Regulation in the European Union

European Data and Security Laws

The collection and use of personal health data and other personal data in the European Union ("EU") is governed by the provisions of the European General Data Protection Regulation (EU) 2016/679 (“GDPR”), which came into force in May 2018, and related data protection laws in individual EU Member States. The GDPR imposes a number of strict obligations and restrictions on the ability to process, including collecting, analyzing and transferring, personal data of individuals, in particular with respect to health data from clinical trials and adverse event reporting. The GDPR includes requirements relating to the legal basis of the processing (such as consent of the individuals to whom the personal data relates), the information provided to the individuals prior to processing their personal data, the personal data breaches which may have to be notified to the national data protection authorities and data subjects, the measures to be taken when engaging processors, and the security and confidentiality of the personal data. EU Member States may also impose additional requirements in relation to health, genetic and biometric data through their national legislation.

InAs ~~addition~~mentioned above, ~~the~~we ~~GDPR~~depend ~~imposes specific restrictions~~ on ~~the~~a ~~transfer~~network of ~~personal~~service ~~data~~providers toand ~~countries~~partners-including ~~outside~~clinical ofsites, ~~the~~contract ~~European~~research ~~Economic~~organizations, ~~Area~~laboratories, ~~("EEA") that are not considered by the European Commission ("EC") to provide an adequate level of~~ data ~~protection.~~hosting ~~Appropriate~~providers, ~~safeguards~~and ~~are~~other ~~required~~ vendors-to ~~enable~~support ~~such~~our ~~transfers.~~operations ~~Among~~and ~~the~~may ~~appropriate~~share ~~safeguards~~personal ~~that can be used, the~~ data ~~exporter~~with ~~may~~these ~~use the standard contractual clauses ("SCCs")~~organizations. ~~When~~As ~~relying~~a ~~on SCCs~~result, ~~data~~we ~~exporters~~implement ~~are~~contractual ~~also required to conduct a transfer risk assessment to verify if anything in the law~~ and~~/or~~ ~~practices~~technical ~~of the third country may impinge on the effectiveness of the SCCs in the context of the transfer at stake and~~controls, ~~if so~~diligence, ~~to identify~~ and ~~adopt~~monitoring ~~supplementary measures that are necessary to bring the level~~ of ~~protection~~third ofparties ~~the~~that ~~data~~create, ~~transferred to the EU standard of essential equivalence. Where no supplementary measure is suitable~~receive, ~~the data exporter should avoid~~maintain, ~~suspend~~ or ~~terminate~~transmit ~~the~~personal ~~transfer. With regard to the transfer of~~ data ~~from the EEA to the United States,~~ on ~~July~~our 10behalf, ~~2023,~~and ~~the~~we ECapply ~~adopted its adequacy decision for the EU~~cross-USborder ~~Data Privacy Framework. On the basis of the new adequacy decision, personal data can flow from the EEA to U.S. companies participating in the framework. With regard to the~~ transfer ofmechanisms ~~data~~and ~~from~~safeguards ~~the~~as EUrequired toby ~~the~~applicable United Kingdom (UK), personal data may freely flow from the EEA to the UK since the UK is deemed to have an adequate data protection level. However, the adequacy decisions include a ‘sunset clause’ which entails that the decisions will automatically expire four years after their entry into force, unless renewed.

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law. We also may rely on pseudonymization or anonymization, coding or limited data sets, along with contractual restrictions (including entering into data processing agreements as required under the GDPR) to manage privacy and data sharing in these contexts.

In addition, the GDPR imposes specific restrictions on the transfer of personal data to countries outside of the European Economic Area ("EEA") that are not considered by the European Commission ("EC") to provide an adequate level of data protection. Appropriate safeguards are required to enable such transfers. Among the appropriate safeguards that can be used, the data exporter may use the standard contractual clauses ("SCCs"). When relying on SCCs, data exporters are also required to conduct a transfer risk assessment to verify if anything in the law and/or practices of the third country may impinge on the effectiveness of the SCCs in the context of the transfer at stake and, if so, to identify and adopt supplementary measures that are necessary to bring the level of protection of the data transferred to the EU standard of essential equivalence. Where no supplementary measure is suitable, the data exporter should avoid, suspend or terminate the transfer. With regard to the transfer of data from the EEA to the United States, on July 10, 2023, the EC adopted its adequacy decision for the EU-US Data Privacy Framework. On the basis of the new adequacy decision, personal data can flow from the EEA to U.S. companies participating in the framework. With regard to the transfer of data from the EU to the United Kingdom (UK), personal data may freely flow from the EEA to the UK since the EC deemed the UK to have an adequate data protection level, and these adequacy decisions were extended in December 2025, and are now valid until December 27, 2031.

Failure to comply with the requirements of the GDPR and the related national data protection laws of the EU Member States may result in significant monetary fines for noncompliance of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater, other administrative penalties and a number of criminal offenses for organizations and, in certain cases, their directors and officers, as well as civil liability claims from individuals whose personal data was processed. Data protection authorities from the different EU Member States may still implement certain variations, enforce the GDPR and national data protection laws differently, and introduce additional national regulations and guidelines, which adds to the complexity of processing personal data in the EU.

27Furthermore, there are specific requirements relating to processing health data from clinical trials, including those related to public disclosure obligations provided in the EU Clinical Trials Regulation No. 536/2014 (“CTR”), European Medicines Agency ("EMA") data transparency initiatives and voluntary commitments by industry. Failure to comply with these obligations could lead to considerable risks of government enforcement actions and significant penalties against us, harm to our reputation, and adversely impact our business performance and operating efficiency.

Additionally, following the UK’s withdrawal from the EU and the EEA, companies also have to comply with the UK’s data protection laws (including the UK GDPR (as defined in section 3(10) (as supplemented by section 205(4)) of the Data Protection Act 2018 (the “DPA 2018”)), the DPA 2018, and related data protection laws in the UK). On June 19, 2025, the UK’s Data (Use and Access) Act (“DUAA”) took effect, which introduces certain relatively minor amendments to the data protection regime in the UK, and therefore creates slight divergences between the EU and UK data protection regimes. Separate from the fines that can be imposed by the GDPR, the UK regime has the ability to fine up to the greater of £17.5 million or 4% of global turnover.

Companies are subject to specific data sharing and transfer rules under the UK regime which broadly mirror the GDPR rules. We therefore also apply or rely on third parties to implement data sharing and cross-border transfer mechanisms and safeguards, as set out above, in these contexts. On February 2, 2022, the UK Secretary of State laid before the UK Parliament the international data transfer agreement (“IDTA”) and the international data transfer addendum to the EC’s standard contractual clauses for international data transfers (Addendum) and a document setting out transitional provisions. The IDTA and Addendum came into force on March 21, 2022 and replaced the old SCCs for the purposes of the UK regime. Regarding transfers from the UK to the EEA, personal data may flow freely since the EEA is deemed to have an adequate data protection level for purposes of the UK regime.

With regard to the transfer of personal data from the UK to the United States, the UK government has adopted an adequacy decision for the United States, the UK-US Data Bridge, which came into force on October 12, 2023. The UK-US Data Bridge recognizes the United States as offering an adequate level of data protection

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~~Furthermore,~~where ~~there~~the ~~are~~transfer ~~specific~~is ~~requirements relating~~ to ~~processing~~a ~~health~~U.S. ~~data~~company ~~from~~participating ~~clinical trials, including public disclosure obligations provided~~ in the EU-US ~~Clinical~~Data ~~Trials~~Privacy ~~Regulation~~Framework ~~No. 536/2014 (“CTR”), European Medical Agency ("EMA") disclosure initiatives~~ and ~~voluntary~~the ~~commitments~~UK ~~by industry~~Extension. Failure to comply with these obligations could lead to government enforcement actions and significant penalties against us, harm to our reputation, and adversely impact our business and operating results.

~~Additionally,~~The ~~following~~EU ~~the~~Directive ~~UK’s~~2002/58/EC ~~withdrawal~~(as ~~from~~amended by Directive 2009/136/EC) (“ePrivacy Directive”) also imposes obligations on organizations operating in the EU. The ePrivacy Directive is transposed into law in each EU member state and in the ~~EEA~~UK, ~~companies~~so ~~also~~local ~~have~~transposition toand ~~comply~~enforcement ~~with~~can ~~the~~vary. UKIt contains a prohibition on accessing information on an individual’s ~~data~~device, ~~protection~~such ~~laws~~as ~~(including~~through the UKuse ~~GDPR~~of ~~(as~~cookies ~~defined~~and inother ~~section~~similar ~~3(10)~~technologies, (without informed consent, as ~~supplemented~~well byas ~~section~~rules ~~205(4))~~on ofdirect ~~the~~marketing. ~~Data~~On ~~Protection~~November ~~Act~~19, ~~2018~~2025, (the EC published the Digital Omnibus Package (“~~DPA~~Omnibus ~~2018~~Proposals”)), aimed at simplifying the ~~DPA~~EU’s ~~2018,~~digital ~~and~~regulatory ~~related~~framework. ~~data~~The ~~protection~~Omnibus ~~laws~~Proposals inwould streamline the ~~UK)~~rules governing cookies and tracking technologies, potentially removing the requirement to obtain explicit consent for certain categories of cookies. ~~Separate~~If ~~from~~adopted, these changes could ease compliance obligations around the ~~fines~~use ~~that~~of ~~can~~cookies beand ~~imposed~~tracking bytools in the ~~GDPR~~EU. In the UK, the ePrivacy Directive was transposed into UK ~~regime~~law ~~has~~as the ~~ability~~Privacy toand ~~fine~~Electronic upCommunications (EC Directive) Regulations 2023 (“PECR”) which imposes equivalent requirements on UK operations. The UK’s DUAA made certain limited amendments to PECR, most notably bringing its enforcement powers in line with the UK GDPR, so that monetary penalties under PECR can now reach the greater of £17.5 million or 4% of ~~global~~an organization’s total worldwide annual turnover.

~~Companies~~The ~~are~~EU ~~subject~~has toalso ~~specific~~recently ~~transfer~~implemented ~~rules~~a ~~under~~number ~~the~~of UKcybersecurity ~~regime which broadly mirror the GDPR rules. On February 2~~laws, ~~2022,~~some ~~the UK Secretary~~ of ~~State~~which ~~laid~~are ~~before~~applicable ~~the~~to ~~UK Parliament~~ the ~~international~~healthcare ~~data~~industry. ~~transfer~~For ~~agreement~~example, ~~(“IDTA”) and~~ the ~~international~~Network ~~data~~and ~~transfer~~Information ~~addendum~~Security toDirective ~~the~~(Directive ~~EC’s standard contractual clauses for international data transfers~~ (~~Addendum~~EU) ~~and a document setting out transitional provisions. The IDTA and Addendum came into force on March 21,~~ 2022/2555) ~~and~~applies ~~replaced~~to ~~the~~organizations ~~old~~operating ~~SCCs~~in ~~for~~ the ~~purposes~~EU ofin the UKhealthcare ~~regime.~~sector ~~Regarding~~and ~~transfers~~imposes ~~from~~stringent ~~the~~cybersecurity UKobligations toon ~~the~~in-scope ~~EEA~~organizations, ~~personal~~including ~~data~~in ~~may~~relation ~~flow freely since the EEA is deemed~~ to ~~have~~supply anchain ~~adequate~~management ~~data~~and ~~protection~~incident ~~level for purposes of the UK regime~~reporting.

Drug and Biologic Development Process

Regardless of where they are conducted, all clinical trials included in applications for marketing authorization ("MA") for human medicines in the EU/EEA must have been carried out in accordance with EU regulations. This means that clinical trials conducted in the EU/EEA have to comply with EU clinical trial legislation but also that clinical trials conducted outside the EU/EEA have to comply with ethical principles equivalent to those set out in the EEA, including adhering to international good clinical practice and the Declaration of Helsinki, a set of internationally agreed ethical principles for medical research involving human participants. The conduct of clinical trials in the EU is governed by the CTR, which entered into force on January 31, 2022. The CTR replaced the Clinical Trials Directive 2001/20/EC, (“Clinical Trials Directive”) and introduced a complete overhaul of the existing regulation of clinical trials for medicinal products in the EU.

~~Under~~The ~~the~~EU ~~former~~Clinical ~~regime~~Trials Regulation, which ~~will~~replaced ~~expire~~the ~~after~~Clinical aTrials ~~transition~~Directive ~~period~~and ofhas ~~three~~been ~~years~~in asforce ~~outlined~~since ~~below~~2022, inaims ~~more~~to ~~detail,~~harmonize ~~before~~and astreamline clinical trial ~~can~~processes beacross ~~initiated~~Member itStates ~~must~~through bea ~~approved~~centralized inapplication ~~each~~system, EUthe ~~member~~Clinical ~~state~~Trials ~~where~~Information ~~there~~System is(CTIS), aenabling ~~site~~sponsors atto ~~which~~submit ~~the~~a ~~clinical~~single ~~trial~~application isfor toapproval. beOne ~~conducted.~~national ~~The~~regulatory ~~approval~~authority, ~~must~~designated beas ~~obtained~~the ~~from~~reporting ~~two~~Member ~~separate~~State, ~~entities:~~leads the ~~National~~validation ~~Competent Authority ("NCA")~~ and ~~one~~evaluation orof ~~more~~applications ~~Ethics~~in ~~Committees.~~consultation ~~The~~with ~~NCA~~other ofconcerned ~~the EU~~ Member States. inApplications ~~which~~may ~~the~~be ~~clinical~~amended ~~trial~~and ~~will~~resubmitted beif ~~conducted~~rejected, ~~must~~and ~~authorize~~approved ~~the~~trials ~~conduct~~may ofcommence ~~the~~in ~~trial,~~all ~~and~~relevant ~~the~~Member ~~independent~~States, ~~Ethics~~although ~~Committee~~individual ~~must~~states ~~grant~~retain athe ~~positive~~right ~~opinion~~to “opt out” in ~~relation~~limited tocircumstances. ~~the~~The ~~conduct~~Regulation ofalso ~~the~~simplifies ~~clinical~~safety ~~trial~~reporting inrules, ~~the~~introduces ~~relevant~~enhanced EUtransparency ~~member~~requirements ~~state~~such ~~before~~as ~~the~~mandatory ~~commencement~~submission of ~~the~~ trial. ~~Any~~results ~~substantial~~summaries ~~changes~~ to the ~~trial~~EU ~~protocol~~Database. orSince ~~other~~January ~~information~~31, ~~submitted~~2023, ~~with~~all ~~the~~initial clinical trial applications must be submitted tothrough orCTIS ~~approved~~which bynow serves as the ~~relevant~~single ~~NCA~~entry ~~and~~point ~~Ethics~~for ~~Committees~~clinical trial-related information and data. ~~Under~~By ~~the~~January ~~current~~31, ~~regime~~2025, all ~~suspected~~ongoing ~~unexpected~~trials ~~serious~~approved ~~adverse~~under ~~reactions~~the former Clinical Trials Directive must transition to CTIS and comply with the ~~investigated~~CTR. ~~drug~~On ~~that~~July ~~occur~~19, ~~during~~2023, the ~~clinical~~EC ~~trial~~published ~~must~~guidance befor ~~reported~~this totransition, ~~the~~clarifying ~~NCA~~that ~~and~~previously toassessed ~~the~~documentation ~~Ethics~~will ~~Committees~~not ofbe ~~the~~reassessed, EU-endorsed ~~member~~templates ~~state~~do ~~where~~not ~~they~~require ~~occur~~updates, and site suitability forms are only needed for new trial sites.

AUnder ~~more unified procedure will apply under~~ the ~~new~~ CTR., ~~A sponsor will be able to submit a single application for approval of a~~ clinical ~~trial through a centralized EU clinical~~ trials ~~portal~~must ~~(the~~comply ~~Clinical~~with ~~Trials Information System or "CTIS”). One~~ national ~~regulatory~~laws, ~~authority~~regulations, ~~(the reporting EU member state proposed by the applicant) will take the lead in validating~~ and ~~evaluating~~ the ~~application~~applicable ~~consult~~GCP and ~~coordinate~~GLP ~~with the other concerned EU Member States. If an application is rejected~~standards, ~~it may be amended~~ and ~~resubmitted through~~ the EUInternational ~~clinical~~Council ~~trials~~for ~~portal.~~Harmonization Ifof anTechnical ~~approval~~Requirements isfor ~~issued,~~Pharmaceuticals ~~the~~for ~~sponsor~~Human ~~may~~Use ~~start~~("ICH") ~~the~~guidelines ~~clinical~~on ~~trial~~Good inClinical ~~all concerned EU Member States. However~~Practice, aas ~~concerned~~well EUas ~~member state may in limited circumstances declare an “opt-out” from an approval and prevent~~ the ~~clinical~~ethical ~~trial~~principles ~~from~~outlined ~~being conducted~~ in ~~such member state. The CTR also aims to streamline and simplify~~ the ~~rules~~Declaration onof ~~safety reporting, and introduces enhanced transparency requirements such~~ Helsinki.

28During the development of a medicinal product, the EMA and national regulators within the EU provide the opportunity for dialogue and guidance on the development program. At the EMA level, this is usually done in the form of scientific advice, which is given by the Committee for Medicinal Products for Human Use (“CHMP”) on the recommendation of the Scientific Advice Working Party ("SAWP"). A fee is incurred with each scientific

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asadvice mandatory submission of a summary of the clinical trial results to the EU Database. The CTR foresees a three-year transition period. EU Member States will work in CTIS immediately after the system has gone live. Since January 31procedure, ~~2023,~~but ~~submission of initial clinical trial applications via CTIS~~ is ~~mandatory~~significantly ~~and~~reduced ~~CTIS serves as the single entry point~~ for ~~submission~~designated oforphan ~~clinical trial-related information and data~~medicines. ByAdvice ~~January~~from ~~31, 2025, all ongoing trials approved under~~ the ~~former~~EMA ~~Clinical~~is ~~Trials~~typically ~~Directive~~provided ~~will~~based ~~need~~on toquestions ~~comply with the CTR and have to be transitioned to CTIS. On July 19, 2023, the EC published guidance~~ concerning ~~the steps to be taken in this transition. This guidance provides~~, ~~among~~for ~~other things~~example, ~~that~~quality (i)chemistry, ~~documentation~~manufacturing ~~which~~and ~~was~~controls ~~previously~~testing), ~~assessed~~nonclinical ~~will~~testing ~~not~~and beclinical ~~reassessed~~studies, ~~(ii)~~and ~~templates~~pharmacovigilance ~~that~~plans ~~were developed~~ and ~~endorsed~~risk-management byprograms. ~~the~~Advice EUis ~~Clinical~~not ~~Trials~~legally ~~Expert~~binding ~~Group to provide compliance~~ with ~~the~~regard ~~CTR~~to doany ~~not~~future ~~need~~Marketing toAuthorization beApplication ~~updated and~~ (~~iii~~“MAA”) ~~there~~of isthe noproduct ~~need to retrospectively create a site suitability form, which are only necessary for new trial sites~~concerned.

Under both the former regime and the new CTR, national laws, regulations, and the applicable GCP and GLP standards must also be respected during the conduct of the trials, including the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use ("ICH") guidelines on Good Clinical Practice and the ethical principles that have their origin in the Declaration of Helsinki.

During the development of a medicinal product, the EMA and national regulators within the EU provide the opportunity for dialogue and guidance on the development program. At the EMA level, this is usually done in the form of scientific advice, which is given by the Committee for Medicinal Products for Human Use (“CHMP”) on the recommendation of the Scientific Advice Working Party ("SAWP"). A fee is incurred with each scientific advice procedure, but is significantly reduced for designated orphan medicines. Advice from the EMA is typically provided based on questions concerning, for example, quality (chemistry, manufacturing and controls testing), nonclinical testing and clinical studies, and pharmacovigilance plans and risk-management programs. Advice is not legally binding with regard to any future Marketing Authorization Application (“MAA”) of the product concerned.

Drug Marketing Authorization

In the EEA, after completion of all required clinical testing, pharmaceutical products may only be placed on the market after obtaining a MA. To obtain an MA of a drug under European Union regulatory systems, an applicant can submit an MAA through, amongst others, athe centralized or decentralized procedure as detailed below.

To be used or sold in the UK, a drug must have an effective MA obtained by a centralized application through EMA or a national application. National applications are governed by the Human Medicines Regulations (SI 2012/1916). Applications are made electronically through the Medicines and Healthcare products Regulatory Agency (“MHRA”) Submissions Portal. The process from application to authorizations generally takes up to 210 days, excluding time taken to provide any additional information or data required by the MHRA.

On August 30, 2023, the MHRA published detailed guidance on its recently announced new International Reliance Procedure (“IRP”) for MAAs. The IRP applies since January 1, 2024 and replaces existing EU reliance procedures to apply for authorizations from seven international regulators (e.g. Health Canada, Swiss Medic, FDA, EMA, among others). The IRP allows medicinal products approved in other jurisdictions that meet certain criteria to undergo a fast-tracked MHRA review to obtain and/or update a MA in the UK. Applicants can submit initial MAAs to the IRP but the procedure can also be used throughout the lifecycle of a product for post-authorization procedures including line extensions, variations and renewals.

Centralized Authorization Procedure

The centralized procedure provides for the grant of a single MA that is issued by the EC following the scientific assessment of the application by the EMA that is valid for all EU Member States as well as in the three additional EEA Member States (Norway, Iceland and Liechtenstein). The centralized procedure is compulsory for specific medicinal products, including for medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, advanced therapy medicinal products (gene therapy, somatic cell therapy, or tissue engineered medicines) and medicinal products with a new active substance indicated for the treatment of certain diseases (HIV/AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and viral diseases). For medicinal products containing a new active substance ~~not~~for ~~yet~~indications ~~authorized~~that indo ~~the~~not ~~EEA~~fall ~~before~~within ~~May~~the 20mandatory centralized procedure, ~~2004~~they ~~and~~are ~~indicated~~eligible for ~~the~~centralized ~~treatment~~assessment ofif ~~other~~they ~~diseases, medicinal products that~~ constitute significant therapeutic, scientific or technical innovations or for which the grant of a MA through the centralized procedure would be in the interest of public health at EU level.

29Under the centralized procedure, the Committee for Medicinal Products for Human Use ("CHMP") at the EMA is responsible for the initial assessment of an MAA. The CHMP also oversees the scientific assessment of various post-authorization and maintenance activities, including the assessment of variations or extensions to an existing MA. The standard timeframe for the evaluation of an MAA by the EMA’s CHMP is 210 days from receipt of a valid MAA, excluding clock-stops for the applicant to provide additional written or oral information in response to the CHMP's list of questions. As a result, the overall process typically takes a year or more, unless the application is eligible for an accelerated assessment. Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation. Upon request, the CHMP may reduce the time frame to 150 days if the applicant provides sufficient justification for an accelerated assessment. The CHMP will provide a positive opinion regarding the application only if it meets the required standards for quality, safety and efficacy. This opinion is then transmitted to the EC, which has the ultimate authority for granting MA, ordinarily within 67 days after receipt of the CHMP opinion.

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through the centralized procedure would be in the interest of public health at EU level, an applicant may voluntarily submit an application for a MA through the centralized procedure.

Under the centralized procedure, the Committee for Medicinal Products for Human Use ("CHMP") established at the EMA, is responsible for conducting the initial assessment of a drug. The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing MA. Under the centralized procedure, the timeframe for the evaluation of an MAA by the EMA’s CHMP is, in principle, 210 days from receipt of a valid MAA. However, this timeline excludes clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP, so the overall process typically takes a year or more, unless the application is eligible for an accelerated assessment. Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation. Upon request, the CHMP can reduce the time frame to 150 days if the applicant provides sufficient justification for an accelerated assessment. The CHMP will provide a positive opinion regarding the application only if it meets certain quality, safety and efficacy requirements. This opinion is then transmitted to the EC, which has the ultimate authority for granting MA within 67 days after receipt of the CHMP opinion.

Decentralized Authorization Procedure

~~Medicines~~The ~~that~~decentralized ~~fall~~procedure ~~outside~~permits ~~the~~companies ~~mandatory~~to ~~scope~~file ofidentical MAAs for a medicinal product not falling within the mandatory centralized procedure ~~have~~to ~~three~~the ~~routes~~competent toauthorities ~~authorization:~~in ~~(i)~~various ~~they~~EU ~~can~~Member beStates ~~authorized~~simultaneously ~~under~~if ~~the~~such ~~centralized~~medicinal ~~procedure~~product ifhas ~~they~~not ~~concern~~received amarketing ~~significant~~approval ~~therapeutic,~~in ~~scientific~~any orEU ~~technical~~Member ~~innovation,~~State. orIn ifthis ~~their~~procedure, ~~authorization~~the ~~would~~reference bemember instate ~~the~~is ~~interest~~appointed ofto ~~public~~lead ~~health;~~the ~~(ii)~~scientific ~~they~~review ~~can~~for beagreement ~~authorized~~with ~~under~~the acompetent ~~decentralized~~authorities ~~procedure~~of ~~where~~the another ~~applicant~~EU ~~applies~~Member ~~for~~States ~~simultaneous~~concerned ~~authorization~~by inthe ~~more~~procedure, ~~than~~the ~~one~~concerned EUmember states. A member state; ormay ~~(iii)~~refuse ~~they~~to ~~can~~accept bethe ~~authorized~~assessment inprovided anby EUthe reference member state inon ~~accordance~~grounds ~~with~~of a potential serious risk to public health that ~~state’s~~is ~~national~~defined ~~procedures~~as ~~and~~a ~~then~~situation bewhere ~~authorized~~there inis ~~other~~a EUsignificant ~~countries~~probability bythat a ~~procedure~~serious ~~whereby~~hazard ~~the~~resulting ~~countries~~from ~~concerned~~a ~~agree~~human tomedicinal ~~recognize~~product in the ~~validity~~context of ~~the~~its ~~original,~~proposed ~~national~~use MAwill ~~(mutual~~affect ~~recognition~~public ~~procedure)~~health.

The decentralized procedure permits companies to file identical MA applications for a medicinal product to the competent authorities in various EU Member States simultaneously if such medicinal product has not received marketing approval in any EU Member State before. This procedure is available for pharmaceutical products not falling within the mandatory scope of the centralized procedure. The competent authority of a single EU Member State, the reference member state, is appointed to review the application and provide an assessment report. The competent authorities of the other EU Member States, the concerned member states, are subsequently required to grant a MA for their territories on the basis of this assessment. The only exception to this is where the competent authority of an EU Member State considers that there are concerns of potential serious risk to public health, the disputed points are subject to a dispute resolution mechanism and may eventually be referred to the EC, whose decision is binding for all EU Member States.

Risk Management Plan

All new MAAs must include a Risk Management Plan (“RMP”) describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product. RMPs are continually modified and updated throughout the lifetime of the medicine as new information becomes available. An updated RMP must be submitted: (i) at the request of EMA or a national competent authority, or (ii) whenever the risk-management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit-risk profile or as a result of an important pharmacovigilance or risk-minimization milestone being reached. The regulatory authorities may also impose specific obligations as a condition of the MA. Since October 20, 2023, all RMPs for centrally authorized products are published by the EMA, subject only to limited redactions.

~~MA Validity Period~~33

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~~pharmacovigilance~~information becomes available. An updated RMP must be submitted: (i) at the request of EMA or a national competent authority, or (ii) whenever the risk-management system is modified, especially as the result of new information being received that may lead to ~~proceed~~a ~~with~~significant ~~only~~change ~~one~~to ~~additional~~the ~~five~~benefit-~~year~~risk ~~renewal~~profile or as a result of an important pharmacovigilance or risk-minimization milestone being reached. ~~Applications~~The ~~for~~regulatory ~~renewal~~authorities ~~must~~may bealso ~~made~~impose tospecific obligations as a condition of the ~~EMA~~MA. atAll ~~least~~RMPs ~~nine~~for ~~months~~centrally ~~before~~authorized products are published by the ~~five-year~~EMA, ~~period~~subject ~~expires~~only to limited redactions.

MA Validity Period

MAs have an initial duration of five years. After these five years, the authorization may subsequently be renewed on the basis of a reevaluation of the risk-benefit balance. Once renewed, the MA is valid for an unlimited period unless the EC or the national competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with only one additional five-year renewal. Applications for renewal must be made to the EMA at least nine months before the five-year period expires.

Any authorization which is not followed by the actual placing of the drug on the EU market (in case of centralized procedure) or on the market of the authorizing member state within three years after authorization ceases to be valid.

~~For~~The ~~the~~ UK applies a rule, consistent with directly applicable EU law, requiring that nationally approved medicinal products must be placed on the ~~period~~market ofwithin three years ~~during~~from ~~which~~the date the ~~drug~~marketing ~~has~~authorization ~~not~~is ~~been~~granted. ~~marketed~~When the Medicines and Healthcare products Regulatory Agency (MHRA) becomes aware that the three-year period is approaching expiry, it will notify the marketing authorization holder in ~~Great~~advance ~~Britain~~that the authorization will cease to be ~~restarted~~valid ~~from~~if the ~~date~~product ofis ~~conversion~~not tomarketed awithin ~~Great~~the ~~Britain~~required MAtimeframe. ~~Conversion~~The ~~refers~~MHRA provides notification to the ~~procedure~~marketing byauthorization ~~which,~~holder asin ofboth ~~January~~scenarios 1,referenced ~~2021~~previously: first, ~~MAs~~where ~~granted~~a onproduct ~~the~~has ~~basis~~held of a ~~centralized~~marketing ~~procedure~~authorization infor three years but has not been placed on the EUmarket ~~are~~at ~~only~~all; ~~valid~~and insecond, ~~Northern~~where ~~Ireland~~a product was previously marketed but has subsequently not inbeen ~~Great~~placed ~~Britain,~~on ~~whereas,~~the ~~prior~~market EUfor ~~authorizations~~a ~~have~~consecutive ~~all~~period ~~been~~of ~~automatically~~three ~~converted~~years. ~~into~~This UKprocess ~~MAs~~ensures ~~effective~~compliance inwith ~~Great~~regulatory ~~Britain~~requirements ~~only~~and maintains the integrity of the national medicines supply.

OnFollowing the ~~other~~UK's ~~hand,~~exit ~~for~~from the EU, in the ~~case~~three-year ~~the~~“sunset ~~drug~~clause” ~~has~~for ~~been~~centrally ~~marketed~~authorized products in the UK, was effectively reset from the ~~placing~~date of conversion (January 1, 2021). This means that any product not placed on the UK market ~~before~~in ~~the~~Great ~~end~~Britain ofby ~~the~~early ~~period~~2024 ~~starting~~risked ~~when~~losing ~~the~~its UKvalidity ~~left~~unless the EUappropriate onnotification ~~January~~was ~~31,~~made. ~~2020~~The Medicines and ~~ending~~Healthcare onproducts ~~December~~Regulatory ~~31,~~Agency ~~2020~~ (~~the~~MHRA) ~~“Brexit~~is ~~Transition~~responsible ~~Period”)~~for ~~will~~managing bethis ~~taken~~process ~~into~~for ~~account.~~UK Ifmarketing authorizations (PLGB MAs), ~~after~~requiring marketing authorization holders to provide updates on the ~~end~~marketing status of ~~the~~their ~~Brexit~~products. ~~Transition~~The ~~Period~~Windsor Framework agreement establishes that, effective from January 1, 2025, the ~~drug~~Medicines isand ~~not~~Healthcare ~~placed~~products onRegulatory ~~any~~Agency ~~other~~(MHRA) ~~market~~will ofserve as the ~~remaining~~sole ~~member~~regulatory ~~states~~authority offor approving medicines for the EUentire UK market, ~~the~~encompassing ~~three~~both ~~year~~Northern ~~period~~Ireland ~~will~~and ~~start~~Great ~~running~~Britain. ~~from~~This change replaces the ~~last~~previous ~~date~~system, ~~the~~where ~~drug~~Northern Ireland followed EU rules and Great Britain was ~~placed~~regulated onindependently by the MHRA. Under the new arrangements, a unified UK-wide ~~market~~authorization ~~before~~process will apply, ensuring that medicines in Northern Ireland are regulated by the ~~end~~MHRA in the same manner as in Great Britain. The primary focus of the ~~Brexit~~Windsor ~~Transition~~Framework ~~Period~~is to streamline regulatory procedures, eliminate the need for separate authorizations, and guarantee equal and timely access to medicines throughout the UK.

On the other hand, for the EU, in the case the drug has been marketed in the UK, the placing on the UK market before the end of the period starting when the UK left the EU on January 31, 2020 and ending on December 31, 2020 (the “Brexit Transition Period”) will be taken into account. If, after the end of the Brexit Transition Period, the drug is not placed on any other market of the remaining member states of the EU, the three year period will start running from the last date the drug was placed on the UK market before the end of the Brexit Transition Period. We do not have approved products that fall within the Brexit Transition Period.

Advanced Therapy Medicinal Products

In the EU, medicinal products, including advanced therapy medicinal products (“ATMPs") are subject to extensive pre- and post-market regulation by regulatory authorities at both the EU and national levels. ATMPs comprise gene therapy products, somatic cell therapy products and tissue engineered products, which are genes, cells or tissues that have undergone substantial manipulation and that are administered to human beings in order to cure, diagnose or prevent diseases or regenerate, repair or replace a human tissue. Pursuant to Regulation (EC) No 1394/2007, the Committee for Advanced Therapies (“CAT”) is responsible in conjunction with the CHMP for the evaluation of ATMPs. The CHMP and CAT are also responsible for providing guidelines on ATMPs. These guidelines provide additional guidance on the factors that the EMA will consider in relation to the development and evaluation of ATMPs and include, among other things, the preclinical studies required to characterize ATMPs. Although such guidelines are not legally binding, compliance with them is often necessary to gain and maintain approval for product candidates.

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beings in order to cure, diagnose or prevent diseases or regenerate, repair or replace a human tissue. Pursuant to Regulation (EC) No 1394/2007, the Committee for Advanced Therapies (“CAT”) is responsible in conjunction with the CHMP for the evaluation of ATMPs. The CHMP and CAT are also responsible for providing guidelines on ATMPs. These guidelines provide additional guidance on the factors that the EMA will consider in relation to the development and evaluation of ATMPs and include, among other things, the preclinical studies required to characterize ATMPs. Although such guidelines are not legally binding, compliance with them is often necessary to gain and maintain approval for product candidates.

In addition to the mandatory RMP, the holder of a MA for an ATMP must put in place and maintain a system to ensure that each individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the relevant healthcare institution where the product is used.

Exceptional Circumstances/ and Conditional Approval

Similar to accelerated approval regulations in the United States, ~~conditional~~EU ~~MAs~~pharmaceutical ~~can~~law beprovides ~~granted~~two inregulatory ~~the~~pathways EUto infacilitate early patient access to medicines when comprehensive clinical data are not yet available: conditional marketing authorization (“CMA”) and marketing authorization under exceptional circumstances (“MAUEC”). AConditional ~~conditional~~marketing MAauthorization ~~can~~is be granted for ~~medicinal~~medicines ~~products~~that ~~where~~address unmet medical needs, ~~although~~such ~~comprehensive~~as ~~clinical~~those ~~data~~for ~~referring~~serious toor ~~the~~rare ~~safety~~diseases, ~~and~~where ~~efficacy~~the immediate availability of the ~~medicinal~~ product ~~have~~offers ~~not~~significant ~~been~~benefit ~~supplied~~despite incomplete data. Under this pathway, athe ~~number~~applicant ofis ~~criteria~~required ~~are~~to ~~fulfilled:~~submit ~~(i)~~additional clinical data within a specified timeframe to confirm the benefit/-risk ~~balance~~profile of the ~~product~~medicine. The authorization is ~~positive,~~valid ~~(ii)~~for itone isyear ~~likely~~and ~~that~~may ~~the~~be ~~applicant~~renewed ~~will~~annually beuntil insufficient adata ~~position~~are provided to ~~provide~~support ~~the~~full ~~comprehensive~~authorization. ~~clinical~~Marketing ~~data,~~authorization ~~(iii)~~under ~~unmet~~exceptional ~~medical~~circumstances ~~needs~~applies ~~will~~when beit ~~fulfilled~~is bynot feasible to obtain comprehensive data, typically due to the ~~grant~~rarity of the MAcondition, ~~and~~limitations ~~(iv)~~in ~~the~~scientific ~~benefit~~knowledge, toor ~~public~~ethical ~~health~~constraints ofthat ~~the~~make ~~immediate~~further ~~availability~~studies onimpossible ~~the~~or ~~market~~inappropriate. Instead of ~~the~~expecting ~~medicinal~~future ~~product~~comprehensive ~~concerned~~data, ~~outweighs~~this ~~the~~pathway relies on ongoing obligations such as enhanced safety monitoring and risk ~~inherent~~management inplans. ~~the~~The ~~fact~~authorization ~~that~~remains ~~additional~~valid ~~data~~as ~~are~~long ~~still~~as ~~required~~these obligations are satisfied. ~~Once~~The akey ~~conditional~~difference MAbetween ~~has~~these ~~been~~pathways ~~granted,~~is that CMA anticipates the MAeventual ~~holder~~completion ~~must~~of ~~fulfil~~the ~~specific~~data ~~obligations~~package, ~~within~~whereas ~~defined~~MAUEC ~~timelines. A~~recognizes ~~conditional~~that MAfull isdata ~~valid~~cannot ~~for~~reasonably ~~one~~be ~~year~~obtained and ~~must~~instead berelies ~~renewed~~on ~~annually,~~alternative ~~but~~measures itto ~~can~~manage berisk. ~~converted~~Both ~~into~~pathways require a ~~standard~~positive MAbenefit-risk ~~once~~assessment, ~~the~~address MAunmet ~~holder~~medical ~~fulfills~~needs, and ensure that the ~~obligations~~immediate ~~imposed~~benefit ~~and~~to patients outweighs the ~~complete~~risks, ~~data~~but ~~confirm~~they ~~that~~differ ~~the~~in ~~medicine’s~~their ~~benefits~~expectations ~~continue~~for tofuture ~~outweigh~~data ~~its~~collection ~~risks~~and regulatory oversight.

Data and ~~Market~~Marketing Exclusivity

AsUnder inEU ~~the~~pharmaceutical ~~United States~~law, itreference ~~may~~medicinal beproducts ~~possible~~are togranted ~~obtain~~8 ayears ~~period~~ of ~~market~~data exclusivity, during which generic and /biosimilar ormanufacturers cannot rely on the originator’s non-clinical and clinical data for regulatory approval. This is followed by 2 years of marketing exclusivity, inpreventing ~~the~~generics EUand ~~that~~biosimilars ~~would~~from ~~have~~entering the ~~effect~~market for a total of ~~postponing~~10 years. If, within the ~~entry~~first ~~into~~8 years, the ~~marketplace~~reference ofproduct is approved for a ~~competitor’s~~new ~~generic~~indication that provides significant clinical benefit, ~~hybrid~~the exclusivity period may be extended to 11 years. These rules ensure that generics and biosimilars cannot seek approval or ~~biosimilar~~enter ~~product~~the ~~(even~~market ifuntil the ~~pharmaceutical~~exclusivity ~~product~~periods ~~has~~have ~~already~~expired, ~~received~~balancing aincentives ~~MA)~~for ~~and~~innovation ~~prohibiting~~with ~~another~~future market competition.

31A reference medicinal product for data and marketing exclusivity typically contains a new active substance and requires a full dossier, including pharmaceutical, non-clinical, and clinical trial data, for approval. The European Medicines Agency (EMA), based on the scientific assessment and opinion of its Committee for Medicinal Products for Human Use (CHMP), determines whether a product contains a new active substance. Data and marketing exclusivity do not prevent other companies from generating their own data through independent development to demonstrate the safety, quality, and efficacy of their own products.

Recent reforms introduced through the EU Pharma Package and the proposed Biotech Act bring significant changes, including streamlined authorization procedures, enhanced measures for access and affordability, stricter management of medicine shortages, strengthened post-market surveillance, and new requirements addressing environmental and ethical considerations. These initiatives are designed to modernize and harmonize medicines regulation, facilitate patient access to innovative therapies, and provide robust oversight of emerging technologies across the EU.

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~~applicant~~The ~~from~~legislative ~~relying~~process onfor the MAEU ~~holder~~Pharma Package began with the European Commission’s ~~pharmacological~~proposal in April 2023, ~~toxicological~~followed by the development of positions by the European Parliament and ~~clinical~~the ~~data~~Council. This culminated in ~~support~~Trilogue ofnegotiations, ~~another~~with MAa ~~for~~political ~~the~~agreement ~~purposes~~reached ofin ~~submitting~~December an2025. ~~application~~The agreed text now awaits formal adoption by both the Parliament and Council, ~~obtaining~~after MAwhich orit ~~placing~~will be published in the ~~product~~Official onJournal of the ~~market~~EU. ~~Innovative~~The ~~medicinal~~new ~~products,~~Directive ~~referred~~and Regulation will then enter into force following a transition period of 18 to as36 ~~New~~months, ~~Chemical~~ultimately ~~Entities~~modernizing ~~("NCEs")~~EU pharmaceutical law to better support innovation, ~~approved~~access, inand supply. Under the agreed EU ~~qualify~~Pharma ~~for~~Package, companies launching new medicines will benefit from eight years of data ~~exclusivity~~protection and 10one ~~years~~year of ~~marketing~~market exclusivity, with a possible additional year for innovative products meeting specific criteria.

AnPediatric additional non-cumulative one-year period of marketing exclusivity is possible if during the data exclusivity period (the first eight years of the 10-year marketing exclusivity period), the MA holder obtains an authorization for one or more new therapeutic indications that are deemed to bring a significant clinical benefit compared to existing therapies.Development

~~The~~In ~~data exclusivity period begins on~~ the ~~date of the product’s first MA in the~~ EU~~. After eight years~~, aan ~~generic~~approved ~~product~~PIP ~~application~~is ~~may~~required to be ~~submitted~~obtained ~~and~~by ~~generic companies may rely on~~ the MAcompany ~~holder’s~~prior ~~data.~~to ~~However,~~any aapplication ~~generic~~for ~~product~~marketing ~~cannot~~authorization ~~launch~~of ~~until two years later (or~~ a ~~total~~medicinal ~~of 10 years after the first MA in the EU of the innovator~~ product), orbased ~~three~~on ~~years later (or~~ a ~~total~~full ofdossier ~~11 years after the first MA in the EU~~ of ~~the innovator product) if the MA holder obtains MA for a new indication with significant clinical benefit within the eight-year data exclusivity period. Additionally~~pharmaceutical, ~~another~~ non-~~cumulative~~clinical, ~~one-year~~and ~~period~~clinical of data ~~exclusivity can be added to the eight years of data exclusivity where an application is made for a new indication for a well-established substance, provided~~ that ~~significant~~has ~~pre-clinical~~not oryet ~~clinical~~been ~~studies~~approved ~~were carried out~~ in ~~relation to~~ the ~~new indication~~EU. ~~Another~~This ~~year~~requirement ofalso ~~data~~applies ~~exclusivity may be added~~ to ~~the~~authorized ~~eight~~products ~~years,~~protected ~~where~~by a ~~change~~supplementary ofprotection ~~classification~~certificate of(SPC) ~~a pharmaceutical product has been authorized on the basis of significant pre-trial tests~~ or ~~clinical~~a ~~trials~~patent ~~(when~~eligible ~~examining~~for an ~~application~~SPC, bywhen ~~another~~seeking ~~applicant~~authorization for ornew ~~holder~~indications, ofpharmaceutical MAforms, ~~for~~or aroutes ~~change~~ of ~~classification of the same substance the competent authority will not refer to the results of those tests or trials for one year after the initial change was authorized)~~administration.

~~Products~~A ~~may~~PIP ~~not~~is bea ~~granted~~research ~~data~~and ~~exclusivity~~development ~~since~~program ~~there~~designed isto noensure ~~guarantee~~ that aadequate ~~product~~data ~~will~~are begenerated ~~considered~~to bydetermine the ~~EU’s~~conditions ~~regulatory~~under ~~authorities~~which ~~to include an NCE. Even if~~ a ~~compound~~medicinal isproduct ~~considered~~may to be aauthorized ~~NCE~~for ~~and~~use in the MApediatric ~~applicant~~population. isCompanies ~~able~~developing tonew ~~gain~~medicinal ~~the~~products ~~prescribed~~must ~~period~~submit ofa ~~data exclusivity~~PIP, ~~another~~along ~~company~~with ~~nevertheless~~a ~~could~~request ~~also~~for ~~market~~agreement, ~~another~~to ~~version of~~ the ~~medicinal~~European ~~product~~Medicines ifAgency ~~such~~(EMA). ~~company~~The ~~can~~EMA’s ~~complete~~Pediatric aCommittee ~~full~~(PDCO) ~~MAA~~evaluates ~~with~~the ~~their~~PIP ~~own~~and ~~complete~~provides ~~database~~an ~~of pharmaceutical tests~~opinion, ~~preclinical~~upon ~~studies~~which ~~and~~the ~~clinical~~EMA ~~trials~~issues ~~and~~a ~~obtain~~binding ~~MA of its product~~decision.

OnCompanies ~~April~~are ~~26,~~required ~~2023,~~to ~~the~~conduct ECpediatric ~~submitted~~clinical atrials ~~proposal~~in ~~for~~accordance with the ~~reform~~agreed ofPIP ~~the~~and ~~European~~within ~~pharmaceutical~~the ~~legislation~~specified timelines. The ~~current~~resulting ~~draft~~pediatric ~~envisages~~study edata must accompany the application for authorization for it to be validated and approved by the EMA.g. However, a ~~shortening~~PIP may include a deferral of the ~~periods~~initiation or completion of ~~data~~some ~~exclusivity~~or all studies, ~~however~~based on scientific, ~~there~~technical, isor ~~currently~~public ~~neither~~health agrounds—for ~~final~~example, ~~version~~if ofit ~~this~~is ~~draft~~appropriate ~~nor~~to aconduct ~~date~~adult ~~for~~studies ~~its~~first ~~entry~~or ~~into~~if ~~force~~pediatric studies will take longer to complete. ~~While~~A ~~the~~waiver ~~European~~from ~~Parliament~~the ~~adopted~~PIP ~~its~~requirement ~~approving~~may ~~position~~be ongranted if the ~~reform~~product onor ~~April~~product 10class is likely to be ineffective or is likely to be to be unsafe in the pediatric population, ~~2024~~if the disease or condition occurs only in adults, noor ~~further~~if ~~required~~the ~~legislative~~product ~~steps~~does ~~have~~not ~~been~~offer ~~taken~~significant ~~since~~therapeutic benefit over existing pediatric treatments.

Unless a waiver or deferral has been granted, the MAA must include the results of all pediatric clinical trials and all information collected in compliance with the approved PIP. If a deferral is granted, the pediatric studies may be completed at a later date. A “PIP Compliance Check” is conducted during the validation period of an MAA to confirm that pediatric product development is being conducted in accordance with the approved PIP at that time.

Medicinal products granted marketing authorization based on pediatric clinical trials conducted in accordance with an approved PIP are eligible for a six-month extension of the SPC (if in effect at the time of approval), or, for orphan medicinal products, a two-year extension of orphan market exclusivity, regardless of whether the pediatric data result in approval of a pediatric indication. For applications resulting in the authorization of a new pediatric indication, a one-year extension of data and marketing exclusivity may be granted. However, the regulatory framework prohibits double awards of these exclusivity rights for the same product.

In the UK, the MHRA has established a closely aligned process, frequently accepting agreed EU PIPs and decisions to streamline UK submissions. However, the MHRA maintains UK-specific requirements, such as the need for a UK PIP for new medicines. Following the Windsor Framework, MHRA is responsible for regulatory control of medicines (including pediatric medicines) for the entire UK market (England, Scotland, Wales, and Northern Ireland).

Orphan Designation and Exclusivity

The criteria for designating an orphan medicinal product in the EU are similar in principle to those in the U.S. The EMA grants orphan drug designation if the medicinal product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting no more than five in 10,000 persons in the EU (prevalence criterion). In addition, orphan drug designation can be granted if, for economic reasons, the medicinal product would be unlikely to be developed without incentives and if there is no other satisfactory method approved in the EU of diagnosing, preventing, or treating the condition, or if such a method exists, the proposed medicinal product is a significant benefit to patients affected by the condition. An application for orphan drug designation (which is not a MA, as not all orphan-designated medicines reach the authorization application stage) must be submitted first before an application for MA of the medicinal product is submitted. The applicant will receive a fee reduction for the MAA if the orphan drug designation has been granted, but not if the designation is still pending at the time the MA is submitted, and sponsors must submit an annual report to EMA summarizing the status of development of the medicine. Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process. Designated orphan medicines are eligible for conditional MA.

The EMA’s Committee for Orphan Medicinal Products (“COMP”) reassesses the orphan drug designation of a product in parallel with the review for a MA; for a product to benefit from market exclusivity it must maintain its orphan drug designation at the time of MA review by the EMA and approval by the EC. Additionally, any MA granted for an orphan medicinal product must only cover the therapeutic indication(s) that 36

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~~are~~persons ~~covered~~in the EU (prevalence criterion). In addition, orphan drug designation can be granted if, for economic reasons, the medicinal product would be unlikely to be developed without incentives and if there is no other satisfactory method approved in the EU of diagnosing, preventing, or treating the condition, or if such a method exists, the proposed medicinal product is a significant benefit to patients affected by the condition. An application for orphan drug designation. ~~Upon~~(which is not an MA, as not all orphan-designated medicines reach the ~~grant~~authorization application stage) must be submitted before an application for MA of the medicinal product is submitted. The applicant will receive a MAfee reduction for the MAA, as well as other fee-based regulatory procedures, if the orphan drug designation ~~provides~~has upbeen granted, but not if the designation is still pending at the time the MAA or application for other regulatory procedures is submitted, and sponsors must submit an annual report to ~~ten~~EMA ~~years~~summarizing the status of ~~market~~development ~~exclusivity~~of the medicine. Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process. Designated orphan ~~indication~~medicines are eligible for conditional MA.

The EMA’s Committee for Orphan Medicinal Products (“COMP”) reassesses the orphan drug designation of a product in parallel with the review for an MA; for a product to benefit from market exclusivity it must maintain its orphan drug designation at the time of MA review by the EMA and approval by the EC. Additionally, any MA granted for an orphan medicinal product must only cover the therapeutic indication(s) that are covered by the orphan drug designation. Upon the grant of an MA, orphan drug designation provides up to ten years of market exclusivity in the orphan indication.

During the 10-year period of market exclusivity, with a limited number of exceptions, the regulatory authorities of the EU Member States and the EMA may not accept applications for MA, accept an application to extend an existing MA or grant a MA for other similar medicinal products for the same therapeutic indication. A similar medicinal product is defined as a medicinal product containing a similar active substance or substances as contained in a currently authorized orphan medicinal product, and which is intended for the same therapeutic indication. An orphan medicinal product can also obtain an additional two years of market exclusivity for an orphan-designated condition when the results of specific studies are reflected in the Summary of Product Characteristics (“SmPC”) addressing the pediatric population and completed in accordance with a fully compliant Pediatric Investigation Plan (“PIP”). No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications.

The 10-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, i.e. the condition prevalence or financial returns criteria under Article 3 of Regulation (EC) No. 141/2000 on orphan medicinal products. When the period of orphan market exclusivity for an indication ends, the orphan drug designation for that indication expires as well. Orphan exclusivity runs in parallel with normal rules on data exclusivity and market protection. Additionally, aan MA may be granted to a similar medicinal product (orphan or not) for the same or overlapping indication subject to certain requirements.

In the UK, following the post-Brexit transition period, a system for incentivizing the development of orphan medicines was introduced. Overall, the requirements for orphan designation largely replicate the requirements in the EU and the benefit of market exclusivity has been retained. Products with an orphan designation in the EU can be considered for an orphan MA in Great Britain, but a UK-wide orphan MA can only be considered in the absence of an active EU orphan designation. The MHRA will review applications for orphan designation at the time of a MA, and will offer incentives, such as market exclusivity and full or partial refunds for MA fees to encourage the development of medicines in rare diseases.

Pediatric Development

In the EU, companies developing a new medicinal product are obligated to study their product in children and must therefore submit a PIP together with a request for agreement to the EMA. The EMA issues a decision on the PIP based on an opinion of the EMA’s Pediatric Committee ("PDCO"). Companies must conduct pediatric clinical trials in accordance with the PIP approved by the EMA, unless a deferral (e.g. until enough information to demonstrate its effectiveness and safety in adults is available) or waiver (e.g. because the relevant disease or condition occurs only in adults) has been granted by the EMA. The MAA for the medicinal product must include the results of all pediatric clinical trials performed and details of all information collected in compliance with the approved PIP, unless a waiver or a deferral has been granted, in which case the pediatric clinical trials may be completed at a later date. Medicinal products that are granted an MA on the basis of the pediatric clinical trials conducted in accordance with the approved PIP are eligible for a six month extension of the protection under a supplementary protection certificate (if any is in effect at the time of approval), or, in the case of orphan medicinal products, a two year extension of the orphan market exclusivity. This pediatric reward is subject to specific conditions and is not automatically available when data in compliance with the approved PIP are developed and submitted. An approved PIP is also required when a MA holder wants to add a new indication, medicinal form or route of administration for a medicine that is already authorized and covered by intellectual property rights.

In the UK, the MHRA has published guidance on the procedures for UK Paediatric Investigation Plans ("PIPs") which, where possible, mirror the submission format and requirements of the EU system. EU PIPs remain applicable for Northern Ireland and EU PIPs agreed by the EMA prior to January 1, 2021 have been adopted as UK PIPs.

PRIME Designation

InThe ~~March~~EMA ~~2016,~~has established the ~~EMA~~Priority ~~launched~~Medicines ("PRIME") scheme, an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist. The ~~Priority~~PRIME ~~Medicines~~scheme (“is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure. Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME”) scheme isif compelling non-clinical data in a relevant model provide early evidence of promising activity or proof of principle. Additionally, first-in-human studies should demonstrate adequate exposure to achieve the desired pharmacotherapeutic effects and tolerability. Products accepted onto the PRIME scheme benefit from, among others, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and

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intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure. Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies on the basis of compelling non-clinical data and tolerability data from initial clinical trials. Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted. Importantly, once a candidate medicine has been selected for the PRIME scheme, a dedicated contact point and rapporteur from the CHMP or CAT are appointed facilitating increased understanding of the product at EMA’s Committee level. A kick-off meeting with the CHMP/CAT rapporteur initiates these relationships and includes a team of multidisciplinary experts to provide guidance on the overall development plan and regulatory strategy. PRIME eligibility does not change the standards for product approval, and there is no assurance that any such designation or eligibility will result in expedited review or approval.

Post-Approval Regulation

Similar to the United States, both MA holders and manufacturers of medicinal products in the EU are subject to comprehensive regulatory oversight by the EMA, the EC and/or the competent regulatory authorities of the EU Member States. ~~This~~The regulatory oversight ~~applies~~covers ~~both~~every ~~before~~stage ~~and~~of ~~after~~the ~~grant~~authorization ofprocess, ~~manufacturing~~from ~~licenses~~initial ~~and~~grant ~~MAs.~~of Itan ~~includes~~approval ~~control~~to ongoing monitoring of compliance with EU ~~good manufacturing practices rules~~cGMPs, manufacturing authorizations, pharmacovigilance rules and requirements governing advertising, promotion, sale, and distribution, recordkeeping, importing and exporting of medicinal products.

These regulatory requirements are designed to ensure that the safety, quality, and efficacy standards of medicinal products are consistently maintained throughout their lifecycle. Failure by us or by any of our third-party partners, including suppliers, manufacturers and distributors to comply with EU laws and the related national laws of individual EU Member States governing the conduct of clinical trials, manufacturing approval, MA of medicinal products and marketing of such products, both before and after grant of MA[, statutory health insurance], bribery and anti-corruption or other applicable regulatory requirements may result in administrative, civil or criminal ~~penalties~~sanctions. These ~~penalties could~~ include delays or refusal to authorize the conduct of clinical trials or to grant MA, product withdrawals and recalls, product seizures, ~~suspension,~~ withdrawal or ~~variation~~suspension of ~~the MA~~authorizations, ~~total~~restrictions oron ~~partial~~regulated ~~suspension~~activities ofsuch as production, distribution, manufacturing or clinical trials, operating restrictions, ~~injunctions,~~financial ~~suspension of licenses, fines and criminal~~ penalties.

The holder of MA for a medicinal product must also comply with EU pharmacovigilance legislation and its related regulations and guidelines, which entail many requirements for conducting pharmacovigilance, or the assessment and monitoring of the safety of medicinal products.

These pharmacovigilance rules ~~can~~require ~~impose on~~ holders of MAs the obligation to ~~conduct~~develop a ~~labor~~system ~~intensive~~capable ~~collection~~ of ~~data~~collecting, ~~regarding~~collating, ~~the~~assessing ~~risks~~ and ~~benefits~~reporting ofpost-authorization ~~marketed~~data ~~medicinal products and~~ to ~~engage~~monitor inthe ongoing ~~assessments~~risks and benefits of ~~those~~marketed ~~risks~~medicinal ~~and~~products ~~benefits,~~as ~~including~~well as the ~~possible~~ requirement to conduct additional clinical studies or post-authorization safety or efficacy studies to ~~obtain~~address ~~further~~uncertainties ~~information~~about onthe abenefit-risk ~~medicine’s safety~~balance, or to measure the effectiveness of risk-management measures,. ~~which~~Such post-authorization measures may be time-consuming and expensive and could impact our profitability. MA holders must establish and maintain a pharmacovigilance system designed to monitor the safety of authorized medicinal products and detect any change to their risk-benefit balance and appoint an individual qualified person for pharmacovigilance, who is responsible for the oversight of that system. Key obligations include expedited reporting of ~~suspected~~unexpected serious adverse reactions and submission of Periodic Safety Update Reports ("PSURs") in relation to medicinal products for which they hold MAs. The EMA reviews PSURs for medicinal products authorized through the centralized procedure. If the EMA, ~~has~~based ~~concerns~~on the scientific assessment conducted by its advisory committees, determines that the risk -benefit profile of a product has ~~varied~~changed, it ~~can~~may ~~adopt~~issue an opinion ~~advising~~recommending ~~that~~suspension, withdrawal, or variation of the existing MA. ~~for~~The ~~the~~scientific ~~product~~opinion must be ~~suspended,~~ratified ~~withdrawn~~by orthe ~~varied.~~EC ~~The~~in ~~agency~~a ~~can~~legally ~~advise~~binding ~~that~~decision. If the MA holder befails ~~obliged~~ to ~~conduct~~meet ~~post-authorization~~the ~~Phase~~obligations IVset ~~safety~~out ~~studies.~~in If the EC’s ~~agrees~~decision, ~~with~~ the ~~opinion,~~validity itof ~~can adopt a decision varying~~ the ~~existing~~ MA. ~~Failure~~may bybe ~~the~~compromised. MAFor ~~holder~~centrally toauthorized ~~fulfill~~products, ~~the~~non-compliance ~~obligations~~with ~~for~~pharmacovigilance ~~which~~requirements ~~the~~can ~~EC’s~~result ~~decision~~in ~~provides~~regulatory ~~can~~sanctions, ~~undermine~~including ~~the~~financial ~~ongoing~~penalties ~~validity~~imposed ofby the MAEC.

~~More~~The ~~generally~~manufacturing process for pharmaceutical products in the EU is highly regulated and regulators may shut down manufacturing facilities that they believe do not comply with regulations. Manufacturing requires a manufacturing authorization, ~~non-compliance~~and the manufacturing authorization holder must comply with ~~pharmacovigilance~~various ~~obligations~~requirements ~~can~~set ~~lead~~out toin the ~~variation~~applicable EU laws, ~~suspension~~regulations orand ~~withdrawal~~guidance, ofincluding Directive 2001/83/EC, Directive 2003/94/EC (repealed by Directive 2017/1572 on January 31, 2022), Regulation (EC) No 726/2004 and the MAEuropean Commission Guidelines for ~~the~~Good ~~product~~Manufacturing orPractice ~~imposition~~("GMP"). These requirements include compliance with EU cGMP standards when manufacturing pharmaceutical products and active pharmaceutical ingredients, including the manufacture of ~~financial~~active ~~penalties~~pharmaceutical oringredients ~~other~~outside ~~enforcement~~of ~~measures.~~the EU

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~~The manufacturing process for pharmaceutical products in the EU is highly regulated and regulators may shut down manufacturing facilities that they believe do not comply~~ with ~~regulations. Manufacturing requires a manufacturing authorization, and~~ the manufacturing authorization holder must comply with various requirements set out in the applicable EU laws, regulations and guidance, including Directive 2001/83/EC, Directive 2003/94/EC (repealed by Directive 2017/1572 on January 31, 2022), Regulation (EC) No 726/2004 and the European Commission Guidelines for Good Manufacturing Practice ("GMP"). These requirements include compliance with EU GMP standards when manufacturing pharmaceutical products and active pharmaceutical ingredients, including the manufacture of active pharmaceutical ingredients outside of the EU with the intention to import the active pharmaceutical ingredients into the EU. Amendments or replacements of at least Directive 2001/83/EC and Regulation (EC) No 726/2004 are part of the reform proposal for European pharmaceutical legislation under the EU Pharma Package, as deta. Similarly, the distribution of pharmaceutical products into and within the EU is subject to compliance with the applicable EU laws, regulations and guidelines, including the requirement to hold appropriate authorizations for distribution granted by the competent authorities of the EU Member States. The manufacturer or importer must have a qualified person who is responsible for certifying that each batch of product has been manufactured in accordance with GMP and the terms of a marketing authorization or clinical trial authorization, before releasing the product for commercial distribution in the EU or for use in a clinical trial. Manufacturing facilities are subject to periodic inspections by the competent authorities for compliance with ~~GMP~~cGMPs.

~~Sales~~Advertising and ~~Marketing~~Promotion Regulations

The advertising and promotion of our products is also subject to EU laws concerning promotion of medicinal products, interactions with physicians, misleading and comparative advertising and unfair commercial practices. In addition, other national legislation of individual EU Member States may apply to the advertising and promotion of medicinal products and may differ from one country to another. These laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics (SmPC) as approved by the competent regulatory authorities. The SmPC is the document that provides information to physicians concerning the safe and effective use of the medicinal product. It forms an intrinsic and integral part of the MA granted for the medicinal product. Promotion of a medicinal product that does not comply with the SmPC is considered to constitute off-label promotion. All advertising and promotional activities for the product must be consistent with the approved SmPC and therefore all off-label promotion is prohibited. Direct-to-consumer advertising of prescription-only medicines is also prohibited in the EU. Violations of the rules governing the promotion of medicinal products in the EU could be penalized by administrative measures, fines and imprisonment. These laws may further limit or restrict the advertising and promotion of our products to the general public and may also impose limitations on its promotional activities with healthcare professionals.

EU regulation ~~with~~advertising ~~regards to dispensing, sale~~ and ~~purchase~~promotion of ~~medicines~~medicinal ~~has~~products ~~generally~~is ~~been~~retained ~~preserved~~ed in the UK following Brexit, ~~through~~as ~~the~~directly ~~Human~~applicable ~~Medicines~~EU ~~Regulations 2012. However~~law, ~~organizations~~by ~~wishing~~virtue toof ~~sell medicines online need to register with~~ the ~~MHRA.~~EU ~~Following~~(Withdrawal) ~~Brexit,~~Act the ~~requirements~~Human toMedicines ~~display~~Regulations ~~the~~2012 ~~common~~and ~~logo~~The noHuman ~~longer~~Medicines ~~apply~~(Amendment toetc.) ~~UK-based~~(EU ~~online~~Exit) ~~sellers,~~Regulations ~~except for those established in Northern Ireland~~2019.

Anti-Corruption Legislation

In the EU, interactions between pharmaceutical companies and physicians are also governed by strict laws, regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct both at EU level and in the individual EU Member States. The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is prohibited in the EU. The provision of benefits or advantages to physicians is also governed by the national anti-bribery laws of the EU Member States. Violation of these laws could result in substantial fines and imprisonment.

Payments made to physicians in certain EU Member States also must be publicly disclosed. Moreover, agreements with physicians must often be the subject of prior notification and approval by the physician’s employer, his/her regulatory professional organization, and/or the competent authorities of the individual EU Member States. These requirements are provided in the national laws, industry codes, or professional codes of conduct, applicable in the individual EU Member States. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

35In the UK, the pharmaceutical sector is recognized as being particularly vulnerable to corrupt practices. The UK Bribery Act 2010 impacts pharmaceutical promotion through its interaction with the self-regulatory Code of Practice of the Association of the British Pharmaceutical Industry (ABPI). The Serious Fraud Office (SFO) and Prescription Medicines Code of Practice Authority (PMCPA) work together to prevent bribes disguised as promotional activities, such as excessive hospitality offered to healthcare professionals for prescription medicines. The ABPI Code, enforced by the PMCPA, serves as the primary self-regulatory safeguard, establishing strict rules on inducements and requiring transparency to prevent violations of both anti-bribery laws and industry codes, especially in relation to prescribing decisions. Due to the Bribery Act 2010’s far-

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In the UK, the pharmaceutical sector is recognized as being particularly vulnerable to corrupt practices, some of which fall within the scope of the Bribery Act 2010. Due to the Bribery Act 2010’s far-reaching territorial application, the potential penalized act does not have to occur in the UK to become within its scope. If the act or omission does not take place in the UK, but the person’s act or omission would constitute an offense if carried out there and the person has a close connection with the UK, an offense will still have been committed.

The Bribery Act 2010 is comprised of four offenses that cover (i) individuals, companies and partnerships that give, promise or offer bribes, (ii) individuals, companies and partnerships that request, agree to receive or accept bribes, (iii) individuals, companies and partnerships that bribe foreign public officials, and (iv) companies and partnerships that fail to prevent persons acting on their behalf from paying bribes. The penalties imposed under the Bribery Act 2010 depend on the offence committed, harm and culpability and penalties range from unlimited fines to imprisonment for a maximum term of ten years and in some cases both.

Regulations in the UK and Other Markets

The UK formally left the EU on January 31, 2020 and EU laws now only apply to the UK in respect of Northern Ireland as laid out in the Protocol on Ireland and Northern Ireland and as amended by the Windsor Framework sets out a long-term set of arrangements for the supply of medicines into Northern Ireland. The EU and the UK agreed on a trade and cooperation agreement (“TCA”), which includes provisions affecting the life sciences sector (including on customs and tariffs). There are some specific provisions concerning pharmaceuticals, including the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP issued documents. The TCA does not, however, contain wholesale mutual recognition of UK and EU pharmaceutical regulations and product standards.

The UK government has adopted the Medicines and Medical Devices Act 2021 (the “MMDA”) to enable the UK’s regulatory frameworks to be updated following the UK’s departure from the EU. The MMDA introduces regulation-making, delegated powers covering the fields of human medicines, clinical trials of human medicines, veterinary medicines and medical devices. The MHRA has since been consulting on future regulations for medicines and medical devices in the UK.

~~The~~To ~~MMDA~~be ~~supplements~~used ~~the~~or UKsold ~~Medical~~in ~~Devices Regulations 2002 (~~the ~~“Regulations”)~~UK, ~~which~~a ~~are~~drug ~~based~~must onhave ~~the~~a EUvalid ~~Medical~~MA ~~Devices~~granted ~~Directive~~through ~~as amended to reflect~~ the ~~United~~national ~~Kingdom’s~~application ~~post-Brexit regulatory regime~~process. ~~Notably,~~National ~~the~~applications ~~Regulations~~are dogoverned ~~not include any of the revisions that have been made~~ by the EUHuman ~~Medical~~Medicines ~~Devices~~Regulations ~~Regulation~~ (~~EU)~~SI ~~2017~~2012/~~745,~~1916). ~~which~~Applications ~~has~~are ~~gained~~made ~~full~~electronically ~~application~~through inthe ~~all~~Medicines EUand ~~Member~~Healthcare ~~States~~products ~~since~~Regulatory ~~May~~Agency ~~26,~~(“MHRA”) ~~2021~~Submissions ~~but~~Portal. isThe ~~not~~MHRA ~~applicable~~operates infixed ~~the~~submission UKand asassessment ~~“retained~~timetables ~~law”.~~for ~~Additionally,~~innovative ~~the~~medicines ~~MHRA~~applications ~~launched~~to afacilitate ~~comprehensive~~ consultation ~~in 2021~~ with ~~proposals~~its tostatutory ~~amend~~advisory committee, the ~~regulatory~~Commission ~~framework~~on ~~for~~Human ~~medical~~Medicines ~~devices in the United Kingdom~~(CHM). The ~~stated~~MHRA ~~objectives~~assessment ofprocedure ~~the~~for ~~proposals~~a ~~include~~marketing ~~expansion~~authorization ofapplication ~~the scope of the Regulations~~ (~~for~~MAA) ~~example,~~involves byan ~~expanding~~initial ~~the in vitro diagnostic medical device definition to include software and other products~~evaluation, including ~~products~~orphan ~~without~~designation anif ~~intended~~applicable, ~~medical~~and ~~purpose~~consultation ~~but~~ with ~~similar~~expert ~~functioning~~advisory ~~and~~groups ~~risk~~as ~~profiles)~~needed. ~~and~~By ~~potentially~~Day ~~through~~90, ~~use~~applicants ofreceive ~~internationally~~a ~~recognized~~consolidated ~~definitions~~request (for ~~example,~~information ~~by excluding products that contain viable biological substances and excluding food~~(RFI), ~~remove~~which ~~trade~~pauses ~~barriers, further~~ the ~~availability~~review ofclock ~~medical~~until ~~devices~~a ~~and~~complete ~~improve~~response ~~the~~is ~~favorability~~submitted ~~of the UK market~~electronically. ~~The~~Responses ~~consultation~~are ~~period~~assessed ~~closed~~by onDay ~~November 25~~150, ~~2021~~with ~~and~~further onRFIs ~~June~~issued ~~26,~~for ~~2022,~~minor ~~the~~issues ~~MHRA~~or ~~published~~ a ~~response~~CHM toletter ~~its~~for ~~consultation,~~major ~~which~~objections. ~~sets~~Each ~~out~~subsequent ~~the~~RFI ~~proposed~~requires ~~new~~a UKcomplete ~~regulatory~~response ~~framework~~within ~~for~~three ~~medical~~months, ~~devices~~ and inthe ~~vitro~~clock ~~diagnostic~~is ~~medical~~restarted ~~devices~~upon submission. ~~The~~Applicants ~~proposals~~may ~~are~~make ~~intended~~written or oral representations to ~~improve~~the ~~patient~~CHM ~~safety~~if ~~and~~major ~~public~~objections ~~health~~remain. ~~through~~Final ~~appropriate~~compliance ~~regulatory~~checks ~~oversight,~~are ~~improve~~conducted ~~the~~once ~~traceability~~all ofissues ~~medical~~are ~~devices~~resolved, ~~improve~~and the ~~regulation~~MHRA ofissues ~~the~~a ~~rules~~grant ~~governing~~or ~~software~~refusal ~~and~~letter AIspecifying asany ~~medical~~conditions ~~devices~~ and ~~introduce~~the ~~alternative~~MA ~~routes~~expiry todate. ~~market~~The toentire ~~ensure~~assessment ~~the~~process UKis ~~aligns~~designed ~~with~~to ~~any~~be ~~superior~~completed ~~international~~within ~~best~~210 ~~practices.~~calendar ~~Core~~days, ~~aspects~~excluding ofany ~~the~~procedural ~~new~~clock-stops ~~framework~~for ~~are~~additional ~~expected~~information torepresentations. ~~apply~~Orphan ~~from~~drug ~~July~~designation 1,is ~~2025~~determined ~~with~~at ~~appropriate transitional measures and~~ the ~~introduction~~time of ~~secondary~~granting ~~legislation~~the MA.

In addition, the MHRA 150-day accelerated review is a specialized, fast-track national MA procedure designed for innovative medicines, new active substances, and biosimilars, aiming for a decision in 150 "clock-on" days rather than the standard 210. It requires high-quality applications, typically involving one round of questions and a 60-day cool-down period for responses.

On August 30, 2023, the MHRA published detailed guidance on its recently announced new International Recognition Procedure (“IRP”) for MAAs. The IRP applies from January 1, 2024 and replaces existing EU decision reliance procedure to apply for authorizations from seven international regulators (e.g. Health Canada, Swissmedic, FDA and EMA, among others). The IRP allows the MHRA to take into account the assessment and decision-making of the "Reference Regulators” to perform a targeted assessment of IRP applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust. There exist two recognition timetables for new IRP MAAs: IRP Route A (60 days) and IRP Route B (110

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days), both starting from validation. Eligibility is determined via an applicant-completed form six weeks before submission. Recognition A applies to applications with Reference Regulator approval within the past two years, with no clock-stop, but may revert to Recognition B if major objections arise. IRP Route B covers Reference Regulatory approvals within the past ten years (or exceptionally older) and applies if specific criteria, such as conditional approvals, manufacturing changes, or UK-specific requirements, are met. IRP Route B allows for consultation with the CHM and aligns with CHM dates for new active substances. Applications not eligible for either timetable may be submitted as full national applications if MHRA requirements are met. IRP can be used for post-authorization measures including line extensions, variations, and renewal applications.

There will be no pre-MA orphan designation. Instead, the MHRA will review applications for orphan designation in parallel to the corresponding MA application. The criteria are essentially the same as the EU rules, but have been tailored for the market, i.e., the prevalence of the condition in UK, rather than the EU, must not be more than five in 10,000. Should an orphan designation be granted, the period or market exclusivity will be set from the date of first approval of the product in Great Britain.

For other countries outside of the EU, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country. In all cases, again, the clinical trials must be conducted in accordance with GCPs and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension of clinical trials, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

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Additional Regulation

In addition to the foregoing, local, state and federal laws, including in the United States and Israel, regarding such matters as safe working conditions, manufacturing practices, environmental protection, fire hazard control and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act and the Toxic Substances Control Act, affect our business. These and other laws govern our use, handling and disposal of various biological, chemical and radioactive substances used in, and wastes generated by, our operations. If our operations result in contamination of the environment or expose individuals to hazardous or biohazardous substances, we could be liable for damages, environmental remediation, and/or governmental fines. We believe that we are in material compliance with applicable environmental laws and occupational health and safety laws that continued compliance therewith will not have a material adverse effect on our business. We cannot predict, however, how changes in these laws may affect our future operations. We may incur significant costs to comply with such laws and regulations now or in the future.

Corporate Information

We were formed as a Limited Liability Company (“LLC”) in Delaware on December 16, 2013 under the name Aeglea BioTherapeutics Holdings, LLC and were converted from a Delaware LLC to a Delaware corporation on March 10, 2015. Pursuant to an Agreement and Plan of Merger, dated June 22, 2023, by and among us, Aspen Merger Sub I, Inc., a Delaware corporation and a wholly owned subsidiary of the Company, Sequoia Merger Sub II, LLC, a Delaware limited liability company and one of our wholly owned subsidiaries, and Pre-Merger Spyre, we acquired Pre-Merger Spyre (the "Asset Acquisition") and on November 27, 2023, we completed our corporate rebranding, changing our name to Spyre Therapeutics, Inc. Through the Asset Acquisition, we received the option to license the intellectual property rights related to four research programs pursuant to the Paragon Agreement, and subsequently executed license agreements for our α4β7, TL1A, and IL-23 programs.

Our common stock currently trades on The Nasdaq Global Select Market under the ticker symbol "SYRE." Our principal executive offices are located at 221 Crescent Street, Building 23, Suite 105, Waltham, MA 02453 and our telephone number is (617) 651-5940. Our website is www.spyre.com. The information on, or that can be accessed through, our website is not part of this Annual Report on Form 10-K and is not incorporated by reference herein. We have included our website address in this Annual Report on Form 10-K solely as an inactive textual reference.

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Available Information

We file Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other information with the U.S. Securities and Exchange Commission ("SEC"). Our filings with the SEC are available free of charge on the SEC’s website at www.sec.gov and on our website, spyre.com, under the “Investors & Media” tab as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC.

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Item 1A. Risk Factors

The following summarizes the principal factors that make an investment in the Company speculative or risky, all of which are more fully described in the Risk Factors section below. This summary should be read in conjunction with the Risk Factors section and should not be relied upon as an exhaustive summary of the material risks facing our business. The occurrence of any of these risks, could harm our business, financial condition, results of operations and/or growth prospects or cause our actual results to differ materially from those contained in forward-looking statements we have made in this Annual Report on Form 10-K and those we may make from time to time. You should consider all of the risk factors described in our public filings when evaluating our business.

Risk Factor Summary

Risks Related to Our Financial Condition and Capital Requirements

•We will not be able to continue as a going concern if we are unable to raise additional capital when needed and raising additional capital may cause dilution to our stockholders and restrict our operations.

•We have never generated any revenue from product sales and may never be profitable.

•We anticipate that we will continue to incur significant losses for the foreseeable future.

Risks Related to Discovery, Development and Commercialization

•Our programs are in clinical and ~~nonclinical~~preclinical stages of development and may fail or suffer delays or may be more costly than anticipated for various reasons, including but not limited to delays or failures in achieving alignment with regulatory authorities on ~~trial designs and~~ interpretation of data and its sufficiency to support safety and efficacy of our product candidates, ~~patient~~participant recruitment or other clinical trial ~~challenges,~~ or ~~unanticipated drug~~ supply ~~disruptions~~challenges.

•We are substantially dependent on the success of the SPY001, SPY002, SPY072 and SPY003 programs, alone or in combination, and may fail to achieve our ~~projected~~ development goals in the time frames we expect.

•Any drug delivery device used may have its own regulatory development, supply, and other risks.

•We may not be successful in building a pipeline of product candidates with commercial value.

•Our studies and trials may be insufficient to support regulatory approval of any product candidates.

•We may not be successful in discovering, developing and commercializing our ~~intraportfolio~~intra-portfolio investigational drug combinations to achieve superior outcomes relative to the use of other therapies.

•Preliminary or “topline” data from our clinical trials may change as more data becomes available.

•Our current or future clinical trials may reveal significant adverse events or undesirable side effects.

•We may fail to capitalize on more profitable or potentially successful product candidates.

•Our products may not achieve regulatory approval, market acceptance or commercial success.

•Our programs may compete with each other and they face third-party program competition.

•~~The~~Regulatory ~~FDA~~authorities may not accept data from clinical trials we conduct at sites outside the United States or other jurisdiction.

Risks Related to Government Regulation

•We may not be able to achieve our timelines or obtain timely regulatory approvals of product candidates.

•We may not be able to meet requirements for chemistry, manufacturing and control of our programs.

•Our product candidates may face competition sooner than anticipated based on rules and regulations that may apply or government decisions with respect to our intellectual property.

•Even if we receive regulatory approval, we will be subject to extensive ongoing regulatory obligations.

•We may ~~face~~be ~~difficulties~~negatively ~~from~~impacted by healthcare ~~and other~~ legislative reform measures and other changes in law.

•Our potential revenue may be adversely affected due to unfavorable regulations, laws and/or policies.

•We may face criminal liability or other consequences if we violate U.S. and foreign trade regulations.

•Any accelerated review designations we may pursue may not hasten development or regulatory review.

38•We may be negatively impacted by disruptions at the FDA and other government agencies, including as a result of a government shutdown.

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Risks Related to Our Intellectual Property

•We may fail in obtaining, maintaining and protecting our patents and other proprietary rights.

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•We may be subject to patent infringement claims or may need to file such claims.

•We may be subject to claims of wrongful hiring of employees or wrongful use of confidential information.

•Our patents and our ability to protect our products may be impaired by changes to patent laws.

•Our patent protection could be reduced or eliminated for non-compliance with legal requirements.

•We may fail to identify or interpret relevant third-party patents.

•We may become subject to claims challenging the inventorship or ownership of our intellectual property.

•Patent terms may be inadequate to protect our competitive position of our programs.

•Our technology licensed from various third parties may be subject to retained rights or may be affected by failure to comply with obligations in license agreements or other disruptions to business relationships with licensors resulting in loss of license rights that are important to our business.

•We have limited foreign intellectual property rights and may not be able to protect our intellectual property and proprietary rights throughout the world.

•The intellectual property landscape around engineered antibodies is highly dynamic, and third parties may initiate legal proceedings alleging that we are infringing, misappropriating, or otherwise violating their intellectual property rights, the outcome of which would be uncertain and may prevent, delay or otherwise interfere with our product discovery and development efforts.

Risks Related to Our Reliance on Third Parties

•We may fail to maintain collaborations and licensing arrangements with third parties that we rely on.

•Third parties we rely on for nonclinical studies and clinical trials may fail to satisfy contractual duties.

•We may be unable to use third-party manufacturing sites, our third-party manufacturers may encounter difficulties in production or we may need to switch or create third-party manufacturer redundancies.

Risks Related to Employee Matters, Managing Growth and Other Risks Related to Our Business

•We may experience difficulties in managing the growth of our organization.

•We may fail to attract or retain highly qualified personnel.

•Our ability to operate in foreign markets is subject to regulatory burdens, risks and uncertainties.

•Our estimates of market opportunity may be inaccurate and our business may not grow at similar rates.

•Our employees or third parties may engage in misconduct or other improper activities.

•We may be impacted by information security incidents, cybersecurity or data breaches or other improper access to our data that could have a negative impact on our business or reputation.

•Our expanding use of AI exposes us to operational, regulatory, legal, and ethical risks that could adversely affect our business, reputation, financial condition, and results of operations.

•Our ability to use our net operating loss carryforwards and certain other tax attributes may be limited.

•We may fail to comply with privacy, data security, safety and other regulations despite compliance efforts.

•We may be subject to adverse legislative or regulatory tax changes.

•We may fail to realize the benefits of our business or product acquisitions or our strategic alliances.

Risks Related to Our Common Stock

•The market price of our common stock has historically been volatile and may drop in the future.

•Our certificate of incorporation, Delaware law and certain contracts include anti-takeover provisions.

•We do not anticipate paying any dividends in the foreseeable future.

•Future sales and issuances of equity/debt may dilute stockholders and/or result in a drop in our stock price.

•Our principal stockholders own a significant percentage of our stock.

General Risk Factors

•Our product liability insurance may be insufficient to cover costly and damaging liability claims.

•Litigation costs and the outcome of litigation could have a material adverse effect on our business.

•We continue to incur significant costs for compliance with public company laws and regulations.

•WeOur ~~may~~failure ~~fail~~ to maintain proper and effective internal controls. Wemay ~~have identified a material weakness in our internal control over financial reporting over financial reporting which could, if not remediated,~~ adversely affect our ability to report our financial condition and results of operations in a timely and accurate manner, decrease investor confidence in us, and reduce the value of our common stock. For example, in the fourth quarter of 2024, we identified a material weakness in our internal control over financial reporting which resulted in restatements of our previously-issued financial statements to amend certain net loss per share disclosures.

•Our business could be adversely affected by macroeconomic conditions, including geopolitical unrest.

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Risks Related to Our Financial Condition and Capital Requirements

We will need to raise additional capital, and if we are unable to do so when needed, we will not be able to continue as a going concern.

As of December 31, ~~2024~~2025, we had $~~603~~756.1 5 million of cash, cash equivalents, and marketable securities. We will need to raise additional capital to continue to fund our operations in the future. If we are unable to raise additional capital when needed, we will not be able to continue as a going concern.

Developing our product candidates requires a substantial amount of capital. We expect our research and development expenses to increase in connection with our ongoing activities, particularly as we advance our product candidates through clinical trials. We will need to raise additional capital to fund our operations and such funding may not be available to us on acceptable terms, or at all, and such funding may become even more difficult to obtain due to macroeconomic conditions, including rising interest rates, tariffs and ~~downturns~~trade restrictions, global conflicts, and other conditions that could result in volatility in the U.S. capital markets and the biotechnology sector in general. Competition for additional capital among biotechnology companies may be particularly intense during economic ~~downturns~~uncertainty. We may be unable to raise capital through public offerings of our common stock and may need to turn to alternative financing arrangements. Such arrangements, if we pursue them, could involve sources of funding, such as issuances of secured debt and structured revenue-based financing, and/or issuances of one or more types of securities, including common stock, preferred stock, convertible debt, warrants to acquire common stock or other securities. These securities could be issued at or below the then prevailing market price for our common stock. In addition, if we issue secured debt or debt securities, the holders of the debt would have a claim to our assets that would be superior to the rights of stockholders until the principal, accrued and unpaid interest and any premium or make-whole has been paid. Interest on any newly-issued debt securities and/or newly-incurred borrowings would increase our operating costs and reduce our net income (or increase our net loss), and these impacts may be material. If the issuance of new securities results in diminished rights to holders of our common stock, the market price of our common stock could be materially and adversely affected.

We do not currently have any products approved for sale and do not generate any revenue from product sales. Accordingly, we expect to rely primarily on equity and/or debt financings to fund our continued operations. Our ability to raise additional funds will depend, in part, on the success of our nonclinical studies and clinical trials and other product development activities, regulatory events, our ability to identify and enter into licensing or other strategic arrangements, and other events or conditions that may affect our value or prospects, as well as factors related to political, financial, economic and market conditions, many of which are beyond our control. There can be no assurances that sufficient funds will be available to us when required or on acceptable terms, if at all.

If we are unable to raise additional capital when required or on acceptable terms, we may be required to:

•significantly delay, scale back, or discontinue the development or commercialization of our product candidates;

•seek strategic partnerships, or amend existing partnerships, for research and development programs at an earlier stage than otherwise would be desirable or that we otherwise would have sought to develop independently, or on terms that are less favorable than might otherwise be available in the future;

•dispose of technology assets, or relinquish or license on unfavorable terms, our rights to technologies or any of our product candidates that we otherwise would seek to develop or commercialize ourselves;

•pursue the sale of our company to a third party at a price that may result in a loss on investment for our stockholders; or

•file for bankruptcy or cease operations altogether (and face any related legal proceedings).

Any of these events could have a material adverse effect on our business, operating results and prospects. Even if successful in raising new capital, we could be limited in the amount of capital we raise due to investor demand restrictions placed on the amount of capital we raise or other reasons.

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Additionally, any capital raising efforts are subject to significant risks and contingencies, as described in more detail under the risk factor titled “Raising additional capital may cause dilution to our stockholders, restrict our operations, or require us to relinquish rights.”

We have never generated any revenue from product sales and may never be profitable.

We have no products approved for commercialization and have never generated any revenue from product sales. Our ability to generate revenue and achieve profitability depends on our ability, alone or with strategic collaborators, to successfully complete the development of, and obtain the regulatory and marketing approvals necessary to commercialize one or more of our product candidates. We do not anticipate generating revenue from product sales for the foreseeable future. Our ability to generate future revenue from product sales depends heavily on our success in many areas, including but not limited to:

•completing research and development of our product candidates;

•obtaining regulatory and marketing approvals for our product candidates for which we complete clinical trials;

•manufacturing product candidates and establishing and maintaining supply and manufacturing relationships with third parties that are commercially feasible, meet regulatory requirements and our supply needs in sufficient quantities to meet market demand for our product candidates, if approved;

•qualify for adequate coverage and reimbursement by government and third-party payors for any product candidates for which we obtain regulatory and marketing approval;

•marketing, launching, and commercializing product candidates for which we obtain regulatory and marketing approval, either directly or with a collaborator or distributor;

•gaining market acceptance of our product candidates as treatment options;

•addressing any competing products and technological and market developments;

•implementing internal systems and infrastructure, as needed;

•protecting and enforcing our intellectual property rights, including patents, trade secrets, and know-how;

•negotiating favorable terms in any collaboration, licensing, or other arrangements into which we may enter;

•obtaining coverage and adequate reimbursement from third-party payors and maintaining pricing for our product candidates that supports profitability; and

•attracting, hiring, and retaining qualified personnel.

Even if one or more of the product candidates that we develop is approved for commercial sale, we anticipate incurring significant costs associated with commercializing any approved product candidate. Our expenses could increase beyond expectations if we are required by regulatory authorities to perform clinical and other studies in addition to those that we are currently conducting or anticipate. Even if we are able to generate revenues from the sale of any approved products, we may not become profitable and may need to obtain additional funding to continue operations. Portions of ~~the~~our research programs with respect to which we have signed a license agreement, exercised the Option to acquire intellectual property license rights to or have the Option to acquire intellectual property license rights to pursuant to the Paragon Agreement may be in-licensed from third parties, which make the commercial sale of such in-licensed products potentially subject to additional royalty and milestone payments to such third parties. We will also have to develop or acquire manufacturing capabilities or continue to contract with contract manufacturers in order to continue development and potential commercialization of our product candidates. For instance, if the costs of manufacturing our ~~drug~~biologic product are not commercially feasible, we will need to develop or procure our ~~drug~~biologic product in a commercially feasible manner in order to successfully commercialize a future approved product, if any. Additionally, if we are not able to generate revenue from the sale of any approved products, we may never become profitable.

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We have historically incurred losses, have a limited operating history on which to assess our business, and anticipate that we will continue to incur significant losses for the foreseeable future.

We are a biopharmaceutical company with a limited operating history. Since inception, we have incurred significant operating losses. For the years ended December 31, ~~2024~~2025, ~~2023~~2024 and ~~2022~~2023, we reported a net loss of $~~208~~155.02 million, $~~338~~208.80 million and $83338.8 million, respectively. As of December 31, ~~2024~~2025, we had an ~~accumulated deficit of $972.4 million. We will need to raise substantial additional capital to continue to fund our operations in the future.~~

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accumulated deficit of $1.1 billion. We will need to raise substantial additional capital to continue to fund our operations in the future.

Failure to raise capital as and when needed, on favorable terms or at all, would have a negative impact on our financial condition and our ability to develop our product candidates. Changing circumstances may cause us to consume capital significantly faster or slower than we currently anticipate. If we are unable to acquire additional capital or resources, we will be required to modify our operational plans to complete future milestones and we may be required to delay, limit, reduce or eliminate development or future commercialization efforts of product candidates and/or programs. We have based these estimates on assumptions that may prove to be wrong, and we could exhaust our available financial resources sooner than we currently anticipate. We may be forced to reduce our operating expenses and raise additional funds to meet our working capital needs, principally through the additional sales of our securities or debt financings or entering into strategic collaborations.

We have devoted substantially all of our financial resources to identify, acquire, and develop our product candidates, including conducting nonclinical and clinical development of the legacy rare disease clinical trials conducted by us prior to the Asset Acquisition and the nonclinical and clinical development of our current pipeline, and providing general and administrative support for our operations. To date, we have funded our operations primarily from the sale and issuance of convertible preferred and common equity securities, pre-funded warrants, the collection of grant proceeds, and the licensing of our product rights for commercialization of pegzilarginase in Europe and certain countries in the Middle East. The amount of our future net losses will depend, in part, on the rate of our future expenditures and our ability to obtain funding through equity or debt financings, strategic collaborations, or grants. Biopharmaceutical product development is a highly speculative undertaking and involves a substantial degree of risk. We expect our losses to increase as our product candidates enter more advanced clinical trials. It may be several years, if ever, before we complete pivotal clinical trials or have a product candidate approved for commercialization. We expect to invest significant funds into the research and development of our current product candidates to determine the potential to advance these product candidates to regulatory approval.

If we obtain regulatory approval to market a product candidate, our future revenue will depend upon the size of any markets in which our product candidates may receive approval, and our ability to achieve sufficient market acceptance, pricing, coverage and adequate reimbursement from third-party payors, and adequate market share for our product candidates in those markets. Even if we obtain adequate market share for our product candidates, because the potential markets in which our product candidates may ultimately receive regulatory approval could be very small, we may never become profitable despite obtaining such market share and acceptance of our products.

We expect to continue to incur significant expenses and increasing operating losses for the foreseeable future and our expenses will increase substantially if and as we:

•continue the nonclinical and clinical development of our product candidates;

•continue efforts to discover and develop new product candidates;

•continue the manufacturing of our product candidates or increase volumes manufactured by third parties;

•advance our product candidates into larger, more expensive clinical trials;

•initiate additional nonclinical studies or clinical trials for our product candidates;

•seek regulatory and marketing approvals and reimbursement for our product candidates;

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•establish a sales, marketing, and distribution infrastructure to commercialize any products for which we may obtain marketing approval and market for ourselves;

•seek to identify, assess, acquire, and/or develop other product candidates;

•make milestone, royalty, or other payments under third-party license agreements;

•seek to maintain, protect, and expand our intellectual property portfolio;

•seek to attract and retain skilled personnel; and

•experience any delays or encounter issues with the development and potential for regulatory approval of our clinical and product candidates such as safety issues, manufacturing delays, clinical trial accrual delays, longer follow-up for planned studies or trials, additional major studies or trials, or supportive trials necessary to support marketing approval.47

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•experience any delays or encounter issues with the development and potential for regulatory approval of our clinical and product candidates such as safety issues, manufacturing delays, clinical trial accrual delays, longer follow-up for ongoing or planned studies or trials, additional major studies or trials, or supportive trials necessary to support marketing approval.

Further, the net losses we incur may fluctuate significantly from quarter to quarter and year to year, such that a period-to-period comparison of our results of operations may not be a good indication of our future performance.

Raising additional capital may cause dilution to our stockholders, restrict our operations, or require us to relinquish rights.

Until such time, if ever, as we can generate substantial revenue from the sale of our product candidates, we expect to finance our cash needs through a combination of equity offerings, debt financings and license and development agreements. To the extent that we raise additional capital through the sale of equity securities or convertible debt securities, the ownership interest of our stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect your rights as a holder of common stock. Debt financing and preferred equity financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures, or declaring dividends.

If we raise additional funds through collaborations, strategic alliances or marketing, distribution or licensing arrangements with third parties, we may be required to relinquish valuable rights to our research programs or product candidates or grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings or other arrangements with third parties when needed, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts or grant rights to third parties to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

To the extent that we raise additional capital through the sale of equity, including pursuant to any sales under convertible debt or other securities convertible into equity, the ownership interest of our stockholders will be diluted, and the terms of these new securities may include liquidation or other preferences that adversely affect the rights of our stockholders. For instance, in December 2023, we sold an aggregate of 6,000,000 shares of our common stock and 150,000 shares of our Series B Preferred Stock pursuant to a private placement to certain investors for gross proceeds of approximately $180 million, ~~and~~ in March 2024, we sold an aggregate of 121,625 shares of our Series B Preferred Stock pursuant to a private placement to certain investors for gross proceeds of approximately $180 million and in October 2025, we sold 17,094,594 shares of our common stock in an underwritten public offering for gross proceeds of approximately $316 million. Subject to certain beneficial ownership limitations set by each holder of Series B Preferred Stock, each share of Series B Preferred Stock is convertible into an aggregate of 40 shares of our common stock. Following stockholder approval of the Series B Conversion Proposal, 254,958 shares of Series B Preferred Stock automatically converted to 10,198,320 shares of common stock; 16,667 shares of Series B Preferred Stock did not automatically convert due to beneficial ownership limitations and remain outstanding as of December 31, ~~2024 due to beneficial ownership limitations~~2025.

Debt financing, if available, would likely involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures, making additional product acquisitions, or declaring dividends. If we raise additional funds through strategic collaborations or licensing arrangements with third parties, we may have to relinquish valuable rights to our product candidates or future revenue streams or grant licenses on terms that are not favorable to us. We cannot be assured that we will be able to obtain additional funding if and when necessary to fund our entire portfolio of product candidates to meet our projected plans. If we are unable to obtain funding on a timely basis, we may be required to delay or discontinue one or more of our development programs or the commercialization of any product candidates or be unable to expand our operations or otherwise capitalize on potential business opportunities, which could materially harm our business, financial condition, and results of operations.

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be assured that we will be able to obtain additional funding if and when necessary to fund our entire portfolio of product candidates to meet our projected plans. If we are unable to obtain funding on a timely basis, we may be required to delay or discontinue one or more of our development programs or the commercialization of any product candidates or be unable to expand our operations or otherwise capitalize on potential business opportunities, which could materially harm our business, financial condition, and results of operations.

Risks Related to Discovery, Development and Commercialization

~~We face competition from entities that have developed or may develop programs for the diseases addressed by our product candidates.~~ 48

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We face competition from entities that have developed or may develop programs for the diseases and/or mechanisms of action targeted by our product candidates.

The development and commercialization of drugs is highly competitive. Our product candidates, if approved, will face significant competition and our failure to effectively compete may prevent us from achieving significant market penetration. We compete with a variety of multinational biopharmaceutical companies, specialized biotechnology companies and emerging biotechnology companies, as well as academic institutions, governmental agencies, and public and private research institutions, among others. Many of the companies with which we are currently competing or will compete against in the future have significantly greater financial resources and expertise in research and development, manufacturing, nonclinical testing, clinical trial conduct, regulatory approvals, and marketing than we do. Mergers and acquisitions in the pharmaceutical and biotechnology industry may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites, recruiting participants for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our product candidates.

Our competitors have developed, are developing or will develop programs and processes competitive with our programs and processes. Competitive therapeutic treatments include those that have already been approved and accepted by the medical community and any new treatments. Our success will depend partially on our ability to develop and commercialize products that have a competitive safety, efficacy, dosing and/or presentation ~~profile~~profiles. Our commercial opportunity and success will be reduced or eliminated if competing products are safer, more effective, have a more attractive dosing profile or presentation or are less expensive than the products we develop, or if our competitors develop competing products or if biosimilars enter the market more quickly than we do and are able to gain market acceptance. See the section titled “Business – Competition” in this Annual Report ~~on Form 10-K~~ for more discussion about our competitors.

Furthermore, adverse events or disappointing results in clinical trials of third parties, including our competitors developing product candidates that target similar mechanisms of action and/or in the same indications as our product candidates, could reduce expectations regarding the potential success or perceived benefits of any of our programs, increase regulatory scrutiny of our product candidates, decrease confidence of current or potential trial participants and clinical trial collaborators in our investigational programs and/or have a negative impact on collaborations or demand for any product we may develop. These events also could result in the suspension, discontinuation, or clinical hold of or modification to our clinical trials. If public perception is influenced by claims that the use of therapies with shared or similar characteristics as ours is unsafe, ineffective or otherwise fails to meet expectations, our product candidates may not be accepted or favored by the general public, the medical community or the investment community and potential clinical trial subjects may be discouraged from enrolling in our clinical trials or may discontinue their participation in our clinical trials. Negative developments could result in reduced probability of success of clinical trials involving our product candidates, challenges enrolling clinical trial participants, greater governmental regulation, stricter labeling requirements, decreased market potential and potential regulatory delays in the testing or approvals of our product candidates.

In addition, because of the competitive landscape for inflammatory and immunology ("I&I") indications, we may also face competition for clinical trial enrollment. Clinical trial enrollment will depend on many factors, including if potential clinical trial participants choose to undergo treatment with approved products or enroll in competitors’ ongoing clinical trials for programs that are under development for the same indications as our programs. An increase in the number of approved products for the indications we are targeting with our programs may further exacerbate this competition. Our inability to enroll a sufficient number of participants could, among other things, delay our development timeline, which may further harm our competitive position.

Our product candidates are in clinical and ~~nonclinical~~preclinical stages of development and may fail in development or suffer delays that materially and adversely affect their commercial viability. If we or our current or future collaborators are unable to complete development of, or commercialize our product candidates, or experience significant delays in doing so, our business will be materially harmed.

We have no products on the market and all of our product candidates are in clinical or nonclinical stages of development, and we have not completed any clinical trials. As a result, we expect it will be many years before we commercialize any product candidate, if ever. Our ability to achieve and sustain profitability depends on obtaining regulatory approvals for, and successfully commercializing, our product candidates, either alone or with third parties, and we cannot guarantee that we will ever obtain regulatory approval for any of our product candidates. We have not yet demonstrated our ability to complete any clinical trials, obtain regulatory approvals, manufacture a commercial-scale product or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful product commercialization. Before obtaining regulatory approval for the commercial distribution of our product candidates, we or an existing or future 49

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We have no products on the market and all of our product candidates are in clinical or preclinical stages of development. As a result, we expect it will be many years before we commercialize any product candidate, if ever. Our ability to achieve and sustain profitability depends on obtaining regulatory approvals for, and successfully commercializing, our product candidates, either alone or with third parties, and we cannot guarantee that we will ever obtain regulatory approval for any of our product candidates. We have not yet demonstrated our ability to obtain regulatory approvals, manufacture a commercial-scale product or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful product commercialization. Before obtaining regulatory approval for the commercial distribution of our product candidates, we or an existing or future collaborator must conduct extensive nonclinical tests and clinical trials to demonstrate the safety, potency and ~~efficacy~~purity ~~in humans~~ of our ~~programs~~current and future product candidates.

We or our collaborators may experience delays in initiating or completing nonclinical studies or clinical trials. We or our collaborators also may experience numerous unforeseen events during, or as a result of, any current or future nonclinical studies and clinical trials that we ~~could~~ conduct that could delay or prevent our ability to achieve our development timelines, receive marketing approval or commercialize our current product candidates or any future product candidates, including:

•regulators, such as the U.S. Food and Drug Administration ("FDA"), or ethics committees (“ECs”)/institutional review boards (“IRBs”) may not authorize us or our investigators to commence a clinical trial, or conduct a clinical trial at a prospective trial site or as otherwise planned;

•we may experience delays in reaching, or fail to reach, agreement on acceptable terms with prospective trial sites and prospective contract research organizations (“CROs”), the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites, and any CRO personnel changes could lead to operational delays or complications;

•clinical trial sites may deviate from trial protocol or drop out of a clinical trial;

•clinical trials of any product candidates may fail to demonstrate safety or efficacy, or produce negative or inconclusive results, or may otherwise fail to improve on the existing standard of care, and we may decide, or regulators may require us, to conduct additional nonclinical studies or clinical trials, or we may decide to abandon product development programs;

•the number of participants required for clinical trials of any product candidates may be larger than we anticipate and enrollment in these clinical trials may be slower than we anticipate or participants may drop out of these clinical trials or fail to return for post-treatment follow-up at a higher rate than we anticipate;

•our CROs or other third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at all, or may deviate from the clinical trial protocol or drop out of the trial, which may require that we add new clinical trial sites or investigators;

•We may fail to adhere to clinical trial protocols or fail to perform in accordance with the FDA’s or any other regulatory authority’s good clinical practice (“GCP”) requirements or applicable regulatory guidelines in other countries or our clinical trial protocols may require changes;

•we may elect to, or regulators and/or ECs/IRBs may require that we or our investigators materially modify, suspend or terminate clinical research or trials for various reasons, including noncompliance with regulatory requirements or a finding that the participants in our trials are being exposed to unacceptable health risks;

•we may select clinical endpoints that require prolonged periods of observation or analyses of resulting data;

•we may experience delays if we or our CMOs are required to make changes to manufacturing processes or us to make any necessary changes to such manufacturing process;

•we may experience delays in identifying, recruiting and training suitable clinical investigators and their study teams;

•the cost of clinical trials of any of our programs may be greater than we anticipate;

•the quality of our product candidates or other materials necessary to conduct clinical trials of our product candidates may be inadequate to initiate or complete a given clinical trial;

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•we may be unable to manufacture sufficient quantities of our product candidates for use in clinical trials;

•reports from clinical testing of other therapies may raise safety or efficacy concerns about our programs;

•the FDA or other regulatory authorities may not agree with our interpretation of the results of clinical trials or non-clinical studies or our clinical trial designs and plans;

•we may fail to establish an appropriate safety profile for a product candidate based on clinical or nonclinical data for such product candidates as well as data emerging from other therapies in the same class as our product candidates; and

•the FDA or other regulatory authorities may require us to submit additional data such as long-term toxicology studies, additional clinical data or additional manufacturing data or impose other requirements before permitting us to initiate clinical trials or approving marketing/commercial sales.

45Commencing clinical trials in the United States and in other countries is subject to acceptance by the FDA and other regulatory authorities of an investigational new drug ("IND") application or similar application and finalizing the trial design based on discussions with the FDA or other regulatory authority. In the event that the FDA or other regulatory authority requires us to complete additional nonclinical studies or clinical trials or we are required to satisfy other regulatory authority requests prior to commencing future planned clinical trials, the start of such planned clinical trials may be delayed or such planned clinical trials may be commenced in a modified manner. Even after we receive and incorporate guidance from these regulatory authorities, the FDA or other regulatory authorities could disagree that we have satisfied their requirements to commence any future clinical trial or change their position on the acceptability of our trial design or the clinical endpoints selected, which may require us to complete additional nonclinical studies or clinical trials, delay the enrollment of our clinical trials or impose stricter approval conditions than we currently expect. Additionally, if the results of our nonclinical studies or clinical trials are not positive or are only modestly positive or if there are safety concerns, we may be required to repeat or conduct additional clinical trials or nonclinical studies for our product candidates beyond those that we currently expect. Even if we conduct such additional nonclinical studies or clinical trials or otherwise modify our planned clinical trials, the FDA or other regulatory authorities could determine that the data from our nonclinical studies or clinical trials are insufficient to support the safety and efficacy of our product candidates. There are equivalent processes and risks applicable to clinical trial applications in other countries outside of the United States, which may require us to complete additional nonclinical studies or clinical trials, delay the enrollment of our clinical trials or otherwise modify our planned clinical trials or impose stricter approval conditions than we currently expect. Most product candidates that commence clinical trials are never approved as products, and our current or future clinical trials ultimately may fail to support the approval of our current or any future product candidates.

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Commencing clinical trials in the United States is subject to acceptance by the FDA of an IND or similar application and finalizing the trial design based on discussions with the FDA and other regulatory authorities. In the event that the FDA requires us to complete additional nonclinical studies or clinical trials or we are required to satisfy other FDA requests prior to commencing future planned clinical trials, the start of such planned clinical trials may be delayed or such planned clinical trials may be commenced in a modified manner. Even after we receive and incorporate guidance from these regulatory authorities, the FDA or other regulatory authorities could disagree that we have satisfied their requirements to commence any future clinical trial or change their position on the acceptability of our trial design or the clinical endpoints selected, which may require us to complete additional nonclinical studies or clinical trials, delay the enrollment of our clinical trials or impose stricter approval conditions than we currently expect. Even if we conduct such additional nonclinical studies or clinical trials, the FDA or other regulatory authorities could determine that the data from our nonclinical studies or clinical trials are insufficient to support the safety and efficacy of our product candidates. There are equivalent processes and risks applicable to clinical trial applications in other countries outside of the United States., which may require us to complete additional nonclinical studies or clinical trials, delay the enrollment of our clinical trials or impose stricter approval conditions than we currently expect.

We may not have the financial resources to continue development of, or to modify existing or enter into new collaborations for, a product candidate if we experience any issues that delay or prevent regulatory approval of, or our ability to commercialize, our product candidates. We or our current or future collaborators’ inability to complete development of, or commercialize our product candidates, or significant delays in doing so, could have a material and adverse effect on our business, financial condition, results of operations and prospects.

We are substantially dependent on the success of our ~~three most advanced programs,~~ SPY001, SPY002, SPY072 and SPY003 programs, alone or in combination, and our current and planned clinical trials of such programs may not be successful.

Our future success is substantially dependent on our ability to timely obtain marketing approval for, and then successfully commercialize, our ~~three most advanced programs,~~ SPY001, SPY002 ~~and SPY003~~, ~~alone~~SPY072 ~~or in combination. We exercised our Option with respect to the SPY001, SPY002~~ and SPY003 programs ~~on July 12~~, ~~2023,~~alone December 14, 2023, and June 5, 2024, respectively. Additionally, in May 2024, we signed license agreements with Paragon for rights to royalty-bearing, world-wide, exclusive licenses to develop, manufacture, commercialize or ~~otherwise exploit certain antibodies and products targeting ɑ4β7 integrin (SPY001 program) and TL1A (SPY002 program) and,~~ in October 2024, we signed a license agreement for rights to a royalty-bearing, world-wide, exclusive license to develop, manufacture, commercialize or otherwise exploit certain antibodies and products targeting IL-23 (SPY003 program) in the field of IBDcombination. The SPY003 License Agreement was subsequently amended and restated in February 2025 to, among other things, clarify each party's rights and obligations with respect to license exclusivity and patent prosecution and correct certain clerical errors. We are investing a majority of our efforts and financial resources into the research and development of these programs. We initiated a a Phase 12 ~~clinical~~platform trial ~~in healthy volunteers~~ of SPY001, SPY002 and ~~announced~~SPY003, ~~the~~including ~~dosing~~combinations, offor ~~our~~IBD ~~first participant~~ in ~~June~~the ~~2024. We~~United ~~also~~States ~~initiated~~and acertain ~~Phase~~other 1countries ~~clinical~~beginning ~~trial~~with inSPY001 ~~healthy volunteers of SPY002~~ in ~~the~~May ~~fourth quarter of 2024~~2025. We ~~anticipate~~are ~~initiating~~currently aenrolling ~~Phase~~subjects 1into ~~clinical~~Part ~~trial~~A ~~in healthy volunteers~~ of ~~SPY003 in~~ the ~~first~~Phase ~~quarter~~2 ofUC ~~2025,~~platform ~~subject~~trial ~~to regulatory feedback~~ and ~~approval. We also~~ plan to initiate aenrollment ~~Phase~~into 2Part ~~platform~~B, ~~trial~~which ofincludes ~~our product candidates in IBD beginning with monotherapies in mid-2025 and subsequent planned addition of~~ combination arms, asin ~~well~~our ~~as a~~ Phase 2 ~~clinical~~UC platform trial ofafter ~~SPY002~~Part inA RAcompletes ~~in mid-2025~~enrollment, with each arm subject to regulatory feedback and approval. ~~The~~We ~~success~~also ofinitiated ~~our~~a ~~programs~~Phase is2 ~~dependent~~basket ontrial ~~observing longer half-lives~~ of ~~our~~SPY072 product candidates in humans and comparable or better safety and efficacy profiles than other mAbs currently marketed or in development. We believe these longer half-lives have the potential to result in more favorable dosing schedules for ~~our~~RD, ~~product~~including ~~candidates~~RA, ~~assuming~~PsA ~~they successfully complete clinical development~~ and ~~obtain~~axSpA, ~~marketing approval. This is based~~ in ~~part on~~ the ~~assumption~~United ~~that~~States ~~the~~and ~~longer~~Europe ~~half-lives observed~~ in ~~NHPs~~September ~~will~~2025 ~~translate into extended half-lives of our product candidates in humans. To the extent we do not observe these extended half-lives with favorable safety~~ and ~~efficacy~~December ~~profiles~~2025, ~~when~~respectively, ~~we dose humans~~ with ~~our~~initiation ~~product~~expected ~~candidates,~~in itcertain ~~would~~other ~~significantly~~countries ~~and~~subject ~~adversely~~to ~~affect~~regulatory ~~the~~feedback ~~clinical and commercial potential of our product candidates.~~

Our programs will require additional clinical development, evaluation of clinical, nonclinical and manufacturing activities, product development, marketing approval in multiple jurisdictions, substantial investment and significant marketing efforts before we generate any revenues from product sales. We are not 51

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~~permitted~~and toapproval. ~~market~~The FDA and/or ~~promote~~other ~~these~~regulatory ~~programs~~authorities may not agree with our clinical trial designs for our SKYWAY Phase 2 basket trial or with our proposed timing for enrollment or trial design of the combination arms of our SKYLINE Phase 2 platform trial. Alignment with regulatory authorities on issues that arise before clinical trials commence, during clinical trials or ~~any~~after ~~other~~our clinical trials are completed could result in additional capital expenditures or delays in development that could have a material adverse impact on our business. The success of our programs is dependent on observing longer half-lives of our product candidates in humans and comparable or better safety and efficacy profiles than other mAbs currently marketed or in development. We believe these longer half-lives have the potential to result in more favorable dosing schedules for our product candidates, ~~before~~assuming wethey ~~receive~~successfully complete clinical development and obtain marketing approval. ~~from~~To the ~~FDA~~extent we do not observe these extended half-lives with favorable safety and ~~comparable~~efficacy ~~foreign~~profiles ~~regulatory~~when ~~authorities~~we dose patients with our product candidates, it would significantly and weadversely ~~may~~affect ~~never~~the ~~receive~~clinical ~~such~~and ~~marketing~~commercial ~~approvals~~potential of our product candidates.

~~The~~Our ~~success~~programs ~~of our product candidates~~ will ~~depend~~require onadditional ~~a variety of factors. We do not have complete control over many of these factors~~clinical, ~~including~~nonclinical ~~certain~~and ~~aspects~~manufacturing ~~of clinical~~ development and ~~the regulatory submission process~~activities, ~~potential~~marketing ~~threats~~approval toin ~~our~~multiple ~~intellectual~~jurisdictions, ~~property~~substantial ~~rights~~investment and ~~the~~significant ~~manufacturing,~~ marketing, ~~distribution~~efforts ~~and~~before ~~sales~~we ~~efforts~~generate of any ~~current~~revenues orfrom ~~future~~product ~~collaborator~~sales. ~~Accordingly,~~We weare ~~cannot~~not ~~assure~~permitted ~~you that we will ever be able~~ to ~~generate~~market ~~revenue~~or ~~through~~promote ~~the sale of~~ these ~~product candidates~~programs, ~~even~~or ifany ~~approved.~~other Ifprograms, before we ~~are~~receive ~~not~~marketing ~~successful~~approval infrom ~~commercializing~~the ~~SPY001,~~FDA ~~SPY002~~and orcomparable ~~SPY003,~~foreign ~~alone~~regulatory ~~or in combination~~authorities, orand ~~are~~we ~~significantly~~may ~~delayed~~never inreceive ~~doing~~such ~~so,~~marketing ~~our business will be materially harmed~~approvals.

The success of our product candidates will depend on a variety of factors. We do not have complete control over many of these factors, including certain aspects of clinical development and the regulatory submission process, potential threats to our intellectual property rights and the manufacturing, marketing, distribution and sales efforts of any current or future collaborator. Accordingly, we cannot assure you that we will ever be able to generate revenue through the sale of these product candidates, even if approved. If we are not successful in commercializing SPY001, SPY002, SPY072 or SPY003, alone or in combination, or are significantly delayed in doing so, our business will be materially harmed.

If we do not achieve our projected development goals in the time frames we announce and expect, the commercialization of our product candidates may be delayed and our expenses may increase and, as a result, our stock price may decline.

From time to time, we estimate the timing of the anticipated accomplishment of various scientific, clinical, regulatory and other product development goals, which we sometimes refer to as milestones. These milestones may include the commencement or completion of nonclinical studies and clinical trials, such as the expected timing ~~for the anticipated completion~~ of ~~our~~enrollment ~~Phase~~and 1readouts ~~clinical~~for ~~trials in healthy volunteers and~~ topline data from our ~~planned~~ongoing ~~Phase 2~~ clinical trials ~~in IBD and RA~~, as well as the submission of regulatory filings. From time to time, we may publicly announce the expected timing of some of these milestones. All of these milestones are and will be based on numerous assumptions. The actual timing of these milestones can vary dramatically compared to our estimates, in some cases for reasons beyond our control, including positions that may be taken by or requirements of regulatory authorities. If we do not meet these milestones as publicly announced, or at all, the commercialization of our product candidates may be delayed or never achieved and, as a result, our stock price may decline. Additionally, delays relative to our projected timelines are likely to cause overall expenses to increase, which may require us to raise additional capital sooner than expected and prior to achieving targeted development milestones.

Any drug delivery device that we potentially use to deliver our product candidates may have its own regulatory, development, supply and other risks.

We expect to deliver our product candidates via a drug delivery device, such as an injector or other delivery system. There may be unforeseen technical complications related to the development activities required to bring such a product to market, including primary container compatibility and/or dose volume requirements. If our product candidates are intended to be used with drug delivery devices, we expect to utilize drug delivery devices authorized for marketing under clearances of approvals held by third parties. Our product candidates may not be approved or may be substantially delayed in receiving approval if the devices that we choose to develop do not gain and/or maintain their own regulatory approvals or clearances. Where approval of the drug product and device is sought under a single application, the increased complexity of the review process may delay approval. In addition, some drug delivery devices are provided by single-source unaffiliated third-party companies. We may be dependent on the sustained cooperation and effort of those third-party companies both to supply the devices and, in some cases, to conduct the studies required for approval or other regulatory clearance of the devices. Even if approval is obtained for our products, we may also be dependent on those third-party companies continuing to maintain such approvals or clearances, if required, for their drug delivery devices once they have been received. Failure of third-party companies to supply the devices, to successfully complete studies on the devices in a timely manner, or to obtain or maintain required approvals or clearances of the devices could result in increased development costs, delays in or failure to obtain regulatory approval and delays in product candidates reaching the market or in gaining approval or clearance for expanded labels for new indications.

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regulatory clearance of the devices. Even if approval is obtained for our products, we may also be dependent on those third-party companies continuing to maintain such approvals or clearances, if required, for their drug delivery devices once they have been received. Failure of third-party companies to supply the devices, to successfully complete studies on the devices in a timely manner, or to obtain or maintain required approvals or clearances of the devices could result in increased development costs, delays in or failure to obtain regulatory approval and delays in product candidates reaching the market or in gaining approval or clearance for expanded labels for new indications.

Our approach to the discovery and development of our programs is unproven, and we may not be successful in our efforts to build a pipeline of programs with commercial value.

Our approach to the discovery and development of ~~the~~our research programs ~~with~~leverages ~~respect~~clinically validated mechanisms of action and incorporates advanced antibody engineering to ~~which~~optimize wehalf-life ~~have~~and ~~signed~~other aproperties ~~license~~designed ~~agreement~~to overcome limitations of existing therapies. Our programs are purposefully designed to improve upon existing product candidates and products while maintaining the same well-established mechanisms of action. However, ~~exercised~~the scientific research that forms the ~~Option~~basis of our efforts to ~~acquire~~develop ~~intellectual~~programs ~~property~~using ~~license~~half-life ~~rights~~extension totechnologies, orincluding YTE and LS amino acid substitutions, is ongoing and may not result in viable programs. We have limited clinical data on product candidates utilizing YTE and LS half-life extension technologies, especially in I&I indications, demonstrating whether they are safe or effective for long-term treatment in patients. The long-term safety and efficacy of these technologies and the ~~Option~~extended tohalf-lives ~~acquire~~and ~~intellectual~~exposure ~~property~~profiles ~~license~~of ~~rights~~our toprograms ~~pursuant~~compared to ~~the~~currently ~~Paragon~~approved ~~Agreement,~~products ~~leverages~~are unknown.

47We may ultimately discover that our investigational products developed with half-life extension technologies do not possess certain properties required for therapeutic effectiveness and could lead to adverse effects. We currently have only interim Phase 1 clinical data in healthy volunteers and nonclinical data regarding the increased half-life and drug clearance properties of our programs and the anticipated half-life extension and/or drug clearance properties of each of our product candidates may not be seen in participants in our clinical trials. In addition, programs using half-life extension technologies may demonstrate different chemical and pharmacological properties in participants than they do in laboratory studies. This technology and any programs resulting therefrom may not demonstrate the same chemical and pharmacological properties in humans and may interact with human biological systems in unforeseen, ineffective or harmful ways.

In addition, we may in the future seek to discover and develop programs that are based on novel targets and technologies that are unproven. If our discovery activities fail to identify novel targets or technologies for drug discovery, or such targets prove to be unsuitable for treating human disease, we may not be able to develop viable additional programs. We and our existing or future collaborators may never receive approval to market and commercialize any product candidate. Even if we or an existing or future collaborator obtains regulatory approval, the approval may be for targets, disease indications or patient populations that are not as broad as we intended or desired or may require labeling that includes significant use or distribution restrictions or safety warnings. If the products resulting from our research programs prove to be ineffective, unsafe or commercially unviable, our programs and pipeline would have little, if any, value, which would have a material and adverse effect on our business, financial condition, results of operations and prospects.

Preclinical and clinical development involve lengthy and expensive processes that are subject to delays and may result in uncertain outcomes, and results of earlier studies and trials may not be predictive of future clinical trial results. If our preclinical studies and clinical trials are not sufficient to support regulatory approval of any of our product candidates, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development of such product candidate.

Before obtaining marketing approval from regulatory authorities for the sale of any product candidate, we must complete preclinical studies and then conduct extensive clinical trials to demonstrate the safety and efficacy of our product candidate in humans. Our clinical trials may not be conducted as planned or completed on schedule, if at all, and failure can occur at any time during the preclinical study or clinical trial process. For example, we depend on the availability of NHPs to conduct certain preclinical studies that we are required to complete prior to submitting an IND or foreign equivalent and initiating clinical development. There is no guarantee that we will always be able to source NHPs for our drug development activities on our preferred timelines. The cost of obtaining NHPs for our future preclinical development activities could increase significantly if short or long term shortages occur in their availability. If we are unable to source NHPs on our

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~~clinically~~preferred ~~validated~~timelines, ~~mechanisms~~it ofcould ~~action~~result ~~and~~in ~~incorporates~~delays ~~advanced~~to ~~antibody~~our ~~engineering~~development totimelines. ~~optimize~~Similarly, ~~half-life~~we ~~and~~may ~~other~~experience ~~properties~~difficulty ~~designed~~in toconducting ~~overcome~~our ~~limitations~~clinical oftrials ~~existing~~as ~~therapies.~~planned ~~Our~~if ~~programs~~we are ~~purposefully~~unable ~~designed~~ to ~~improve~~enroll ~~upon~~a ~~existing~~sufficient ~~product~~number ~~candidates~~of ~~and~~participants ~~products~~in ~~while~~any ~~maintaining~~such ~~the~~trial ~~same~~as ~~well-established~~a ~~mechanisms~~result of ~~action.~~variables ~~However,~~outside ~~the scientific research that forms the basis~~ of our ~~efforts~~control. toSee ~~develop~~the ~~programs~~risk ~~using~~factor ~~half-life~~titled ~~extension~~“If ~~technologies,~~we ~~including~~encounter ~~YTE~~difficulties ~~and~~enrolling LSparticipants ~~amino~~in ~~acid~~our ~~substitutions,~~current ~~is ongoing~~ and ~~may~~future ~~not result in viable programs. We have limited~~ clinical ~~data on product candidates utilizing YTE and LS half-life extension technologies~~trials, ~~especially~~our inclinical ~~I&I~~development ~~indications,~~activities ~~demonstrating~~could ~~whether~~be ~~they~~delayed ~~are safe~~ or ~~effective~~otherwise ~~for~~adversely ~~long-term treatment in humans~~affected. ~~The long-term safety and efficacy of these technologies and the extended half-lives and exposure profiles of our programs compared to currently approved products are unknown.~~”

WeFurthermore, ~~may~~a ~~ultimately~~failure ~~discover~~of ~~that~~one ~~our~~or ~~investigational~~more ~~products~~clinical ~~developed~~trials ~~with~~can ~~half~~occur at any stage of testing. The outcome of preclinical studies and early-~~life~~stage ~~extension~~clinical ~~technologies~~trials domay not ~~possess~~be ~~certain~~predictive ~~properties~~of ~~required~~the ~~for~~success ~~therapeutic~~of ~~effectiveness~~later ~~and~~stage ~~could~~clinical ~~lead~~trials. toMoreover, ~~adverse~~preclinical ~~effects.~~and ~~Other~~clinical ~~than~~data ~~for~~are ~~our~~often ~~SPY001~~susceptible ~~program~~to varying interpretations and analyses, weand ~~currently~~many ~~have~~companies ~~only~~that ~~nonclinical~~have ~~data~~believed ~~regarding~~their ~~the~~product ~~increased~~candidates ~~half-life~~performed ~~properties~~satisfactorily ofin ~~our~~preclinical ~~programs~~studies and aclinical ~~similar~~trials ~~half-life~~have ~~extension~~nonetheless ~~may~~failed ~~not~~to beobtain ~~seen~~marketing inapproval ~~humans~~of their product candidates. In addition, ~~programs~~we ~~using~~expect ~~half-life~~to ~~extension~~rely ~~technologies~~on ~~may~~participants ~~demonstrate~~to ~~different~~provide ~~chemical~~feedback ~~and~~on ~~pharmacological~~measures ~~properties~~such inas ~~participants~~measures ~~than~~of ~~they~~disease doactivity inand ~~laboratory~~measures ~~studies.~~of ~~This~~quality ~~technology~~of life, which are subjective and ~~any~~inherently ~~programs~~difficult ~~resulting~~to ~~therefrom~~evaluate. ~~may~~These ~~not~~measures ~~demonstrate~~can ~~the~~be ~~same~~influenced ~~chemical~~by ~~and~~factors ~~pharmacological~~outside ~~properties~~of inour ~~humans~~control and ~~may~~can ~~interact~~vary ~~with~~widely ~~human~~from ~~biological~~day ~~systems~~to inday ~~unforeseen~~for a particular participant, ~~ineffective~~and orfrom ~~harmful~~participant ~~ways~~to participant and from site to site within a clinical trial.

InWe ~~addition,~~cannot webe ~~may~~sure inthat the ~~future~~FDA, ~~seek~~or tocomparable ~~discover~~foreign ~~and~~regulatory ~~develop~~authority, ~~programs~~as ~~that~~applicable, ~~are~~will ~~based~~agree onwith ~~novel~~our ~~targets~~clinical ~~and~~development ~~technologies that are unproven~~plans. If ~~our~~the ~~discovery~~FDA ~~activities fail to identify novel targets~~ and/or ~~technologies~~comparable ~~for~~foreign ~~drug~~regulatory ~~discovery,~~authority orrequires ~~such~~us ~~targets prove~~ to bematerially ~~unsuitable~~modify ~~for~~our ~~treating~~proposed ~~human~~trial ~~disease~~designs, weconduct ~~may~~additional ~~not~~trials beor ~~able~~enroll ~~to develop viable~~ additional ~~programs.~~participants, ~~We and~~ our ~~existing~~development ortimelines ~~future collaborators~~ may ~~never~~be ~~receive approval to market and commercialize any product candidate~~delayed. ~~Even~~We ifcannot ~~we or an existing or future collaborator obtains regulatory approval, the approval may~~ be ~~for~~sure ~~targets, disease indications or patient populations~~ that ~~are~~submission ~~not~~of asan ~~broad~~IND, asclinical wetrial ~~intended~~application or ~~desired~~similar orapplication ~~may~~will ~~require~~result ~~labeling~~in ~~that~~the ~~includes~~FDA ~~significant use~~ or ~~distribution~~comparable ~~restrictions~~foreign orregulatory ~~safety~~authorities, ~~warnings.~~as ~~If the products resulting from the research programs with respect to which we have signed license agreements with Paragon~~applicable, ~~exercised~~allowing ~~the~~clinical ~~Option~~trials to ~~acquire~~begin ~~intellectual~~in ~~property~~a ~~license~~timely ~~rights to or have the Option to acquire intellectual property license rights to pursuant to the Paragon Agreement prove to be ineffective~~manner, ~~unsafe~~if orat ~~commercially~~all. ~~unviable~~Moreover, ~~our~~even ~~programs~~if ~~and~~these ~~pipeline~~trials ~~would have little~~begin, ifissues ~~any,~~may ~~value,~~arise ~~which~~that ~~would~~could ~~have~~cause aregulatory ~~material~~authorities ~~and~~to ~~adverse~~suspend ~~effect~~or onterminate ~~our business, financial condition, results of operations and prospects~~them.

~~Nonclinical~~We ~~and~~could ~~clinical~~also ~~development~~encounter ~~involve~~delays ~~lengthy~~if ~~and~~an ~~expensive~~ongoing ~~processes~~or ~~that~~planned ~~are~~clinical ~~subject~~trial is required to ~~delays~~be ~~and~~materially ~~may~~modified ~~result~~or insuspended ~~uncertain~~or ~~outcomes~~terminated by us, ~~and~~by ~~results~~the ECs/IRBs of ~~earlier~~the ~~studies~~institutions ~~and~~in which such clinical trials ~~may~~are ~~not~~being beconducted, ~~predictive~~by ofthe ~~future~~external Data Monitoring Committee or equivalent body, if any, for such clinical trial ~~results~~or by the FDA or comparable foreign regulatory authorities. IfSuch ~~our~~authorities ~~nonclinical~~may ~~studies~~suspend, ~~and~~put on clinical ~~trials~~hold ~~are~~or terminate a clinical trial due to a number of factors, including not ~~sufficient~~aligning with or supporting our clinical trial designs or our failure to ~~support~~conduct the clinical trial in accordance with regulatory ~~approval~~requirements or our clinical trial protocols, inspection of ~~any~~the clinical trial operations or trial site by the FDA or comparable foreign regulatory authorities resulting in the imposition of ~~our~~a ~~product~~clinical ~~candidates~~hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from the programs, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial. If we ~~may~~are ~~incur~~required to conduct additional ~~costs~~clinical trials or ~~experience~~other ~~delays~~testing inof ~~completing~~our product candidates beyond those that we currently contemplate, orif ~~ultimately~~we beare unable to successfully complete clinical trials of our product candidates, if the ~~development~~results of ~~such~~these ~~product~~trials ~~candidate.~~are not positive or are only moderately positive or if there are safety concerns, our business and results of operations may be adversely affected and we may incur significant additional costs.

~~Before~~A ~~obtaining~~key ~~marketing~~element ~~approval from regulatory authorities for the sale~~ of ~~any~~our ~~product~~strategy ~~candidate,~~is ~~we must complete nonclinical studies and then conduct extensive clinical trials to demonstrate~~ the ~~safety~~development ~~and efficacy~~ of ~~our~~intra-portfolio ~~product~~investigational ~~candidate~~drug ~~in humans~~combinations. ~~Our~~If ~~clinical~~we ~~trials~~are ~~may~~ not besuccessful ~~conducted~~in ~~as planned or completed on schedule~~discovering, ifdeveloping ~~at all,~~ and ~~failure~~commercializing ~~can~~investigational ~~occur~~products atthat ~~any~~take ~~time~~advantage ~~during~~of ~~the~~different ~~nonclinical~~mechanisms ~~study or clinical trial process. For example, we depend on the availability~~ of ~~NHPs~~action to ~~conduct~~achieve ~~certain~~superior ~~nonclinical~~outcomes ~~studies~~relative ~~that we are required~~ to ~~complete~~the ~~prior~~use to submitting an IND or foreign equivalent and initiating clinical development. There is no guarantee that we will always be able to source NHPs for our drug development activities on our preferred timelines. The cost of ~~obtaining~~monotherapies ~~NHPs for our future nonclinical development activities could increase significantly if short~~ or ~~long~~other ~~term shortages occur in their availability. If we are unable to source NHPs on our preferred timelines~~combinations, ~~it could result in delays to~~ our ~~development~~ability ~~timelines. Similarly, we may experience difficulty in conducting our clinical trials as planned if we are unable~~ to ~~enroll~~achieve ~~a sufficient number of participants in any such trial as a result of variables outside of~~ our ~~control.~~strategic ~~See~~objectives ~~the~~would ~~risk~~likely ~~factor titled “If we encounter difficulties enrolling participants in our current and future clinical trials, our clinical development activities could~~ be ~~delayed or otherwise adversely affected~~impaired.”

~~Furthermore,~~A key element of our strategy is to build a ~~failure~~broad portfolio of ~~one~~investigational products that will allow for the development of intra-portfolio combinations. We believe that by developing or ~~more~~licensing ~~clinical~~these ~~trials~~investigational products, we can ~~occur~~control atthe ~~any~~combinations ~~stage~~we pursue and, if and when approved, maximize the commercial potential of ~~testing~~these combinations. ~~The~~However, ~~outcome~~these ofcombinations ~~nonclinical~~have ~~studies~~not been tested before and ~~early-stage~~may ~~clinical~~fail ~~trials~~to achieve superior outcomes relative to the use of single agents or other combinations, may ~~not~~exacerbate beadverse ~~predictive~~events associated with one of the ~~success~~investigational products when used as monotherapy, may yield new adverse events not observed with either of ~~later~~the monotherapies, or may fail to demonstrate sufficient safety or efficacy in clinical trials to enable us to complete those clinical trials or obtain marketing approval for the combinations. ~~Moreover~~In addition, ~~nonclinical~~demonstrating ~~and~~that ~~clinical~~our ~~data~~combinations are ~~often~~superior ~~susceptible~~to our single agents is likely necessary for marketing authorization of the combinations. However, comparing active treatments may be difficult to ~~varying~~do ~~interpretations~~in ~~and~~a ~~analyses~~controlled manner in our clinical trials, and ~~many~~we may be unable to interpret the results of comparisons between our combinations and single agents in a manner that satisfies regulatory requirements.

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~~companies~~Even ~~that~~if ~~have~~we ~~believed~~are ~~their~~successful ~~product candidates performed satisfactorily~~ in ~~nonclinical~~developing ~~studies and clinical trials have nonetheless failed to obtain marketing approval of their product candidates. In addition~~combinations, wecompetition ~~expect~~from toother ~~rely~~investigational onproducts ~~participants~~in tothe ~~provide~~same ~~feedback~~class ~~on measures such as measures of disease activity and measures of quality of life,~~ which are ~~subjective~~either ~~and~~already ~~inherently~~approved ~~difficult~~or tofurther ~~evaluate.~~along ~~These~~in ~~measures~~development ~~can~~than beours ~~influenced~~may byprevent ~~factors~~us ~~outside of our control and can vary widely~~ from ~~day~~realizing tothe ~~day~~commercial ~~for~~potential aof ~~particular~~our ~~participant,~~combinations and ~~from~~prevent ~~participant~~us ~~to participant and~~ from ~~site~~achieving toour ~~site~~strategic ~~within a clinical trial~~objectives.

We cannot be sure that the FDA, or comparable foreign regulatory authority, as applicable, will agree with our clinical development plans. We plan to use the data from our ongoing and planned Phase 1 trials of our SPY001, SPY002 and SPY003 programs in healthy volunteers to support Phase 2 trials in IBD, RA and other I&I indications. If the FDA and/or comparable foreign regulatory authority requires us to materially modify our proposed trial designs, conduct additional trials or enroll additional participants, our development timelines may be delayed. We cannot be sure that submission of an IND, CTA or similar application will result in the FDA or comparable foreign regulatory authorities, as applicable, allowing clinical trials to begin in a timely manner, if at all. Moreover, even if these trials begin, issues may arise that could cause regulatory authorities to suspend or terminate them. Events that may prevent successful or timely initiation or completion of clinical trials include: inability to generate sufficient nonclinical, toxicology or other in vivo or in vitro data; delays in reaching a consensus with regulatory authorities on trial design or implementation of the clinical trials; delays or failure in obtaining regulatory authorization to commence a trial; delays in reaching agreement on acceptable terms with current and prospective CROs and clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and clinical trial sites; CRO personnel changes which could lead to operational delays or complications; delays in identifying, recruiting and training suitable clinical investigators and their study teams; delays in obtaining required EC/IRB approval at each clinical trial site; delays in manufacturing, testing, releasing, validating or importing/exporting sufficient stable quantities of our product candidates or other supplies for use in clinical trials or the inability to do any of the foregoing; failure by our CROs, other third parties or us to adhere to clinical trial protocols; failure to perform in accordance with the FDA’s or any other regulatory authority’s good clinical practice requirements (“GCPs”) or applicable regulatory guidelines in other countries; changes to the clinical trial protocols; clinical sites deviating from trial protocol or dropping out of a trial; changes in regulatory requirements and guidance that require amending or submitting new clinical protocols; selection of clinical endpoints that require prolonged periods of observation or analyses of resulting data; transfer of manufacturing processes to facilities operated by a contract manufacturing organization (“CMO”) and delays or failure by our CMOs or us to make any necessary changes to such manufacturing process; and third parties being unwilling or unable to satisfy their contractual obligations to us.

We could also encounter delays if a planned clinical trial is required to be materially modified or suspended or terminated by us, by the ECs/IRBs of the institutions in which such clinical trials are being conducted, by the external Data Monitoring Committee, if any, for such clinical trial or by the FDA or comparable foreign regulatory authorities. Such authorities may suspend, put on clinical hold or terminate a clinical trial due to a number of factors, including not aligning with or supporting our clinical trial designs or our failure to conduct the clinical trial in accordance with regulatory requirements or our clinical trial protocols, inspection of the clinical trial operations or trial site by the FDA or comparable foreign regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from the programs, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial. If we are required to conduct additional clinical trials or other testing of our product candidates beyond those that we currently contemplate, if we are unable to successfully complete clinical trials of our product candidates, if the results of these trials are not positive or are only moderately positive or if there are safety concerns, our business and results of operations may be adversely affected and we may incur significant additional costs.

A key element of our strategy is the development of intra-portfolio investigational drug combinations. If we are not successful in discovering, developing and commercializing investigational products that take advantage of different mechanisms of action to achieve superior outcomes relative to the use of monotherapies or other combination therapies, our ability to achieve our strategic objectives would likely be impaired.

A key element of our strategy is to build a broad portfolio of investigational products that will allow for the development of intra-portfolio combinations. We believe that by developing or licensing these investigational products, we can control the combinations we pursue and, if and when approved, maximize the commercial

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potential of these combinations. However, these combinations have not been tested before and may fail to achieve superior outcomes relative to the use of single agents or other combination therapies, may exacerbate adverse events associated with one of the investigational products when used as monotherapy, may yield new adverse events not observed with either of the monotherapies, or may fail to demonstrate sufficient safety or efficacy in clinical trials to enable us to complete those clinical trials or obtain marketing approval for the combination therapy. In addition, demonstrating that our combinations are superior to our single agents is likely necessary for marketing authorization of the combinations. However, comparing active treatments may be difficult to do in a controlled manner in our clinical trials, and we may be unable to interpret the results of comparisons between our combinations and single agents in a manner that satisfies regulatory requirements.

Even if we are successful in developing combination therapies, competition from other investigational products in the same class which are either already approved or further along in development than ours may prevent us from realizing the commercial potential of our combination therapies and prevent us from achieving our strategic objectives.

Development of combination therapies may present more or different challenges than development of monotherapies.

We plan to pursue development of our investigational products in combination with one or more additional products or investigational products. The development of combination therapies may be more complex than the development of monotherapies and generally requires that sponsors demonstrate the contribution of each investigational product to the claimed effect and the safety and efficacy of the combination as a whole. Regulatory authority requirements for the development of combination therapies may make the design and conduct of clinical trials more complex and/or burdensome, requiring more clinical trial participants and additional time and cost to complete than we plan or anticipate. We also may not be able to meet the FDA’s or comparable foreign regulatory authority's current or future approval standards required for combination therapies or combination products, if we decided to administer or package acombinations ~~combination therapy~~ as a single drug product. For example, under the "combination rule", the FDA may not file or approve a fixed-dose combination product unless each component of a proposed drug product is shown to make a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is safe and effective for the intended population. To satisfy these requirements, the FDA typically requires a clinical factorial trial, designed to assess the effects attributable to each drug in the combination product. This is particularly true when the ingredients are directed at the same sign or symptom of the disease or condition. The FDA has accepted a variety of approaches to satisfy the combination rule, but the FDA has stated that factorial studies may be unethical (e.g., omitting a drug known to improve survival) or impractical (there may be too many components to conduct a factorial trial, meaning the trial cannot be conducted). The FDA has also stated that it may be possible to use other types of clinical and nonclinical data and mechanistic information available to demonstrate the contributions of the individual active ingredients to the effect of the combination. In addition, combination products may require dose selection for each agent in the combination, which may require more and/or larger groups of participants than single agents. Our clinical trial and research efforts may not satisfy regulators' expectations of adequate exploration of dose ranging required for drug approval. Moreover, the applicable requirements for approval of acombinations ~~combination therapy~~ may differ from country to country.

In the event that one of our investigational products were to fail to demonstrate sufficient safety and efficacy data or establish its contribution to the claimed effects of acombinations ~~combination therapy~~ or if we are unable to meet the FDA’s or comparable foreign regulatory authority's current or future approval standards required for combination therapies or combination products in a timely manner, we would need to identify and research alternative monotherapy or combination treatments, run additional trials to produce supportive data or modify existing clinical trial plans. In the event we are unable to do so or are unable to do so on commercially reasonable terms or we are unable to continue development of one or more of investigational products, our business and prospects would be materially harmed.

If we encounter difficulties enrolling participants in our current and future clinical trials, our clinical development activities could be delayed or otherwise adversely affected.

We may experience difficulties in participant enrollment in our current and future clinical trials for a variety of reasons. The timely completion of clinical trials in accordance with their protocols depends, among other things, on our ability to enroll a sufficient number of participants who remain in the trial until its conclusion. The enrollment of participants will depend on many factors, including: ~~if participants choose to enroll in clinical~~

50•the prevalence and severity of the disease under investigation;

•the participant eligibility and the inclusion and exclusion criteria defined in the protocol;

•the incidence and prevalence of target trial populations under clinical investigation;

•the proximity of participants to trial sites;

•the design of the trial;

•our ability to recruit clinical trial investigators with the appropriate competencies and experience;

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~~trials,~~•clinicians’ ~~rather than using approved products, or if our competitors have ongoing clinical trials for programs that are under development for the same indications as our programs,~~ and participants’ ~~instead~~perceptions ~~enroll~~as into ~~such clinical trials. Additionally,~~ the ~~number~~potential ofadvantages ~~participants required for clinical trials~~ of ~~our~~the ~~programs~~drug ~~may~~candidate(s) bebeing ~~larger~~studied ~~than we anticipate. Even if we are able to enroll a sufficient number of participants for our current or future clinical trials, we may have difficulty maintaining participants~~ in ~~our~~relation ~~clinical trials. Our inability~~ to ~~enroll~~other oravailable ~~maintain a sufficient number of participants would result in significant delays in completing clinical trials or receipt of marketing approvals~~therapies, ~~increased~~including ~~development~~any ~~costs~~new ordrugs ~~our~~that ~~cessation~~may ofbe ~~one~~approved orfor ~~more~~the ~~clinical~~indications ~~trials~~we ~~altogether.~~are investigating;

•our ability to obtain and maintain participant consents;

•our ability to monitor participants adequately during and after treatment;

•the risk that participants enrolled in clinical trials will drop out of the trials before completion or fail to attend scheduled trial visits; and

•factors we may not be able to control, including the impacts of public health crises, which may limit the availability of participants, investigators or their staff, or clinical sites.

In addition, our clinical trials will compete with other clinical trials with product candidates that are in the same therapeutic areas as our product candidates, and this competition will reduce the number and types of participants available to us, because some participants who might have opted to enroll in our trials may instead opt to enroll in a trial being conducted by one of our competitors. Since the number of qualified clinical investigators is limited, we expect to conduct some of our clinical trials at the same clinical trial sites that some of our competitors use, which will reduce the number of participants who are available for our clinical trials at such clinical trial sites. Additionally, the number of participants required for clinical trials of our programs may be larger than we anticipate. Even if we are able to enroll a sufficient number of participants for our current or future clinical trials, we may have difficulty maintaining participants in our clinical trials. Our inability to enroll or maintain a sufficient number of participants would result in significant delays in completing clinical trials or receipt of marketing approvals, increased development costs or our cessation of one or more clinical trials altogether.

Additionally, our ability to successfully initiate, enroll, and complete a clinical trial in any foreign country is subject to numerous risks unique to conducting business in foreign countries, including, without limitation: difficulty in establishing or managing relationships with CROs and physicians; different standards for the conduct of clinical trials; different standard-of-care for patients with a particular disease; difficulty in locating qualified local consultants, physicians and partners; and potential burden of complying with a variety of foreign laws, medical standards and regulatory requirements, including the regulation of pharmaceutical and biotechnology products and treatment.

Preliminary, “topline” or interim data from our clinical trials that we announce or publish from time to time may change as more participant data become available and are subject to audit and verification procedures.

From time to time, we may publicly disclose preliminary or topline data from our nonclinical studies and clinical trials, which are based on a preliminary analysis of then-available data. The results and related findings and conclusions are subject to change following a more comprehensive review or taking into account additional data that becomes available. In reviewing preliminary or topline data, we also make assumptions, estimations, calculations and conclusions as part of our analyses that may change once a complete data set is available. As a result, the preliminary or topline results that we report may differ from future results of the same studies, or different conclusions or considerations may qualify such results, once additional data have been received and fully evaluated or subsequently made subject to audit and verification procedures. Any preliminary or topline data should be viewed with caution until the final data are available.

Further, others, including regulatory agencies, may not accept or agree with our assumptions, estimates, calculations, conclusions or analyses or may interpret or weigh the importance of data differently, which could impact the value of the particular product candidate, the approvability or commercialization of the particular product candidate and our company in general. In addition, the information we choose to publicly disclose regarding a particular nonclinical study or clinical trial is based on what is typically extensive information, and you or others may not agree with what we determine is material or otherwise appropriate information to include in our disclosure. If the preliminary, topline or interim data that we report differ from actual results, or if others, including regulatory authorities, disagree with the conclusions reached, our ability to obtain approval for, and commercialize, our product candidates may be harmed, which could harm our business, operating results, prospects or financial condition.

Our current and future clinical trials or those of our future collaborators may reveal significant adverse events or undesirable side effects not seen in our nonclinical studies and may result in a safety profile that could halt clinical development, inhibit regulatory approval or limit commercial potential or market acceptance of any of our product candidates.56

Results of our non-clinical studies or clinical trials could reveal a high and unacceptable severity and prevalence of side effects, adverse events or unexpected characteristics at any point in time during the development process for our product candidates. We cannot assure you that the future results of our nonclinical studies or clinical trials will not reveal such characteristics. If significant adverse events or undesirable side effects are observed in any of our current or future non-clinical studies or clinical trials, we may have difficulty recruiting participants to such trials, participants may drop out of our trials, or we may be required to cease or materially modify our development efforts of one or more programs. We, the FDA or other applicable regulatory authorities, or an EC/IRB, may suspend or require the material modification of any clinical trials of any program at any time for various reasons, including a belief that participants in such trials are being exposed to unacceptable health risks or adverse side effects. Some potential products developed in the biotechnology industry that initially showed therapeutic promise in early-stage studies and trials have later been found to cause side effects that prevented their further development. Other potential products have shown side effects in nonclinical studies, which side effects do not present themselves in clinical trials in humans. Even if the side effects do not preclude the product candidate from obtaining or maintaining marketing approval, undesirable side effects may inhibit market acceptance of the approved product due to its tolerability versus other therapies. In addition, an extended half-life could prolong the duration of undesirable side effects, which could also inhibit market acceptance. Treatment-emergent adverse events could also affect participant recruitment or the ability of enrolled participants to complete our clinical trials or could result in potential product liability claims. Potential side effects associated with our product candidates may not be appropriately recognized or managed by the treating medical staff, as toxicities resulting from our product candidates may not be normally encountered in

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~~the~~Our ~~general~~current ~~patient~~and ~~population~~future clinical trials or those of our future collaborators may reveal significant adverse events or undesirable side effects not seen in our clinical and bynonclinical ~~medical~~studies ~~personnel.~~and ~~Any~~may ofresult ~~these~~in ~~occurrences~~a safety profile that could ~~harm~~halt ~~our~~clinical ~~business~~development, ~~financial~~inhibit ~~condition,~~regulatory ~~results~~approval or limit commercial potential or market acceptance of ~~operations~~any ~~and~~of ~~prospects~~our ~~significantly~~product candidates.

~~Our~~Results of our nonclinical studies or clinical trials could reveal a high and unacceptable severity and prevalence of side effects, adverse events or unexpected characteristics at any point in time during the development process for our product candidates. ~~have~~We ~~mechanisms~~cannot ofassure ~~action~~you that ~~have~~the ~~been~~future ~~associated~~results ~~with~~of ~~certain~~our nonclinical studies or clinical trials will not reveal such characteristics. If significant adverse ~~reactions~~events or undesirable side effects are observed in ~~patients. For~~any ~~example,~~of ~~nasopharyngitis,~~our ~~headache,~~current ~~arthralgia,~~or ~~nausea,~~future ~~pyrexia,~~nonclinical ~~upper~~studies ~~respiratory~~or ~~tract~~clinical ~~infection~~trials, ~~fatigue,~~we ~~cough,~~may ~~bronchitis,~~have ~~influenza~~difficulty recruiting participants to such trials, ~~back~~participants ~~pain~~may drop out of our trials, ~~rash~~or we may be required to cease or materially modify our development efforts of one or more programs. We, ~~pruritus~~the FDA or other applicable regulatory authorities, ~~sinusitis~~or an EC/IRB, ~~oropharyngeal~~may ~~pain~~suspend or require the material modification of any clinical trials of any program at any time for various reasons, ~~and~~including ~~pain~~a belief that participants in ~~extremities~~such trials are ~~the~~being ~~most~~exposed ~~common~~to unacceptable health risks or adverse ~~reactions~~side ~~noted~~effects. ~~with~~Some ~~Entyvio,~~potential ~~which~~products isdeveloped in the ~~same~~biotechnology ~~drug~~industry ~~class~~that asinitially ~~SPY001~~showed ~~and~~therapeutic ispromise ~~approved~~in ~~for~~early-stage ~~the~~studies ~~treatment~~and oftrials ~~moderately~~have later been found to ~~severely~~cause ~~active~~side ~~ulcerative~~effects ~~colitis~~that prevented their further development. Other potential products have shown side effects in ~~adults~~nonclinical ~~and~~studies, ofwhich ~~moderately~~side toeffects ~~severely~~do ~~active~~not ~~Crohn’s~~present ~~disease~~themselves in ~~adults~~clinical trials in humans. In ~~addition,~~Even ~~mAbs~~if ~~targeting~~the ~~TL1A~~side ~~such~~effects asdo ~~our~~not preclude the product candidate ~~SPY002,~~from inobtaining ~~clinical~~or ~~research~~maintaining ~~are~~marketing ~~associated~~approval, ~~with~~undesirable ~~patient~~side ~~adverse~~effects ~~reactions~~may ~~that~~inhibit ~~most~~market ~~commonly~~acceptance ~~include~~of ~~headache,~~the ~~nasopharyngitis,~~approved ~~arthralgia,~~product ~~and~~due ~~back~~to ~~pain~~its tolerability versus other therapies. ~~Finally~~ In addition, ~~for~~an ~~Skyrizi~~extended half-life could prolong the duration of undesirable side effects, which iscould inalso ~~the~~inhibit ~~same~~market ~~drug~~acceptance. ~~class~~Treatment-emergent asadverse ~~SPY003~~events ~~and~~could isalso ~~approved~~affect ~~for~~participant recruitment or the ~~treatment~~ability of ~~moderately~~enrolled participants to ~~severely~~complete ~~active~~our ~~ulcerative~~clinical ~~colitis~~trials inor ~~adults~~could ~~and~~result ofin ~~moderately~~potential toproduct ~~severely~~liability ~~active~~claims. ~~Crohn’s~~Potential ~~disease~~side ineffects ~~adults,~~associated ~~the~~with ~~most~~our ~~common~~product ~~adverse~~candidates ~~reactions~~may ~~are~~not ~~upper~~be ~~respiratory~~appropriately ~~infections,~~recognized ~~headache,~~or ~~arthalgia,~~managed ~~injection~~by ~~site~~the ~~reactions,~~treating ~~abdominal~~medical ~~pain~~staff, ~~anemia,~~as ~~pyrexia,~~toxicities ~~back~~resulting ~~pain,~~from ~~arthropathy,~~our ~~and~~product ~~urinary~~candidates ~~tract~~may ~~infection~~not be normally encountered in ~~patients~~the ~~with~~general ~~Crohn's~~patient ~~disease~~population and ~~arthralgia,~~by ~~pyrexia,~~medical ~~injection~~personnel. ~~site~~In ~~reactions~~addition, ~~and~~safety ~~rash~~findings inassociated ~~patients~~ with ~~UC. Patients~~competing products or product candidates that target similar pathways could result in the FDA or comparable foreign regulatory authorities imposing restrictions on our clinical trials ~~for~~or ~~SPY001,~~product ~~SPY002~~labeling ~~and~~or ~~SPY003,~~denying orapproval ~~combinations~~of ~~thereof~~our products. Any of these occurrences could harm our business, ~~may~~financial ~~experience~~condition, ~~similar~~results orof ~~additional~~operations ~~adverse~~and ~~reactions~~prospects significantly.

Our product candidates have mechanisms of action in common with other approved drugs that have been associated with certain adverse reactions in patients. For example, nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities are the most common adverse reactions noted with ENTYVIO®, which is in the same drug class as SPY001 and is approved for the treatment of moderately to severely active UC in adults and of moderately to severely active CD in adults. In addition, mAbs targeting TL1A such as our product candidates SPY002 and SPY072 in clinical trials are associated with patient adverse reactions that most commonly include headache, nausea, nasopharyngitis, urinary tract infection, SARS-CoV-2 infection, fever, fatigue, arthralgia, and back pain. Finally, for SKYRIZI®, which is in the same drug class as SPY003 and is approved for the treatment of moderately to severely active UC in adults and of moderately to severely active CD in adults, the most common adverse reactions are upper respiratory infections, headache, arthralgia, injection site reactions, abdominal pain, anemia, pyrexia, back pain, arthropathy, and urinary tract infection in patients with CD and arthralgia, pyrexia, injection site reactions, and rash in patients with UC. Participants in our clinical trials for SPY001, SPY002, SPY072 and SPY003, or combinations thereof, may experience similar or additional adverse reactions such as infections (including rare infections such as tuberculosis or JC virus reactivation, which could lead to multifocal leukoencephalopathy), infusion-related reactions, other hypersensitivity reactions (including injection site reactions and delayed hypersensitivity reactions), and hepatotoxicity, as has been observed with other biologics, including those with similar mechanisms of action.

In addition, even if we successfully advance our product candidates or any future product candidates through clinical trials, such trials will only include a limited number of participants and limited duration of exposure to our product candidates. As a result, we cannot be assured that adverse effects of our product candidates will not be uncovered when a significantly larger number of participants are exposed to the product after approval. Further, any clinical trials may not be sufficient to determine the effect and safety consequences of using any of our products over a multi-year period.

If any of the foregoing events occur or if one or more of the research programs with respect to which we have signed a licensed agreement for or exercised the Option to acquire intellectual property license rights to or have the Option to acquire intellectual property license rights to pursuant to the Paragon Agreement prove to be unsafe, our entire pipeline could be affected, which would have a material adverse effect on our business, financial condition, results of operations and prospects.57

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If any of the foregoing events occur or if one or more of our research programs prove to be unsafe, our entire pipeline could be affected, which would have a material adverse effect on our business, financial condition, results of operations and prospects.

We may expend our limited resources to pursue a particular program and fail to capitalize on programs that may be more profitable or for which there is a greater likelihood of success.

Because we have limited financial and managerial resources, we focus our research and development efforts on certain selected programs. For example, we are initially focused on our ~~most advanced programs,~~ SPY001, SPY002 and SPY003 programs, including combinations thereof, and our SPY072 program. As a result, we may forgo or delay pursuit of opportunities with other programs that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and development programs for specific indications may not yield any commercially viable product candidates. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.

Any approved products resulting from our current programs or any future program may not achieve adequate market acceptance among clinicians, patients, healthcare third-party payors and others in the medical community necessary for commercial success and we may not generate any future revenue from the sale or licensing of such products.

Even if regulatory approval is obtained for a product candidate resulting from one of our current or future programs, they may not gain market acceptance among physicians, patients, healthcare payors or the medical community. We may not generate or sustain revenue from sales of the product due to factors such as whether the product can be sold at a competitive cost and whether it will otherwise be accepted in the market. There are several approved products and product candidates in later stages of development for the treatment of IBD and the treatment of RARD. However, our programs incorporate advanced antibody engineering to optimize the half-life and formulation of antibodies; to date, no such antibody has been approved by the FDA for the treatment of IBD, RA, PsA or RAaxSpA. Market participants with significant influence over acceptance of new treatments, such as clinicians and third-party payors, may not adopt a biologic that incorporates half-life extension for our targeted indications, and we may not be able to convince the medical community and third-party payors to accept and use, or to provide favorable reimbursement for, any programs developed by us or our existing or future collaborators. An extended half-life may make it more difficult for patients to change treatments and there is a perception that half-life extension could exacerbate side effects, each of which may adversely affect our ability to gain market acceptance. Market acceptance of our product candidates will depend on many factors, including factors that are not within our control.

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as clinicians and third-party payors, may not adopt a biologic that incorporates half-life extension for our targeted indications, and we may not be able to convince the medical community and third-party payors to accept and use, or to provide favorable reimbursement for, any programs developed by us or our existing or future collaborators. An extended half-life may make it more difficult for patients to change treatments and there is a perception that half-life extension could exacerbate side effects, each of which may adversely affect our ability to gain market acceptance. Market acceptance of our product candidates will depend on many factors, including factors that are not within our control.

Sales of medical products also depend on the willingness of clinicians to prescribe the treatment. We cannot predict whether clinicians, clinicians’ organizations, hospitals, other healthcare providers, government agencies or private insurers will determine that our product is safe, therapeutically effective, cost effective or less burdensome as compared with competing treatments. If any current or future product candidate is approved but does not achieve an adequate level of acceptance by such parties, we may not generate or derive sufficient revenue from that product candidate and may not become or remain profitable.

Some of our programs may compete with our other programs, which could negatively impact our business and reduce our future revenue.

We have multiple product candidates, alone and in combination, in development for the same indication, IBD, and are ~~planning~~developing ~~to develop~~ one product candidate (~~SPY002~~SPY072) for RARD. We may in the future develop our programs for other I&I indications. Each such program targets a ~~different~~single ~~mechanism~~or multiple mechanisms of action that could provide differentiation from standard of care or each other. However, developing multiple programs for a single indication may negatively impact our business if the programs compete with each other. For example, if multiple programs are conducting clinical trials at the same time, they could compete for the enrollment of participants. In addition, if multiple product candidates are approved for the same indication, they may compete for market share, which could limit our future revenue.

~~We are conducting and may conduct future clinical trials for our programs at sites outside the United States, and the FDA may not accept data from trials conducted in such locations.~~58

WeTable ~~are conducting our Phase 1 clinical trials for SPY001 and SPY002 in Canada and the United States, and we may choose to conduct one or more~~ of our future clinical trials outside the United States. Although the FDA may accept data from clinical trials conducted outside the United States, acceptance of this data is subject to conditions imposed by the FDA. For example, the clinical trial must be well-designed and conducted and performed by qualified investigators in accordance with ethical principles. The trial population must also adequately represent the U.S. population, and the data must be applicable to the U.S. population and U.S. medical practice in ways that the FDA deems clinically meaningful. In addition, while these clinical trials are subject to the applicable local laws, FDA acceptance of the data will depend on its determination that the trials also complied with all applicable U.S. laws and regulations. If the FDA does not accept the data from any trial that we conduct outside the United States, it would likely result in the need for additional trials, which would be costly and time-consuming and would delay or permanently halt our development of the applicable product candidates. Even if the FDA accepted such data, it could require us to modify our planned clinical trials to receive clearance to initiate such trials in the United States or to continue such trials once initiated. Contents

~~Further,~~We are conducting ~~international~~and ~~clinical trials presents additional risks that~~ may ~~delay~~conduct ~~completion~~future ~~of our~~ clinical trials. ~~These~~for ~~risks~~our ~~include~~programs ~~the~~at ~~failure~~sites ~~of enrolled participants~~ in ~~foreign~~the ~~countries~~United toStates ~~adhere~~and tovarious ~~clinical~~other ~~protocol as a result of differences in healthcare services or cultural customs that could restrict or limit our ability to conduct our clinical trials~~jurisdictions, and the ~~administrative~~FDA ~~burdens~~and ofcomparable ~~conducting clinical trials under multiple sets of~~ foreign ~~regulations,~~regulatory ~~foreign~~authorities ~~exchange~~may ~~fluctuations,~~not asaccept ~~well~~data asfrom ~~political~~such ~~and economic risks relevant to foreign countries~~trials.

We are conducting and may conduct future clinical trials in the United States and various other countries. The acceptance of trial data from clinical trials conducted outside the United States or other jurisdiction by the FDA or comparable foreign regulatory authority may be subject to conditions imposed by such regulatory authority or may not be accepted at all. For example, in cases where data from foreign clinical trials are intended to serve as the basis for marketing approval in the United States, the FDA will generally not approve the applicable clinical trial data on the basis of foreign data alone unless, among other conditions, (i) the clinical trial is well-designed and conducted and performed by qualified investigators in accordance with ethical principles, (ii) the trial population adequately represents the U.S. population, and (iii) the data is applicable to the U.S. population and U.S. medical practice in ways that the FDA deems clinically meaningful. Many foreign regulatory authorities have similar approval requirements. In addition, clinical trials are subject to the applicable local laws of the jurisdictions where the trials are conducted and acceptance of the data by the FDA or any comparable foreign regulatory authority may depend on its determination that the trials also complied with all applicable local laws and regulations. There can be no assurance that the FDA or any comparable foreign regulatory authority will accept data from trials conducted outside of the United States or the applicable jurisdiction. If the FDA or any comparable foreign regulatory authority does not accept such data, it would likely result in the need for additional trials, which would be costly and time-consuming and would delay or permanently halt our development of the applicable product candidates. Even if the FDA or any comparable foreign regulatory authority accepted such data, it could require us to modify our ongoing or planned clinical trials to receive clearance to initiate such trials in the applicable jurisdiction or to continue such trials once initiated.

Further, conducting international clinical trials presents additional risks that may delay completion of our clinical trials. These risks include the failure of enrolled participants in foreign countries to adhere to clinical protocol as a result of differences in healthcare services or cultural customs that could restrict or limit our ability to conduct our clinical trials, the administrative burdens of conducting clinical trials under multiple sets of foreign regulations, foreign exchange fluctuations, as well as political and economic risks relevant to foreign countries. For additional disclosures regarding political and economic risks involved with international clinical trials, see the risk factor titled “Our business could be adversely affected by economic downturns, inflation, increases in interest rates, natural disasters, public health crises, political crises, U.S. elections, international or geopolitical events, such as the conflict between Russia and Ukraine, recent events in Venezuela, and conflicts in the Middle East, the implementation of measures that restrict international trade or other macroeconomic conditions, which could have a material and adverse effect on our results of operations and financial condition.”

Risks Related to Government Regulation

The regulatory approval processes of the FDA and other comparable foreign regulatory authorities are lengthy, time-consuming and inherently unpredictable. If we are not able to obtain, or if there are delays in obtaining, required regulatory approvals for our product candidates, we will not be able to commercialize, or will be delayed in commercializing, our product candidates, and our ability to generate revenue will be materially impaired.

53The process of obtaining regulatory approvals, both in the United States and abroad, is unpredictable, expensive and typically takes many years following commencement of clinical trials, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved. We cannot commercialize product candidates in the United States without first obtaining regulatory approval from the FDA. Similarly, we cannot commercialize product candidates outside of the United States without obtaining regulatory approval from comparable foreign regulatory authorities. Before obtaining regulatory approvals for the commercial sale of our product candidates, including SPY001, SPY002, SPY072 and SPY003, alone or in combination, we must demonstrate through lengthy, complex and expensive nonclinical studies and clinical trials that our product candidates are both safe and effective for each targeted indication. Securing regulatory approval also requires the submission of information about the drug manufacturing process to, and inspection of manufacturing facilities by, the relevant regulatory authority. Further, our product candidates may not be effective, may be only moderately effective or may prove to have undesirable or unintended side effects, toxicities or other characteristics that may preclude our obtaining

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The process of obtaining regulatory approvals, both in the United States and abroad, is unpredictable, expensive and typically takes many years following commencement of clinical trials, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved. We cannot commercialize product candidates in the United States without first obtaining regulatory approval from the FDA. Similarly, we cannot commercialize product candidates outside of the United States without obtaining regulatory approval from comparable foreign regulatory authorities. Before obtaining regulatory approvals for the commercial sale of our product candidates, including our most advanced product candidates, SPY001, SPY002 and SPY003, we must demonstrate through lengthy, complex and expensive nonclinical studies and clinical trials that our product candidates are both safe and effective for each targeted indication. Securing regulatory approval also requires the submission of information about the drug manufacturing process to, and inspection of manufacturing facilities by, the relevant regulatory authority. Further, our product candidates may not be effective, may be only moderately effective or may prove to have undesirable or unintended side effects, toxicities or other characteristics that may preclude our obtaining marketing approval. The FDA and comparable foreign regulatory authorities have substantial discretion in the approval process and may refuse to accept any application or may decide that our data are insufficient for approval and require additional nonclinical, clinical or other data. Our product candidates could be delayed in receiving, or fail to receive, regulatory approval for many reasons, including: the FDA or comparable foreign regulatory authorities may disagree with the design or implementation of our clinical trials; we may be unable to demonstrate to the satisfaction of the FDA or comparable foreign regulatory authorities that a product candidate is safe and effective for its proposed indication; the results of clinical trials may not meet the level of statistical significance required by the FDA or comparable foreign regulatory authorities for approval; serious and unexpected drug-related side effects may be experienced by participants in our clinical trials or by individuals using drugs similar to our product candidates; we may be unable to demonstrate that a product candidate’s clinical and other benefits outweigh its safety risks; the FDA or comparable foreign regulatory authorities may disagree with our interpretation of data from nonclinical studies or clinical trials; the data collected from clinical trials of our product candidates may not be acceptable or sufficient to support the submission of a BLA or other submission or to obtain regulatory approval in the United States or elsewhere, and we may be required to conduct additional clinical trials; the FDA or the applicable foreign regulatory authority may disagree regarding the formulation, labeling and/or the specifications of our product candidates; the FDA or comparable foreign regulatory authorities may fail to approve the manufacturing processes or facilities of third-party manufacturers with which we contract for clinical and commercial supplies; and the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval. In addition, the FDA and comparable foreign regulatory authorities may undergo leadership changes, change their policies, issue additional regulations or revise existing regulations, or take other actions, which may impact our clinical development plans or prevent or delay approval of our programs under development on a timely basis. Such policy or regulatory changes could impose additional requirements upon us that could delay our ability to obtain approvals and increase the costs of compliance.

Of the large number of drugs in development, only a small percentage successfully complete the FDA or foreign regulatory approval processes and are commercialized. The lengthy approval process as well as the unpredictability of future clinical trial results may result in our failing to obtain regulatory approval to market our product candidates, which would significantly harm our business, results of operations and prospects.

If we were to obtain approval, regulatory authorities may approve any of our product candidates for fewer or more limited indications than we request, including failing to approve the most commercially promising indications, may grant approval contingent on the performance of costly post-marketing clinical trials, or may approve a product candidate with a label that does not include the labeling claims necessary or desirable for the successful commercialization of that product candidate. If we are not able to obtain, or if there are delays in obtaining, required regulatory approvals for our product candidates, we will not be able to commercialize, or will be delayed in commercializing, our product candidates and our ability to generate revenue will be materially impaired.

We may not be able to meet requirements for the chemistry, manufacturing and control of our programs.

In order to receive approval of our products by the FDA and comparable foreign regulatory authorities, we must show that we and our contract manufacturing partners are able to characterize, control and manufacture our drug products and drug delivery devices safely and in accordance with regulatory requirements. This includes manufacturing the active ingredient, developing an acceptable formulation and drug delivery device, manufacturing the drug product and drug delivery device, performing tests to adequately characterize the formulated product, documenting a repeatable manufacturing process, meeting facility, process, testing validation and commercialization requirements, and demonstrating that our drug products meet standards for parenteral administration as well as stability and quality requirements. Meeting these chemistry, manufacturing and control requirements is a complex task that requires specialized expertise. If we are not able to meet the chemistry, manufacturing and control requirements, we may not be successful in getting our products approved.

54Manufacturing biologics is highly susceptible to losses due to contamination, equipment failure, improper installation or operation of equipment, vendor or operator error, inconsistency in yields, variability in product characteristics and difficulties in scaling the production process. The impact to drug supply may be compounded by the long lead times needed to manufacture additional drug product due to plant capacity

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~~standards~~limitations ~~for~~or ~~parenteral~~other ~~administration~~potential asrestrictions ~~well~~at asour ~~stability~~CMOs. ~~and~~In ~~quality~~some ~~requirements.~~cases, ~~Meeting~~even ~~these~~minor ~~chemistry,~~deviations from normal manufacturing ~~and~~processes ~~control~~may ~~requirements~~result isin areduced ~~complex~~production ~~task~~yields, ~~that~~lot ~~requires~~failures, ~~specialized~~product ~~expertise~~defects, product liability claims, or other supply disruptions. If weissues ~~are~~arise ~~not~~at ~~able~~our third-party manufacturers’ facilities, such facilities may need to ~~meet~~be ~~the~~closed ~~chemistry,~~for ~~manufacturing~~an extended period of time to investigate and ~~control~~remedy ~~requirements~~the issues, wewhich ~~may~~could ~~not~~delay beclinical ~~successful~~trials and adversely affect our business. Problems in ~~getting~~third-party manufacturing process or facilities could restrict our ~~products~~ability ~~approved~~to ensure sufficient clinical material for our clinical trials or delay or prevent us from obtaining marketing approval.

Scaling up a biologic manufacturing process can be a difficult task and is associated with additional risks, including cost overruns, process scale-up, process reproducibility, stability issues, compliance with current good manufacturing practices (“cGMPs”), lot consistency and timely availability of sufficient quantity of raw materials. Even if we obtain regulatory approval for any of our product candidates, manufacturers may not be able to manufacture the approved product to specifications acceptable to the FDA or other comparable foreign regulatory authorities, to produce it in sufficient quantities to meet the requirements for the potential launch of the product or to meet potential future demand. If our third-party manufacturers are unable, or decide not, to adequately validate or scale-up the manufacturing process at our current manufacturers’ facilities, we will need to transfer to another manufacturer and complete the manufacturing validation process, which can be lengthy. If our manufacturers are unable to produce sufficient quantities of drug substance and/or drug product for clinical trials or for commercialization we will need to identify and negotiate with other CMOs an agreement for clinical and/or commercial supply and it is not certain we will be able to come to agreement timely or on terms acceptable to us, which would likely jeopardize our ability to provide any product candidates to trial subjects in clinical trials and products to patients, if approved.

Our product candidates for which we intend to seek approval as biologics may face competition sooner than anticipated.

The Patient Protection and Affordable Care Act, as amended by the Healthcare and Education Reconciliation Act ~~(the “ACA”)~~, includes a subtitle called the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which created an abbreviated approval pathway for biological products that are biosimilar to or interchangeable with an FDA-licensed reference biological product. Under the BPCIA, an application for a highly similar or “biosimilar” product may not be submitted to the FDA until four years following the date that the reference product was first approved by the FDA. In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first approved. During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing the sponsor’s own nonclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of their product.

We believe that any of our product candidates approved as biologics under a BLA should qualify for the 12-year period of exclusivity. However, there is a risk that this exclusivity could be shortened due to congressional action or otherwise, or that the FDA will not accord our product candidates reference product exclusivity relative to biosimilar products, potentially creating the opportunity for competition sooner than anticipated. Other aspects of the BPCIA, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent litigation. Moreover, the extent to which a biosimilar, once approved, will be substituted for any reference products in a way that is similar to traditional generic substitution for non-biological products ~~is not yet clear, and~~ will depend on a number of marketplace and regulatory factors that are still developing.

Even if we receive regulatory approval of our product candidates, we will be subject to extensive ongoing post marketing regulatory obligations and continued regulatory review, which may result in significant additional expense and we may be subject to penalties if we fail to comply with post marketing regulatory requirements or experience unanticipated problems with our ~~product candidates~~products.

Any regulatory approvals that we may receive for our product candidates will require the submission of reports to regulatory authorities and surveillance to monitor the safety and efficacy of the product ~~candidate~~, may ~~contain~~impose significant limitations related to use restrictions for specified age groups, warnings, precautions or contraindications, and may include burdensome post-approval trial or risk management requirements. For example, the FDA may require a risk evaluation and mitigation strategy in order to approve our product candidates, which could entail requirements for a medication guide, physician training and communication plans or additional elements to ensure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. In addition, if the FDA or comparable foreign regulatory authorities approve our product candidates, our product candidates and the activities associated with their development and commercialization, including their design, testing, manufacture, safety, efficacy, recordkeeping, labeling, storage, approval, advertising, promotion, sale, distribution, import and export will be subject to comprehensive regulation by the FDA and other regulatory agencies in the United States and by comparable foreign regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration, as well as on-going compliance with current cGMPs, good pharmacovigilance practices (“GVPs”) and GCPs for any post-approval trials that we conduct following approval. In addition, manufacturers of drug products and their facilities are subject to continual review and periodic, unannounced inspections by the FDA and other regulatory authorities for compliance with cGMPs. Following approval, sponsors are also subject to continual review and periodic, unannounced inspections for compliance with GVPs.

If we or a regulatory authority discover previously unknown problems with a product, such as adverse events of unanticipated severity or frequency, or problems with the facilities where the product is manufactured, a regulatory authority may impose restrictions on that product, the manufacturing facility or us, including requiring recall or withdrawal of the product from the market or suspension of manufacturing, restrictions on our 61

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~~ability~~risk tominimization ~~conduct~~tools. ~~post-approval~~In ~~trials~~addition, ~~including~~if ~~full~~the FDA or ~~partial~~comparable ~~holds~~foreign onregulatory ~~ongoing~~authorities orapprove ~~planned~~our ~~trials~~product candidates, ~~restrictions~~our onproduct candidates and the ~~manufacturing~~activities ~~process~~associated with their development and commercialization, ~~warning~~including ortheir ~~untitled~~design, ~~letters~~testing, ~~civil~~manufacture, ~~and~~safety, ~~criminal~~efficacy, ~~penalties~~recordkeeping, ~~injunctions~~labeling, ~~product~~storage, ~~seizures~~approval, ~~detentions~~advertising, orpromotion, ~~import~~sale, ~~bans~~distribution, ~~voluntary~~import orand ~~mandatory~~export ~~publicity~~will ~~requirements~~be subject to comprehensive regulation by the FDA and ~~imposition~~other ofregulatory ~~restrictions~~agencies onin ~~operations,~~the ~~including~~United ~~costly~~States ~~new~~and ~~manufacturing~~by ~~requirements~~comparable foreign regulatory authorities. ~~The~~These ~~occurrence~~requirements include submissions of ~~any~~safety ~~event~~and orother ~~penalty~~post-marketing ~~described~~information ~~above~~and ~~may~~reports, ~~inhibit~~registration, ~~our~~as ~~ability~~well toas ~~commercialize~~on-going ~~our~~compliance ~~product~~with ~~candidates~~current cGMPs, good pharmacovigilance practices (“GVPs”) and ~~generate~~GCPs ~~revenue~~for any post-approval trials that we conduct following approval. In addition, manufacturers of drug products and ~~could~~their ~~require~~facilities usare subject to ~~expend~~continual ~~significant~~review ~~time~~and periodic, unannounced inspections by the FDA and ~~resources~~other inregulatory ~~response~~authorities for compliance with cGMPs. Following approval, sponsors are also subject to continual review and ~~could~~periodic, ~~generate~~unannounced ~~negative~~inspections ~~publicity~~for compliance with GVPs.

WeIf we or a regulatory authority discover previously unknown problems with a product, such as adverse events of unanticipated severity or frequency, or problems with the facilities where the product is manufactured, a regulatory authority may ~~face~~impose ~~difficulties~~restrictions on that product, the manufacturing facility or us, including requiring recall or withdrawal of the product from ~~healthcare~~the ~~legislative~~market ~~reform~~or ~~measures~~suspension of manufacturing, restrictions on our ability to conduct post-approval trials, including full or partial holds on ongoing or planned trials, restrictions on the manufacturing process, warning or untitled letters, civil and ~~other~~criminal ~~changes~~penalties, injunctions, product seizures, detentions or import bans, voluntary or mandatory publicity requirements and imposition of restrictions on operations, including costly new manufacturing requirements. The occurrence of any event or penalty described above may inhibit our ability to commercialize our product candidates and generate revenue and could require us to expend significant time and resources in ~~law~~response and could generate negative publicity.

~~Existing regulatory policies may change, and additional government regulations may be enacted that could prevent, limit or delay development of or regulatory approval of our product candidates.~~ We ~~cannot predict the likelihood, nature or extent of government regulation that~~ may arise from future legislation or administrative action, either in the United States or abroad. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, our product candidates may be ~~delayed~~negatively inimpacted obtaining regulatory approval or may lose any marketing approval that we may have obtained and we may not achieve or sustain profitability. In addition, the impact of legislative, executive, and administrative actions and any future healthcare measures and agency rules implemented by ~~the~~changes ~~current government administration on us and the pharmaceutical industry as a whole is unclear. These government actions could cause delays~~ in ~~our~~law ~~business plans, increase cost of execution of our business plans~~ or ~~otherwise~~other ~~have a material adverse affect on our business. For example~~policy, ifincluding legislation similar to the BIOSECURE Act is passed with terms that require us to switch or move development of our product candidates from one CMO to another, we may incur additional development costs or delays in manufacturing product for clinical trials or commercialization. See the section titled “Business – Government Regulation – Healthcare Reform” in this Annual Report on Form 10-K for a more detailed description of healthcare reform ~~measures that may prevent us from being able to generate revenue, attain profitability, or commercialize our product candidates~~initiatives.

~~Our~~Existing ~~business~~regulatory ~~operations~~policies may change, and ~~current~~additional government regulations may be enacted that could prevent, limit or delay development of or regulatory approval of our product candidates and/or increase our manufacturing costs, general operating costs or other costs. We cannot predict the likelihood, nature or extent of government regulation that may arise from future ~~arrangements~~legislation ~~with~~or ~~investigators~~administrative action, either in the United States or abroad. If we fail to adequately prepare for the impacts of or are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, our product candidates may be delayed in obtaining regulatory approval or may lose any marketing approval that we may have obtained and we may not achieve or sustain profitability. In addition, the impact of legislative, executive, and administrative actions and any future healthcare ~~professionals~~measures and agency rules implemented by the current presidential administration on us and the pharmaceutical industry as a whole is unclear. These government actions could cause delays in our business plans, ~~consultants~~increase the cost of execution of our business plans or otherwise have a material adverse effect on our business. For example, ~~third~~the federal government recently announced tariffs on goods imported from China and other countries, which have been followed by threatened or enacted counter-~~party~~measures ~~payors~~by certain countries. These measures could impact the cost of manufacturing our product candidates for our ongoing and planned clinical trials and may increase other costs such as import and export costs across different jurisdictions, ~~patient~~costs ~~organizations~~of drug product and ~~customers~~clinical ~~will~~trial supplies, and other costs of running our trials and executing on our business plans, which could negatively impact our financial position. We may seek alternative or additional sources for our drug substance or drug product for our clinical trials, clinical trial sites, or service providers, which could negatively impact our expected costs, timelines and business plan. Additionally, the BIOSECURE Act enacted as part of the FY 2026 National Defense Authorization Act has the potential to severely restrict our ability to purchase services or products from, or otherwise collaborate with, certain Chinese “biotechnology companies of concern” without losing the ability to contract with, or otherwise receive funding from, the U.S. government. If any of our CMOs are identified as a BCOC, we could be ~~subject~~required to ~~applicable~~switch or move development of our product candidates from one CMO to another, and as a result we may incur additional development costs or delays in manufacturing product for clinical trials or commercialization. In the U.S., in recent years, the pharmaceutical industry has been a particular focus of healthcare ~~regulatory~~reform ~~laws~~efforts and has been significantly affected by major legislative, ~~which~~administrative ~~could~~and ~~expose~~executive initiatives addressing drug pricing and payment, access to healthcare or funding of healthcare as well as more general actions affecting federal budgets and tariffs. See the section titled “Business – Government Regulation – Healthcare Reform” in this Annual Report for a more detailed description of healthcare reform measures that may prevent us from being able to ~~penalties~~generate revenue, attain profitability, or commercialize our product candidates.

Our business operations and current and future arrangements with investigators, healthcare professionals, consultants, third-party payors, patient organizations and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations. These laws may constrain the business or financial arrangements and relationships through which we conduct our operations, including how we research, market, sell and distribute our product candidates, if approved. See the section titled “Business – Government Regulation – Other Healthcare Laws and Compliance Requirements” in this Annual Report on Form 10-K for a more detailed description of the laws that may affect our ability to operate.62

Ensuring that our internal operations and future business arrangements with third parties comply with applicable healthcare laws and regulations will involve substantial costs. If our operations are found to be in violation of any of these laws or any other governmental laws and regulations that may apply to us, we may be subject to significant penalties, including civil, criminal and administrative penalties, damages, fines, exclusion from government-funded healthcare programs, integrity oversight and reporting obligations to resolve allegations of non-compliance, disgorgement, individual imprisonment, contractual damages, reputational harm, diminished profits and the curtailment or restructuring of our operations. Further, defending against any such actions can be costly and time-consuming and may require significant personnel resources. Therefore, even if we are successful in defending against any such actions that may be brought against us, our business may be impaired.

Even if we are able to commercialize any product candidates, due to unfavorable pricing regulations and/or third-party coverage and reimbursement policies, we may not be able to offer such product candidates at competitive prices, which would seriously harm our business.

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~~candidates~~Our ~~and~~business ~~related~~operations ~~treatments~~and ~~will~~current beand ~~available~~future ~~from~~arrangements ~~government~~with ~~health~~investigators, ~~administration~~healthcare ~~authorities~~professionals, ~~private~~consultants, ~~health insurers and other organizations. Government authorities and other~~ third-party payors, ~~such~~patient ~~as private health insurers and health maintenance~~ organizations, ~~decide~~patients ~~which~~and ~~medications~~others ~~they~~ will ~~pay~~be ~~for~~subject ~~and establish reimbursement levels. Government authorities and other third-party payors have attempted~~ to ~~control~~applicable ~~costs~~healthcare byregulatory ~~limiting coverage and the amount of reimbursement for particular medications. These entities may create preferential access policies for a competitor’s product~~laws, ~~including a branded or generic/biosimilar product, over our products in an attempt to reduce their costs,~~ which ~~may~~could ~~reduce~~expose ~~our~~us ~~commercial opportunity. Additionally, if any of our product candidates are approved and we are found~~ to ~~have improperly promoted off-label uses of those product candidates, we may become subject to significant liability, which would materially adversely affect our business and financial condition~~penalties. See the sections titled “Business – Government Regulation – Coverage and Reimbursement” and “Business – Government Regulation – Regulation in the European Union” in this Annual Report on Form 10-K for a more detailed description of the government regulations and third-party payor practices that may affect our ability to commercialize our product candidates.

Our business operations and current and future arrangements with investigators, healthcare professionals, consultants, third-party payors, patient organizations and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations. These laws may constrain the business or financial arrangements and relationships through which we conduct our operations, including how we research, market, sell and distribute our product candidates, if approved. In the U.S., these laws include, but are not limited to the following, some of which are likely to apply only if or when we obtain marketing approval for a product candidate:

•federal false claims, false statements, and civil monetary penalties laws prohibiting, among other things, any person from knowingly presenting, or causing to be presented, a false claim for payment of government funds or knowingly making, or causing to be made, a false statement to get a false claim paid;

•the federal anti-kickback law, which prohibits, among other things, persons from offering, soliciting, receiving, or providing remuneration, directly or indirectly, to induce either the referral of an individual for, or the purchasing or ordering of, a good or service for which payment may be made under federal healthcare programs such as Medicare and Medicaid;

•the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), which, in addition to privacy protections applicable to healthcare providers and other entities, prohibits executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;

•the FDCA, which among other things, strictly regulates drug marketing, prohibits manufacturers from marketing products prior to approval or for off-label use and regulates the distribution of samples;

•federal laws that require pharmaceutical manufacturers to calculate, report and certify certain complex product prices and other data to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under government healthcare programs, which data may be used in the calculation of reimbursement and/or discounts on approved products;

•the federal Open Payments (or federal “sunshine” law), which requires pharmaceutical and medical device companies to monitor and report certain financial interactions with certain healthcare providers to the Center for Medicare & Medicaid Services within the U.S. Department of Health and Human Services for re-disclosure to the public, as well as ownership and investment interests held by physicians and their immediate family members;

•federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers;

•analogous state laws and regulations, including state anti-kickback and false claims laws, consumer protection and unfair competition laws and laws governing privacy, security and breaches of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts; and

•state laws that require pharmaceutical companies to comply with specific compliance standards, restrict financial interactions between pharmaceutical companies and healthcare providers, report drug product pricing information, financial interactions with health care providers, or marketing expenditures and/or require the registration of pharmaceutical sales representatives.

The distribution of biopharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.

See the section titled “Business – Government Regulation – Other Healthcare Laws and Compliance Requirements” in this Annual Report for a more detailed description of certain laws that may affect our ability to operate.

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Ensuring compliance is time-consuming and costly. If and when one of our product candidates is approved, our compliance efforts will need to expand and evolve to address newly applicable laws. Given the breadth of the laws and regulations, limited guidance for certain laws and regulations and evolving government interpretations of the laws and regulations, governmental authorities may possibly conclude that our business practices are non-compliant. Any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business. If our operations are found to be in violation of any of the laws described above or any other government regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, damages, fines, exclusion from participation in government healthcare programs, such as Medicare and Medicaid, imprisonment, and the curtailment or restructuring of our operations, any of which could adversely affect our business, financial condition, results of operations, and prospects.

We intend to seek approval to market our product candidates in both the United States and in selected foreign jurisdictions. If we obtain approval in one or more foreign jurisdictions for our product candidates, we will be subject to rules and regulations in those jurisdictions. Our ability to successfully commercialize any product candidates that we may develop will depend in significant part on the extent to which reimbursement for these product candidates and related treatments will be available from government health administration authorities, government health benefit programs, private health insurers, such as managed care plans, and other organizations. Government authorities and other third-party payors decide which medications they will pay for and establish reimbursement levels. Government authorities and other third-party payors have attempted to control costs by restricting coverage, controlling utilization and limiting the amount of reimbursement for particular medications. Third party payors may take action to encourage use of other products perceived to be clinically superior or more cost effective which may limit demand for our products. Our ability to commercialize our product candidates successfully may also be adversely affected by discounts or rebates that we are required to provide in order to ensure coverage of our products and compete in the marketplace. Additionally, if any of our product candidates is approved and we are found to have improperly promoted off-label uses of those product candidates, we may become subject to significant liability, which would materially adversely affect our business and financial condition. See the sections titled “Business – Government Regulation – Coverage and Reimbursement” and “Business – Government Regulation – Regulation in the European Union” in this Annual Report for a more detailed description of the government regulations and third-party payor practices that may affect our ability to commercialize our product candidates.

We are subject to U.S. and certain foreign export and import controls, sanctions, embargoes, anti-corruption laws, and anti-money laundering laws and regulations. We can face criminal liability and other serious consequences for violations, which can harm our business.

We are subject to export control and import laws and regulations, including the U.S. Export Administration Regulations, U.S. Customs regulations, various economic and trade sanctions regulations administered by the U.S. Treasury Department’s Office of Foreign Assets Controls, the U.S. Foreign Corrupt Practices Act of 1977, as amended, the U.S. domestic bribery statute contained in 18 U.S.C. § 201, the U.S. Travel Act, the USA PATRIOT Act, ~~the U.S. Physician Payments Sunshine Act~~ and other state and national anti-bribery and anti-money laundering laws in the countries in which we conduct activities. Anti-corruption laws are interpreted broadly and prohibit companies and their employees, agents, contractors, and other collaborators from authorizing, promising, offering, or providing, directly or indirectly, improper payments or anything else of value to or from recipients in the public or private sector. We may engage third parties to sell our products outside the United States, to conduct clinical trials, and/or to obtain necessary permits, licenses, patent registrations, and other regulatory approvals. We have direct or indirect interactions with officials and employees of government agencies or government-affiliated hospitals, universities, and other organizations. We can be held liable for the corrupt or other illegal activities of our employees, agents, contractors, and other collaborators, even if we do not explicitly authorize or have actual knowledge of such activities. Any violations of the laws and regulations described above may result in substantial civil and criminal fines and penalties, imprisonment, the loss of export or import privileges, debarment, tax reassessments, breach of contract and fraud litigation, reputational harm, and other consequences.

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Governments outside the United States tend to impose strict price controls, which may adversely affect our revenue, if any.

In some countries, particularly member states of the EU, the pricing of prescription drugs is subject to governmental control. In these countries, pricing negotiations with governmental authorities can take considerable time after receipt of marketing approval for a therapeutic. In addition, there can be considerable pressure by governments and other stakeholders on prices and reimbursement levels, including as part of cost containment measures. Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained. Reference pricing used by various EU member states and parallel distribution, or arbitrage between low-priced and high-priced member states, can further reduce prices. To obtain coverage and reimbursement or pricing approvals in some countries, we or current or future collaborators may be required to conduct a clinical trial or other studies that compare the cost-effectiveness of our product candidates to other available therapies in order to obtain or maintain reimbursement or pricing approval. Publication of discounts by third-party payors or authorities may lead to further pressure on the prices or reimbursement levels within the country of publication and other countries. If reimbursement of any product candidate approved for marketing is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our business, financial condition, results of operations or prospects could be materially and adversely affected. If the UK or certain EU member states were to significantly alter their regulations affecting the pricing of prescription pharmaceuticals, we could face significant new costs.

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A breakthrough therapy, fast track, or other expedited designation for our product candidates may not lead to a faster development or regulatory review or approval process, and it does not increase the likelihood that those product candidates will receive marketing approval.

We may seek a breakthrough therapy, fast track, or other designation for appropriate product candidates. Designations such as these are within the discretion of the FDA, or other comparable foreign regulatory authorities. The receipt of a designation for a product candidate may not result in a faster development process, review or approval compared to products considered for approval under conventional FDA procedures and does not assure ultimate approval by the FDA. In addition, even if one or more of our product candidates qualify under one of FDA’s designation programs, the FDA may later decide that the products no longer meet the conditions for qualification or decide that the time period for FDA review or approval will not be shortened. Additionally, changes in the leadership of the FDA and other actions taken by the presidential administration, including mass layoffs within the federal government, may impose constraints on the FDA’s ability to engage in activities in the normal course and may result in reductions to the FDA’s budget, employees and operations, which may lead to slower response times and longer review periods, potentially affecting our ability to take advantage of the benefits for the Fast Track Designation and progress development of our programs or obtain regulatory approval for our programs. See the section titled “Business – Government Regulation – United States Biologics Regulation – Expedited Development and Review Programs” in this Annual Report ~~on Form 10-K~~ for a more detailed description of the process for seeking expedited designations such as fast track or breakthrough therapy designations.

Disruptions at the FDA and other government agencies, including as a result of the government shutdown, could negatively affect the review of our regulatory submissions, which could negatively impact our business.

The ability of the FDA to review and approve regulatory submissions can be affected by a variety of factors, including the government shutdown as well as statutory, regulatory and policy changes, inadequate government budget funding levels or a reduction in the FDA’s workforce and its ability to hire and retain key personnel, disruptions caused by government shutdowns and public health crises. There have been mass layoffs of federal employees since the start of the current presidential administration in January 2025, the full impact of which is unclear at this time. Such disruptions could significantly impact the ability of the FDA or other regulatory authorities to timely review and process our regulatory submissions, which could have a material adverse effect on our business. In addition, the presidential administration has made and is expected to continue to make significant changes in the leadership of the FDA and other U.S. federal regulatory agencies and changes to U.S. federal government policy that have led to, in some cases, legal challenges and uncertainty around the funding, functioning and policy priorities of the U.S. federal regulatory agencies, including the FDA.

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We are unable to predict the extent to which the presidential administration may impose or seek to impose leadership or policy changes at the FDA or changes to rules and policies impacting our business and operations. It is unclear how these executive actions or other potential actions by the federal government will impact the FDA or other regulatory authorities that oversee our business. Government proposals to reduce or eliminate budgetary deficits may include reduced allocations to the FDA and other related government agencies. These budgetary pressures may reduce the FDA’s ability to perform its responsibilities, which could result in delays in our clinical trial timelines. If a significant reduction in the FDA’s workforce occurs, the FDA’s budget is significantly reduced or a prolonged government shutdown occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions or take other actions critical to the development or manufacturing of our product candidates, which could have a material adverse effect on our business.

Additionally, the U.S. Supreme Court’s June 2024 decision in Loper Bright Enterprises v. Raimondo overturned the longstanding Chevron doctrine, under which courts were required to give deference to regulatory agencies’ reasonable interpretations of ambiguous federal statutes. The Loper decision could result in additional legal challenges to regulations and guidance issued by federal agencies, including FDA and the Center for Medicare & Medicaid Services, on which we rely. Any such legal challenges, if successful, could have a material impact on our business. Additionally, the Loper decision may result in increased regulatory uncertainty, inconsistent judicial interpretations, and other impacts to the agency rulemaking process, any of which could adversely impact our business and operations. We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative action or as a result of legal challenges, either in the United States or abroad. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, our business could be materially harmed.

Risks Related to Our Intellectual Property

Our ability to obtain and protect our patents and other proprietary rights is uncertain, exposing us to the possible loss of competitive advantage.

We rely upon a combination of patents, trademarks, trade secret protection, confidentiality agreements, license agreements, including the License Agreements, and the Paragon Agreement to protect the intellectual property related to our programs and technologies and to prevent third parties from competing unfairly with us. Our success depends in large part on our ability to obtain and maintain patent protection for our platform technologies, programs and their uses, as well as our ability to operate without infringing on or violating the proprietary rights of others. We own and have licensed rights to pending patent applications and expect to continue to file patent applications in the United States and abroad related to our novel discoveries and technologies that are important to our business. However, we may not be able to protect our intellectual property rights throughout the world and the legal systems in certain countries may not favor enforcement or protection of patents, trade secrets and other intellectual property. Filing, prosecuting and defending patents on programs worldwide would be expensive and our intellectual property rights in some foreign jurisdictions can be less extensive than those in the United States; the reverse may also occur. As such, we may not have patents in all countries or all major markets and may not be able to obtain patents in all jurisdictions even if we apply for them. Our competitors may operate in countries where we do not have patent protection and can freely use our technologies and discoveries in such countries to the extent such technologies and discoveries are publicly known or disclosed in countries where we do have patent protection or pending patent applications.

Our pending and future patent applications may not result in patents being issued. Any issued patents may not afford sufficient protection of our programs or their intended uses against competitors, nor can there be any assurance that the patents issued will not be infringed, designed around, invalidated by third parties, or effectively prevent others from commercializing competitive technologies, products or programs. Even if these patents are granted, they may be difficult to enforce. Further, any issued patents that we may license or own covering our programs could be narrowed or found invalid or unenforceable if challenged in court or before administrative bodies in the United States or abroad, including the United States Patent and Trademark Office (“USPTO”). Further, if we encounter delays in our clinical trials or delays in obtaining regulatory approval, the period of time during which we could market our product candidates under patent protection would be reduced. Thus, the patents that we may own ~~and~~or license may not afford us any meaningful competitive advantage.

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In addition to seeking patents for some of our technology and programs, we may also rely on trade secrets, including unpatented know-how, technology and other proprietary information, to maintain our competitive position. Any disclosure, either intentional or unintentional, by our employees, the employees of third parties with whom we share our facilities or third-party consultants and vendors that we engage to perform research, clinical trials or manufacturing activities, or misappropriation by third parties (such as through a cybersecurity breach) of our trade secrets or proprietary information could enable competitors to duplicate or surpass our technological achievements, thus eroding our competitive position in our market. In order to protect our proprietary technology and processes, we rely in part on confidentiality agreements with our collaborators, employees, consultants, outside scientific collaborators and sponsored researchers and other advisors. These agreements may not effectively prevent disclosure of confidential information and may not provide an adequate remedy in the event of unauthorized disclosure of confidential information. We may need to share our proprietary information, including trade secrets, with future business partners, collaborators, contractors and others located in countries at heightened risk of theft of trade secrets, including through direct intrusion by private parties or state actors and those affiliated with or controlled by state actors. In addition, while we undertake efforts to protect our trade secrets and other confidential information from disclosure, others may independently discover trade secrets and proprietary information, and in such cases, we may not be able to assert any trade secret rights against such party. Costly and time-consuming litigation could be necessary to enforce and determine the scope of our proprietary rights and failure to obtain or maintain trade secret protection could adversely affect our competitive business position. Enforcing a claim that a party illegally obtained and is using our trade secrets is challenging and the outcome is unpredictable. In addition, courts outside of the U.S. may be less willing to protect trade secrets.

Lastly, if our trademarks and trade names are not registered or adequately protected, then we may not be able to build name recognition in our markets of interest and our business may be adversely affected.

We may not be successful in obtaining or maintaining necessary rights to our programs through acquisitions and in-licenses.

Because our development programs currently do and may in the future require the use of proprietary rights held by third parties, the growth of our business may depend in part on our ability to acquire, in-license, or use these third-party proprietary rights. We may be unable to acquire or in-license any compositions, methods of use, processes or other third-party intellectual property rights from third parties that we identify as necessary for our programs. The licensing and acquisition of third-party intellectual property rights is a competitive area, and a number of more established companies may pursue strategies to license or acquire third-party intellectual property rights that we may consider attractive or necessary. These established companies may have a competitive advantage over us due to their size, capital resources and greater clinical development and commercialization capabilities. In addition, companies that perceive us to be a competitor may be unwilling to assign or license rights to us. We also may be unable to license or acquire third-party intellectual property rights on terms that would allow us to make an appropriate return on our investment or at all. If we are unable to successfully obtain rights to required third-party intellectual property rights or maintain the existing intellectual property rights we have, we may have to abandon development of the relevant program, which could have a material adverse effect on our business, financial condition, results of operations, and prospects.

While we normally seek to obtain the right to control prosecution, maintenance and enforcement of the patents relating to our programs, there may be times when the filing and prosecution activities for patents and patent applications relating to our programs are controlled by our current and future licensors or collaboration partners. If any of our current and future licensors or collaboration partners fail to prosecute, maintain and enforce such patents and patent applications in a manner consistent with the best interests of our business, including by payment of all applicable fees for patents covering our product candidates, we could lose our rights to the intellectual property or our exclusivity with respect to those rights, our ability to develop and commercialize those product candidates may be adversely affected and we may not be able to prevent competitors from making, using and selling competing products. In addition, even where we have the right to control patent prosecution of patents and patent applications we have licensed to and from third parties, we may still be adversely affected or prejudiced by actions or inactions of our licensees, our current and future licensors and their counsel that took place prior to the date upon which we assumed control over patent prosecution.

Our current and future licensors may rely on third-party consultants or collaborators or on funds from third parties such that our current and future licensors are not the sole and exclusive owners of the patents we in-license. If other third parties have ownership rights to our current and future in-licensed patents, they may be able to license such patents to our competitors, and our competitors could market competing products and technology. This could have a material adverse effect on our competitive position, business, financial conditions, results of operations, and prospects.

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doin-license. ~~so,~~If weother ~~may~~third beparties ~~unable~~have toownership ~~develop~~rights orto ~~commercialize the affected product candidates, which could harm~~ our ~~business,~~current ~~financial~~and ~~condition,~~future ~~results~~in-licensed ~~of operations~~patents, ~~and~~they ~~prospects~~may ~~significantly.~~be Weable ~~cannot~~to ~~provide~~license ~~any~~such ~~assurances that third-party~~ patents doto ~~not~~our ~~exist~~competitors, ~~which~~and ~~might be enforced against~~ our ~~current~~competitors ~~technology,~~could ~~manufacturing~~market ~~methods,~~competing ~~programs,~~products orand ~~future~~technology. ~~methods~~This orcould ~~products~~have ~~resulting~~a inmaterial ~~either~~adverse aneffect ~~injunction~~on ~~prohibiting~~ our ~~manufacture~~competitive ~~or future sales~~position, orbusiness, ~~with~~financial ~~respect to our future sales~~conditions, anresults ~~obligation on our part to pay royalties and/or other forms~~ of ~~compensation to third parties~~operations, ~~which~~and ~~could be significant~~prospects.

It is possible that we may be unable to obtain licenses at a reasonable cost or on reasonable terms, if at all. Even if we are able to obtain a license, it may be non-exclusive, thereby giving our competitors access to the same technologies licensed to us. In that event, we may be required to expend significant time and resources to redesign our technology, programs, or the methods for manufacturing them or to develop or license replacement technology, all of which may not be feasible on a technical or commercial basis. If we are unable to do so, we may be unable to develop or commercialize the affected product candidates, which could harm our business, financial condition, results of operations, and prospects significantly. We cannot provide any assurances that third-party patents do not exist which might be enforced against our current technology, manufacturing methods, programs, or future methods or products resulting in either an injunction prohibiting our manufacture or future sales, or, with respect to our future sales, an obligation on our part to pay royalties and/or other forms of compensation to third parties, which could be significant.

Disputes may arise between us and our current and future licensors regarding intellectual property subject to a license agreement, including: the scope of rights granted under the license agreement and other interpretation-related issues; whether and the extent to which our technology and processes infringe on intellectual property of the licensor that is not subject to the licensing agreement; our right to sublicense patents and other rights to third parties; our right to transfer or assign the license; the inventorship and ownership of inventions and know-how resulting from the joint creation or use of intellectual property by our current and future licensors and us and our partners; and the priority of invention of patented technology.

We may be subject to patent infringement claims or may need to file claims to protect our intellectual property, which could result in substantial costs and liability and prevent us from commercializing our potential products.

Because the intellectual property landscape in the biotechnology industry is rapidly evolving and interdisciplinary, it is difficult to conclusively assess our freedom to operate and guarantee that we can operate without infringing on or violating third-party rights. If certain of our product candidates are ultimately granted regulatory approval, patent rights held by third parties, if found to be valid and enforceable, could be alleged to render one or more of our product candidates infringing. If a third party successfully brings a claim against us, we may be required to pay substantial damages, be forced to abandon any affected product candidate and/or seek a license from the patent holder. In addition, any intellectual property claims (e.g. patent infringement or trade secret theft) brought against us, whether or not successful, may cause us to incur significant legal expenses and divert the attention of our management and key personnel from other business concerns. We cannot be certain that patents owned or licensed by us will not be challenged by others in the course of litigation. Some of our competitors may be able to sustain the costs of complex intellectual property litigation more effectively than we can because they have substantially greater resources. In addition, any uncertainties resulting from the initiation and continuation of any litigation could have a material adverse effect on our ability to raise funds and on the market price of our common stock.

Competitors may infringe or otherwise violate our patents, trademarks, copyrights or other intellectual property. To counter infringement or other violations, we may be required to file claims, which can be expensive and time-consuming. Any such claims could provoke these parties to assert counterclaims against us, including claims alleging that we infringe their patents or other intellectual property rights. In addition, in a patent infringement proceeding, a court or administrative body may decide that one or more of the patents we assert is invalid or unenforceable, in whole or in part, construe the patent’s claims narrowly or refuse to prevent the other party from using the technology at issue on the grounds that our patents do not cover the technology. Similarly, if we assert trademark infringement claims, a court or administrative body may determine that the marks we have asserted are invalid or unenforceable or that the party against whom we have asserted trademark infringement has superior rights to the marks in question. In such a case, we could ultimately be forced to cease use of such marks. In any intellectual property litigation, even if we are successful, any award of monetary damages or other remedy we receive may not be commercially valuable.

Further, we may be required to protect our patents through procedures created to attack the validity of a patent at the USPTO. An adverse determination in any such submission or proceeding could reduce the scope or enforceability of, or invalidate, our patent rights, which could adversely affect our competitive position. Because of a lower evidentiary standard in USPTO proceedings compared to the evidentiary standard in United States federal courts necessary to invalidate a patent claim, a third party could potentially provide evidence in a USPTO proceeding sufficient for the USPTO to hold a claim invalid even though the same evidence would be insufficient to invalidate the claim if first presented in a district court action. 68

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~~result~~Further, ofwe ~~these~~may ~~claims,~~be ~~which~~required ~~may~~to ~~require~~protect usour patents through procedures created to ~~initiate~~attack the validity of a patent at the USPTO. An adverse determination in any such submission or ~~defend~~proceeding ~~protracted~~could ~~and~~reduce ~~costly~~the ~~litigation~~scope onor ~~behalf~~enforceability of, ~~licensees~~or ~~and~~invalidate, ~~other~~our ~~parties~~patent ~~regardless~~rights, which could adversely affect our competitive position. Because of a lower evidentiary standard in USPTO proceedings compared to the ~~merits~~evidentiary ofstandard ~~such~~in ~~claims.~~United IfStates ~~any~~federal ofcourts ~~these~~necessary ~~claims~~to ~~succeed~~invalidate a patent claim, wea ~~may~~third beparty ~~forced~~could potentially provide evidence in a USPTO proceeding sufficient for the USPTO to ~~pay~~hold ~~damages~~a onclaim ~~behalf~~invalid ofeven ~~those~~though ~~parties~~the orsame ~~may~~evidence would be ~~required~~insufficient to ~~obtain~~invalidate ~~licenses~~the ~~for~~claim ~~the~~if ~~products~~first ~~they~~presented ~~use~~in a district court action.

In addition, if our programs are found to infringe the intellectual property rights of third parties, these third parties may assert infringement claims against our future licensees and other parties with whom we have business relationships and we may be required to indemnify those parties for any damages they suffer as a result of these claims, which may require us to initiate or defend protracted and costly litigation on behalf of licensees and other parties regardless of the merits of such claims. If any of these claims succeed, we may be forced to pay damages on behalf of those parties or may be required to obtain licenses for the products they use.

Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation or other legal proceedings relating to our intellectual property rights, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation or other proceedings.

We may be subject to claims that we have wrongfully hired an employee from a competitor or that our employees, consultants or independent contractors have wrongfully used or disclosed confidential information of third parties.

As is common in the biotechnology industry, in addition to our employees, we engage the services of consultants to assist us in the development of our programs. Many of these consultants, and many of our employees, were previously employed at, or may have previously provided or may be currently providing consulting services to, other biotechnology or pharmaceutical companies including our competitors or potential competitors. Despite our training and compliance efforts, we could in the future be subject to claims that we or our employees have inadvertently or otherwise used or disclosed alleged trade secrets or other confidential information of former employers or competitors. Although we try to ensure that our employees and consultants do not use the intellectual property, proprietary information, know-how or trade secrets of others in their work for us, we may become subject to claims that we caused an employee to breach the terms of his or her non-competition or non-solicitation agreement, or that we or these individuals have, inadvertently or otherwise, used or disclosed the alleged trade secrets or other proprietary information of a former employer or competitor.

While we may litigate to defend ourselves against these claims, even if we are successful, litigation could result in substantial costs and could be a distraction to management. If our defenses to these claims fail, in addition to requiring us to pay monetary damages, a court could prohibit us from using technologies or features that are essential to our programs, if such technologies or features are found to incorporate or be derived from the trade secrets or other proprietary information of the former employers. Moreover, any such litigation or the threat thereof may adversely affect our reputation, our ability to form strategic alliances or sublicense our rights to collaborators, engage with scientific advisors or hire employees or consultants, each of which would have an adverse effect on our business, results of operations and financial condition. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management.

Changes to patent laws in the United States and other jurisdictions could diminish the value of patents in general, thereby impairing our ability to protect our products.

Changes in either the patent laws or interpretation of patent laws in the United States, including patent reform legislation such as the Leahy-Smith America Invents Act (the “Leahy-Smith Act”) could increase the uncertainties and costs surrounding the prosecution of our owned and in-licensed patent applications and the maintenance, enforcement or defense of our owned and in-licensed issued patents. The Leahy-Smith Act includes a number of significant changes to United States patent law. These changes include provisions that affect the way patent applications are prosecuted, redefine prior art, provide more efficient and cost-effective avenues for competitors to challenge the validity of patents, and enable third-party submission of prior art to the USPTO during patent prosecution and additional procedures to attack the validity of a patent at USPTO-administered post-grant proceedings, including post-grant review, inter partes review and derivation proceedings. Assuming that other requirements for patentability are met, prior to March 2013, in the United States, the first to invent the claimed invention was entitled to the patent, while outside the United States, the first to file a patent application was entitled to the patent. After March 2013, under the Leahy-Smith Act, the United States transitioned to a first-to-file system in which, assuming that the other statutory requirements for patentability are met, the first inventor to file a patent application will be entitled to the patent on an invention regardless of whether a third party was the first to invent the claimed invention. As such, the Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business, financial condition, results of operations and prospects.

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InUSPTO ~~addition,~~during ~~the~~ patent ~~positions~~prosecution ~~of companies in the development~~ and ~~commercialization~~additional ofprocedures ~~biologics~~to ~~and~~attack ~~pharmaceuticals~~the ~~are~~validity ~~particularly uncertain. U.S. Supreme Court and U.S. Court~~ of ~~Appeals~~a ~~for~~patent ~~the~~at ~~Federal~~USPTO-administered ~~Circuit~~post-grant ~~rulings~~proceedings, ~~have~~including ~~narrowed~~post-grant ~~the~~review, ~~scope~~inter ofpartes ~~patent~~review ~~protection~~and ~~available~~derivation inproceedings. ~~certain~~Assuming ~~circumstances~~that ~~and~~other ~~weakened~~requirements ~~the~~for ~~rights~~patentability ofare ~~patent~~met, ~~owners~~prior into ~~certain~~March ~~situations~~2013, ~~including~~ in the ~~antibody arts. For example, the~~ United States ~~Supreme Court in Amgen~~, ~~Inc.~~the v.first ~~Sanofi (Amgen) recently held that Amgen’s patent claims~~ to ainvent ~~class~~the ofclaimed ~~antibodies~~invention ~~functionally~~was ~~defined~~entitled ~~by their ability~~ to ~~bind a particular antigen were invalid for lack of enablement where~~ the patent, ~~specification~~while ~~provided~~outside ~~twenty-six~~the ~~exemplary~~United ~~antibodies~~States, ~~but~~ the ~~claimed~~first ~~class~~to offile ~~antibodies covered~~ a ~~“vast number” of additional antibodies not disclosed in the specification. The Court stated that if~~ patent ~~claims~~application ~~are~~was ~~directed~~entitled to ~~an entire class of compositions of matter, then~~ the patent. ~~specification~~After ~~must~~March ~~enable~~2013, aunder ~~person skilled in~~ the ~~art~~Leahy-Smith toAct, ~~make and use~~ the ~~entire~~United ~~class~~States oftransitioned ~~compositions. This decision makes it unlikely that we will be granted U.S. patents with composition of matter claims directed~~ to ~~antibodies functionally defined by their ability to bind~~ a ~~particular antigen. Even if we are granted claims directed~~ first-to-file ~~functionally~~system ~~defined~~in ~~antibodies~~which, itassuming ~~is possible~~ that athe ~~third~~other ~~party~~statutory ~~may~~requirements ~~challenge~~for ~~our~~patentability ~~patents,~~are ~~when issued~~met, ~~relying on~~ the ~~reasoning~~first ininventor ~~Amgen~~to orfile ~~other~~a ~~recent~~patent ~~precedential~~application ~~court~~will ~~decisions.~~be ~~Additionally,~~entitled ~~there have been proposals for additional changes~~ to the patent ~~laws~~on ofan ~~the~~invention ~~United~~regardless ~~States~~of ~~and~~whether ~~other~~a ~~countries~~third ~~that,~~party ifwas ~~adopted,~~the ~~could~~first ~~impact our ability~~ to ~~enforce~~invent ~~our~~the ~~proprietary~~claimed ~~technology~~invention. ~~This~~As ~~combination~~such, ofthe ~~events~~Leahy-Smith ~~has~~Act ~~created~~and ~~uncertainty~~its ~~with~~implementation ~~respect~~could toincrease the ~~validity~~uncertainties and ~~enforceability~~costs ofsurrounding ~~patents once obtained. Depending on future actions by~~ the ~~U.S.~~prosecution ~~Congress,~~of ~~the~~our ~~federal~~patent ~~courts,~~applications ~~the USPTO~~ and the ~~relevant~~enforcement ~~law-making~~or ~~bodies~~defense inof ~~other~~our ~~countries,~~issued ~~the laws and regulations governing~~ patents, ~~could~~all ~~change~~of inwhich ~~unpredictable ways that~~ could have a material adverse effect on our ~~patent~~business, ~~rights~~financial ~~and~~condition, ~~our~~results ~~ability~~of tooperations ~~protect, defend~~ and ~~enforce our patent rights in the future~~prospects.

~~Geopolitical~~In ~~instability~~addition, in the ~~United~~patent ~~States~~positions ~~and~~of companies in ~~foreign countries could increase~~ the ~~uncertainties~~development and ~~costs~~commercialization ~~surrounding the prosecution or maintenance~~ of ~~patent~~biologics ~~applications~~ and ~~the~~pharmaceuticals ~~maintenance,~~are ~~enforcement~~particularly oruncertain. ~~defense of issued patents~~U.S. ~~For~~Supreme ~~example,~~Court ~~the United States~~ and ~~foreign~~U.S. ~~government~~Court ~~actions related to Russia’s invasion~~ of ~~Ukraine~~Appeals ~~may~~for ~~limit~~the orFederal ~~prevent~~Circuit ~~filing,~~rulings ~~prosecution~~have ~~and~~narrowed ~~maintenance~~the scope of patent ~~applications~~protection available in ~~Russia.~~certain ~~Government~~circumstances ~~actions~~and ~~may~~weakened ~~also~~the ~~prevent~~rights ~~maintenance~~ of ~~issued~~patent ~~patents~~owners in ~~Russia.~~certain ~~These~~situations, ~~actions~~including ~~could result~~ in ~~abandonment~~the orantibody ~~lapse~~arts. ofFor ~~patents or patent applications~~example, ~~resulting~~the inUnited ~~partial~~States orSupreme ~~complete~~Court ~~loss~~in ofAmgen, ~~patent~~Inc. ~~rights in Russia~~v. IfSanofi ~~such~~(Amgen) anrecently ~~event~~held ~~were~~that toAmgen’s ~~occur,~~patent itclaims ~~could~~to ~~have~~ a ~~material~~class ~~adverse~~of ~~effect~~antibodies onfunctionally ~~our~~defined ~~business. In addition, a decree was adopted~~ by ~~the~~their ~~Russian~~ability ~~government~~to inbind ~~March~~a ~~2022,~~particular ~~allowing~~antigen ~~Russian~~were ~~companies~~invalid ~~and~~for ~~individuals~~lack toof ~~exploit~~enablement ~~inventions~~where ~~owned~~the bypatent ~~patentees~~specification ~~that~~provided ~~have~~twenty-six ~~citizenship~~exemplary orantibodies, ~~nationality~~but ~~in,~~the ~~are~~claimed ~~registered~~class ~~in,~~of orantibodies ~~have~~covered ~~predominately~~a ~~primary~~“vast ~~place~~number” of ~~business~~additional orantibodies ~~profit-making~~not ~~activities~~disclosed in the ~~United~~specification. ~~States~~The ~~and~~Court ~~other~~stated ~~countries~~ that ~~Russia~~if ~~has~~patent ~~deemed~~claims ~~unfriendly~~are ~~without~~directed ~~consent or compensation. Consequently, we would not be able~~ to ~~prevent~~an ~~third~~entire ~~parties~~class ~~from~~of ~~practicing~~compositions ~~our~~of ~~inventions~~matter, inthen ~~Russia~~the orpatent ~~from~~specification ~~selling~~must orenable ~~importing~~a ~~products~~person ~~made~~skilled ~~using our inventions~~ in ~~and~~the ~~into~~art ~~Russia.~~to ~~Accordingly,~~make ~~our competitive position may be impaired,~~ and ~~our~~use ~~business,~~the ~~financial~~entire ~~condition,~~class ~~results~~ of ~~operations and prospects may be adversely affected~~compositions. InThis ~~addition,~~decision amakes ~~European~~it ~~Unified~~unlikely ~~Patent~~that ~~Court~~we ~~(“UPC”)~~will ~~entered~~be ~~into~~granted ~~force on June 1, 2023~~U.S. ~~The~~patents ~~UPC~~with iscomposition aof ~~common~~matter ~~patent~~claims ~~court~~directed ~~that~~to ~~hears~~antibodies ~~patent~~functionally ~~infringement~~defined ~~and~~by ~~revocation~~their ~~proceedings~~ability ~~effective~~to ~~for~~bind ~~member~~a ~~states~~particular ofantigen. ~~the~~Even ~~EU.~~if ~~This~~we ~~could~~are ~~enable~~granted ~~third~~claims ~~parties~~directed to ~~seek~~functionally ~~revocation~~defined ofantibodies, ait ~~European~~is ~~patent~~possible inthat a ~~single~~third ~~proceeding~~party atmay ~~the~~challenge ~~UPC~~our ~~rather~~patents, ~~than~~when ~~through~~issued, ~~multiple~~relying ~~proceedings~~on ~~in each of~~ the ~~jurisdictions~~reasoning in ~~which~~Amgen ~~the~~or ~~European~~other ~~patent~~recent isprecedential ~~validated~~court decisions. ~~Although~~Additionally, wethere dohave ~~not~~been ~~currently~~proposals ~~own any European patents or applications~~ for ~~our~~additional ~~current~~changes ~~pipeline,~~to ifthe wepatent ~~obtain~~laws ~~such~~of ~~patents and applications in~~ the ~~future,~~United ~~any~~States ~~such revocation~~ and ~~loss~~other ofcountries ~~patent~~that, ~~protection~~if adopted, could ~~have a material adverse~~ impact on our ~~business and our~~ ability to ~~commercialize~~enforce ~~or license~~ our ~~technology~~proprietary ~~and products~~technology. ~~Moreover,~~This ~~the~~combination ~~controlling laws and regulations~~ of ~~the~~events ~~UPC~~has ~~will~~created ~~develop~~uncertainty ~~over~~with ~~time,~~respect ~~and may adversely affect our ability~~ to ~~enforce or defend~~ the validity ofand ~~any~~enforceability ~~European~~of patents weonce ~~may obtain~~obtained. WeDepending ~~may~~on ~~decide~~future toactions ~~opt~~by ~~out from~~ the ~~UPC~~U.S. ~~any~~Congress, ~~future~~the ~~European~~federal ~~patent~~courts, ~~applications~~the ~~that~~USPTO ~~we may file~~ and ~~any~~the ~~patents~~relevant welaw-making ~~may~~bodies ~~obtain.~~in Ifother ~~certain formalities and requirements are not met~~countries, ~~however,~~the ~~such~~laws ~~European patents~~ and ~~patent~~regulations ~~applications~~governing patents could bechange ~~challenged~~in ~~for~~ways ~~non-compliance~~that ~~and~~could ~~brought~~have ~~under~~a ~~the~~material ~~jurisdiction~~adverse ofeffect ~~the~~on ~~UPC.~~our Wepatent ~~cannot~~rights ~~be certain that future European patents~~ and ~~patent~~weaken ~~applications~~our ~~will~~ability ~~avoid~~to ~~falling under the jurisdiction of the UPC~~protect, ifdefend weand ~~decide~~enforce toour ~~opt~~patent ~~out~~rights ofin the ~~UPC~~future.

~~Obtaining~~Geopolitical instability in the United States and ~~maintaining~~in foreign countries could increase the uncertainties and costs surrounding the prosecution or maintenance of patent ~~protection~~applications ~~depends~~and the maintenance, enforcement or defense of issued patents. For example, the United States and foreign government actions related to Russia’s invasion of Ukraine may limit or prevent filing, prosecution and maintenance of patent applications in Russia. Government actions may also prevent maintenance of issued patents in Russia. These actions could result in abandonment or lapse of patents or patent applications, resulting in partial or complete loss of patent rights in Russia. If such an event were to occur, it could have a material adverse effect on ~~compliance~~our ~~with~~business. ~~various~~In ~~procedural~~addition, ~~document~~a ~~submissions~~decree was adopted by the Russian government in March 2022, ~~fee~~allowing ~~payment~~Russian companies and ~~other~~individuals ~~requirements~~to ~~imposed~~exploit inventions owned by ~~governmental~~patentees ~~patent~~that ~~agencies~~have citizenship or nationality in, are registered in, or have predominately primary place of business or profit-making activities in the United States and other countries that Russia has deemed unfriendly without consent or compensation. Consequently, we would not be able to prevent third parties from practicing our inventions in Russia or from selling or importing products made using our inventions in and into Russia. Accordingly, our competitive position may be impaired, and our business, financial condition, results of operations and prospects may be adversely affected. In addition, a European Unified Patent Court (“UPC”) entered into force on June 1, 2023. The UPC is a common patent court that hears patent infringement and revocation proceedings effective for member states of the EU. This could enable third parties to seek revocation of a European patent in a single proceeding at the UPC rather than through multiple proceedings in each of the jurisdictions in which the European patent is validated. Given that we own or license certain European patents or applications for our current pipeline, any such revocation and loss of patent protection could behave ~~reduced~~a material adverse impact on our business and our ability to commercialize or ~~eliminated~~license our technology and products. Moreover, the controlling laws and regulations of the UPC will develop over time, and may adversely affect our ability to enforce or defend the validity of any European patents we may obtain. We may decide to opt out from the UPC any future European patent applications that we may file and any patents we may obtain. If certain formalities and requirements are not met, however, such European patents and patent applications could be challenged for non-compliance ~~with~~and ~~these~~brought ~~requirements~~under the jurisdiction of the UPC. We cannot

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~~similar~~be ~~provisions~~certain ~~during~~that ~~the~~future ~~patent~~European ~~application~~patents ~~process.~~and ~~While~~patent anapplications ~~inadvertent~~will ~~lapse~~avoid ~~can~~falling inunder ~~many~~the ~~cases~~jurisdiction ~~be cured by payment~~ of ~~a late fee or by other means in accordance with~~ the ~~applicable rules~~UPC, ~~there~~if ~~are~~we ~~situations~~decide into ~~which~~opt ~~noncompliance~~out ~~can result in abandonment or lapse~~ of the ~~patent or patent application~~UPC, ~~resulting in partial~~ or ~~complete~~that ~~loss~~we ofwill ~~patent~~have ~~rights in~~ the ~~relevant~~ability ~~jurisdiction. Non-compliance events that could result in abandonment or lapse of a patent or patent application include, but are not limited~~ to, ~~failure~~opt toout ~~respond to official actions within prescribed time limits, non-payment~~ of ~~fees~~the ~~and~~UPC ~~failure~~in ~~to properly legalize and submit formal documents. If we fail to maintain~~ the ~~patents and patent applications covering our programs, our competitive position would be adversely affected~~future.

Obtaining and maintaining patent protection depends on compliance with various procedural, document submissions, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.

Periodic maintenance fees, renewal fees, annuities fees and various other governmental fees on patents and/or patent applications are due to be paid to the USPTO and foreign patent agencies in several stages over the lifetime of the patent and/or patent application. The USPTO and various foreign governmental patent agencies also require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application process. While an inadvertent lapse can in many cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. Non-compliance events that could result in abandonment or lapse of a patent or patent application include, but are not limited to, failure to respond to official actions within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal documents. If we fail to maintain the patents and patent applications covering our programs, our competitive position would be adversely affected.

We may not identify relevant third-party patents or may incorrectly interpret the relevance, scope or expiration of a third-party patent, which might adversely affect our ability to develop and market our products.

We cannot guarantee that any of our patent searches or analyses, including the identification of relevant patents, the scope of patent claims or the expiration of relevant patents, are complete or thorough, nor can we be certain that we have identified each and every third-party patent and pending application in the United States and abroad that is relevant to or necessary for the commercialization of our product candidates in any jurisdiction. The scope of a patent claim is determined by an interpretation of the law, the written disclosure in a patent and the patent’s prosecution history. Our interpretation of the relevance or the scope of a patent or a pending application may be incorrect. For example, we may incorrectly determine that our products are not covered by a third-party patent or may incorrectly predict whether a third party’s pending application will issue with claims of relevant scope. Our determination of the expiration date of any patent in the United States or abroad that we consider relevant may be incorrect. Our failure to identify and correctly interpret relevant patents may negatively impact our ability to develop and market our products.

In addition, because some patent applications in the United States may be maintained in secrecy until the patents are issued, patent applications in the United States and many foreign jurisdictions are typically not published until 18 months after priority filing, and publications in the scientific literature often lag behind actual discoveries, we cannot be certain that others have not filed patent applications for technology covered by our issued patents or our pending applications, or that we were the first to invent the technology. Our competitors may have filed, and may in the future file, patent applications covering our products or technology similar to ours. Any such patent application may have priority over our patent applications or patents, which could require us to obtain rights to issued patents covering such technologies.

We may become subject to claims challenging the inventorship or ownership of our patents and other intellectual property.

We may be subject to claims that former employees, collaborators or other third parties have an interest in our patents or other intellectual property as an inventor or co-inventor. The failure to name the proper inventors on a patent application can result in the patents issuing thereon being unenforceable. Inventorship disputes may arise from conflicting views regarding the contributions of different individuals named as inventors, the effects of foreign laws where foreign nationals are involved in the development of the subject matter of the patent, conflicting obligations of third parties involved in developing our programs or as a result of questions regarding co-ownership of potential joint inventions. Litigation may be necessary to resolve these and other claims challenging inventorship and/or ownership. Alternatively, or additionally, we may enter into agreements to clarify the scope of our rights in such intellectual property. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, valuable intellectual property. Such an outcome could have a material adverse effect on our business. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees.

Our current and future licensors may have relied on third-party consultants or collaborators or on funds from third parties, such as the U.S. government, such that our licensors are not the sole and exclusive owners of the patents we in-licensed. The U.S. government therefore has certain rights in such inventions under the applicable funding agreements and under applicable law. If other third parties have ownership rights or other rights to our in-licensed patents, they may be able to license such patents to our competitors, and our competitors could market competing products and technology. This could have a material adverse effect on our competitive position, business, financial conditions, results of operations, and prospects.71

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paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, valuable intellectual property. Such an outcome could have a material adverse effect on our business. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees.

Our current and future licensors may have relied on third-party consultants or collaborators or on funds from third parties, such as the U.S. government, such that our licensors are not the sole and exclusive owners of the patents we in-licensed. The U.S. government has certain rights in such inventions under the applicable funding agreements and under applicable law. If other third parties have ownership rights or other rights to our in-licensed patents, they may be able to license such patents to our competitors, and our competitors could market competing products and technology. This could have a material adverse effect on our competitive position, business, financial conditions, results of operations, and prospects.

Patent terms may be inadequate to protect the competitive position of our product candidates for an adequate amount of time.

Patents have a limited lifespan. In the United States, if all maintenance fees are timely paid, the natural expiration of a patent is generally 20 years from its earliest United States non-provisional filing date. Various extensions may be available, but the life of a patent, and the protection it affords, is limited. Even if patents covering our product candidates are obtained, once the patent life has expired, we may be open to competition from competitive products, including generics or biosimilars. Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such product candidates might expire before or shortly after such product candidates are commercialized. As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.

Our technology licensed from various third parties may be subject to retained rights or may be affected by our failure to comply with obligations under license agreements or other disruptions to business relationships with licensors resulting in loss of license rights that are important to our business.

Our current or future licensors may retain certain rights under the relevant agreements with us, including the right to use the underlying technology for noncommercial academic and research use, to publish general scientific findings from research related to the technology, and to make customary scientific and scholarly disclosures of information relating to the technology. It is difficult to monitor whether our licensors limit their use of the technology to these uses, and we could incur substantial expenses to enforce our rights to our licensed technology in the event of misuse. In addition, under our license agreements, we may be generally responsible for bringing any actions against third parties for infringing on the patents we have licensed. Certain of our license agreements may also require us to meet development thresholds to maintain the license, including establishing a set timeline for developing and commercializing products. In spite of our efforts, our licensors might conclude that we have materially breached our obligations under such license agreements and might therefore terminate the license agreements, thereby removing or limiting our ability to develop and commercialize products and technology covered by these license agreements. If these in-licenses are terminated, or if the underlying patents fail to provide the intended exclusivity, competitors or other third parties may seek regulatory approval of, and to market, products identical to ours or we may be required to cease our development and commercialization of one or more product candidates. Any of the foregoing could have a material adverse effect on our competitive position, business, financial conditions, results of operations, and growth prospects. Disputes may arise regarding intellectual property subject to a licensing agreement, including:

•the scope of rights granted under the license agreement and other interpretation-related issues;

•the extent to which our technology and processes infringe on intellectual property of the licensor that is not subject to the licensing agreement;

•the sublicensing of patent and other rights to third parties under our collaborative development relationships;

•our diligence obligations under the license agreement with respect to the use of the licensed technology in relation to our development and commercialization of our product candidates and what activities satisfy those diligence obligations;

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•the inventorship and ownership of inventions and know-how resulting from the joint creation or use of intellectual property by our licensors and us and our partners; and

•the priority of invention of patented technology.

In addition, the agreements under which we currently license intellectual property or technology from third parties are complex, and certain provisions in such agreements may be susceptible to multiple interpretations. The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology or broaden what we believe to be the scope of the licensor’s rights to our intellectual property and technology, or increase what we believe to be our financial or other obligations under the relevant agreement, any of which could have a material adverse effect on our business, financial condition, results of operations, and prospects. Moreover, if disputes over intellectual property that we have licensed prevent or impair our ability to maintain our current licensing arrangements on commercially acceptable terms, we may be unable to successfully develop and commercialize the affected product candidates. It is also possible that a third party could be granted limited licenses to some of the same technology, in certain circumstances. Any such events could result in the loss of our ability to develop and commercialize one or more product candidates or we could lose other significant rights, any of which could have a material adverse effect on our business, financial conditions, results of operations, and prospects.

We have limited foreign intellectual property rights and may not be able to protect our intellectual property and proprietary rights throughout the world.

We have limited intellectual property rights outside of the United States. Filing, prosecuting, and defending patents on product candidates in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the United States can be less extensive than those in the United States. In addition, the laws of foreign countries do not protect intellectual property rights to the same extent as the federal and state laws of the United States. In addition, intellectual property license agreements we enter into may not always include worldwide rights. Consequently, we may not be able to prevent third parties from using our intellectual property in all countries outside the United States, or from selling or importing products made using our intellectual property in and into the United States or other jurisdictions. Competitors may use our technologies in jurisdictions where we have not obtained patent protection to develop their own products and, further, may export otherwise infringing products to territories where we have patent protection but where enforcement is difficult or impractical. These products may compete with our product candidates and our patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.

Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets, and other intellectual property protection, particularly those relating to biotechnology and pharmaceutical products, which could make it difficult for us to stop the infringement of our patents or marketing of competing products against third parties in violation of our intellectual property and proprietary rights generally. Proceedings to enforce our patents and intellectual property rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing, and could provoke third parties to assert claims against us. We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful. Moreover, the initiation of proceedings by third parties to challenge the scope or validity of our patent rights in foreign jurisdictions could result in substantial cost and divert our efforts and attention from other aspects of our business. Accordingly, our efforts to enforce our intellectual property and proprietary rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.

Many countries have invoked compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties. In addition, many countries limit the enforceability of patents against government agencies or government contractors. In these countries, the patent owner may have limited remedies, which could materially diminish the value of such patent. If we or any of our licensors is forced to grant a license to third parties with respect to any patents relevant to our business, our competitive position may be impaired, and our business, financial condition, results of operations, and prospects may be adversely affected.

The intellectual property landscape around engineered antibodies is highly dynamic, and third parties may initiate legal proceedings alleging that we are infringing, misappropriating, or otherwise violating

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their intellectual property rights, the outcome of which would be uncertain and may prevent, delay or otherwise interfere with our product discovery and development efforts.

Due to the intense research and development that is taking place in the field of engineered antibodies, including by us and our competitors, the intellectual property landscape is evolving and in flux, and it may remain uncertain for the coming years. There may be significant intellectual property related litigation and proceedings relating to our owned and in-licensed, and other third party, intellectual property and proprietary rights in the future.

Our commercial success depends upon our ability and the ability of our collaborators and licensors to develop, manufacture, market, and sell any product candidates that we may develop and use our proprietary technologies without infringing, misappropriating, or otherwise violating the intellectual property and proprietary rights of third parties. The biotechnology and pharmaceutical industries are characterized by extensive litigation regarding patents and other intellectual property rights as well as administrative proceedings for challenging patents, including interference, derivation, inter partes review, post grant review, and reexamination proceedings before the USPTO or oppositions and other comparable proceedings in foreign jurisdictions. We may be subject to and may in the future become party to, or threatened with, adversarial proceedings or litigation regarding intellectual property rights with respect to our product candidates we may develop, including interference proceedings, post-grant review, inter partes review, and derivation proceedings before the USPTO and similar proceedings in foreign jurisdictions such as oppositions before the EPO. Numerous U.S. and foreign issued patents and pending patent applications that are owned by third parties exist in the fields in which we are developing our product candidates and they may assert infringement claims against us based on existing patents or patents that may be granted in the future, regardless of their merit.

As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our product candidates may give rise to claims of infringement of the patent rights of others. Moreover, it is not always clear to industry participants, including us, which patents cover various types of therapies, products or their methods of use or manufacture. We are aware of certain third-party patent applications that, if issued, may be construed to cover some of our product candidates. There may also be third-party patents of which we are currently unaware with claims to technologies, methods of manufacture or methods for treatment related to the use or manufacture of our product candidates. Because patent applications can take many years to issue, there may be currently pending patent applications that may later result in issued patents that our product candidates may infringe. In addition, third parties may obtain patents in the future and claim that use of our technologies infringes upon these patents.

Because of the large number of patents issued and patent applications filed in our field, third parties may allege they have patent rights encompassing our product candidates, technologies or methods. Third parties may assert that we are employing their proprietary technology without authorization and may file patent infringement claims or lawsuit against us, and if we are found to infringe such third-party patents, we may be required to pay damages, cease commercialization of the infringing technology, or obtain a license from such third parties, which may not be available on commercially reasonable terms or at all.

Our ability to commercialize our product candidates in the United States and abroad may be adversely affected if we cannot obtain a license on commercially reasonable terms to relevant third-party patents that cover our product candidates. Even if we believe third-party intellectual property claims are without merit, there can be no assurance that a court would find in our favor on questions of infringement, validity, enforceability, or priority. A court of competent jurisdiction could hold that these third-party patents are valid, enforceable, and infringed, which could materially and adversely affect our ability to commercialize any product candidates we may develop and any other product candidates or technologies covered by the asserted third-party patents. In order to successfully challenge the validity of any such U.S. patent in federal court, we would need to overcome a presumption of validity. As this burden is a high one requiring us to present clear and convincing evidence as to the invalidity of any such U.S. patent claim, there can be no assurance that a court of competent jurisdiction would invalidate the claims of any such U.S. patent. If we are found to infringe a third party’s intellectual property rights, and we are unsuccessful in demonstrating that such patents are invalid or unenforceable, we could be required to obtain a license from such third party to continue developing, manufacturing, and marketing impacted product candidates we may develop and our technology. However, we may not be able to obtain any required license on commercially reasonable terms or at all. Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors and other third parties access to the same technologies licensed to us, and it could require us to make substantial licensing and royalty payments. If we are unable to obtain a necessary license to a third-party patent on commercially reasonable terms, we may be unable to commercialize certain product candidates or such commercialization efforts may be significantly delayed, which could in turn significantly harm our business. We also could be forced, including by court order, to cease

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developing, manufacturing, and commercializing the infringing technology or product candidates. In addition, we could be found liable for significant monetary damages, including treble damages and attorneys’ fees, if we are found to have willfully infringed a patent or other intellectual property right. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar material adverse effect on our business, financial condition, results of operations, and prospects.

Defense of third-party claims of infringement of misappropriation, or violation of intellectual property rights involves substantial litigation expense and would be a substantial diversion of management and employee time and resources from our business. Some third parties may be able to sustain the costs of complex patent litigation more effectively than we can because they have substantially greater resources. In addition, any uncertainties resulting from the initiation and continuation of any litigation could have a material adverse effect on our ability to raise the funds necessary to continue our operations or could otherwise have a material adverse effect on our business, financial condition, results of operations and prospects. There could also be public announcements of the results of hearings, motions, or other interim proceedings or developments, and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock. Any of the foregoing events could have a material adverse effect on our business, financial condition, results of operations and prospects.

Risks Related to Our Reliance on Third Parties

We rely on collaborations and licensing arrangements with third parties, including our arrangement with Paragon. If we are unable to maintain these collaborations or licensing arrangements, or if these collaborations or licensing arrangements are not successful, our business could be negatively impacted.

We currently rely on our collaborations and licensing arrangements with third parties, including Paragon, for a substantial portion of our discovery capabilities and in-licenses.

Collaborations or licensing arrangements that we enter into may not be successful, and any success will depend heavily on the efforts and activities of such collaborators or licensors. If any of our collaborators or licensors experiences delays in performance of, or fails to perform its obligations under their agreement with us, disagrees with our interpretation of the terms of such agreement or terminates their agreement with us, ~~the~~our research programs with respect to which we have signed license agreements for or exercised the Option to acquire intellectual property license rights to or have the Option to acquire intellectual property license rights to pursuant to the Paragon Agreement and development timeline could be adversely affected. If we fail to comply with any of the obligations under our collaborations or license agreements, including payment terms and diligence terms, our collaborators or licensors may have the right to terminate such agreements, in which event we may lose intellectual property rights and may not be able to develop, manufacture, market or sell the products covered by our agreements or may face other penalties under our agreements. Our collaborators and licensors may also fail to properly maintain or defend the intellectual property we have licensed from them, if required by our agreement with them, or even infringe upon, our intellectual property rights, leading to the potential invalidation of our intellectual property or subjecting us to litigation or arbitration, any of which would be time-consuming and expensive and could harm our ability to commercialize our product candidates. In addition, collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our programs and products if the collaborators believe that the competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours.

As part of our strategy, we plan to evaluate additional opportunities to enhance our capabilities and expand our development pipeline or provide development or commercialization capabilities that complement our own. We may not realize the benefits of such collaborations, alliances or licensing arrangements. Any of these relationships may require us to incur non-recurring and other charges, increase our near and long-term expenditures, issue securities that dilute our existing stockholders or disrupt our management and business.

64We may face significant competition in attracting appropriate collaborators, and more established companies may also be pursuing strategies to license or acquire third-party intellectual property rights that we consider attractive. These companies may have a competitive advantage over us due to their size, financial resources and greater clinical development and commercialization capabilities. In addition, companies that perceive us to be a competitor may be unwilling to assign or license rights to us. Whether we reach a definitive agreement for a collaboration will depend upon, among other things, our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of a number of factors. Collaborations are complex and time-consuming to negotiate,

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We may face significant competition in attracting appropriate collaborators, and more established companies may also be pursuing strategies to license or acquire third-party intellectual property rights that we consider attractive. These companies may have a competitive advantage over us due to their size, financial resources and greater clinical development and commercialization capabilities. In addition, companies that perceive us to be a competitor may be unwilling to assign or license rights to us. Whether we reach a definitive agreement for a collaboration will depend upon, among other things, our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of a number of factors. Collaborations are complex and time-consuming to negotiate, document and execute. In addition, consolidation among large pharmaceutical and biotechnology companies has reduced the number of potential future collaborators. We may not be able to negotiate additional collaborations on a timely basis, on acceptable terms or at all. If we fail to enter into collaborations and do not have sufficient funds or expertise to undertake the necessary development and commercialization activities, we may not be able to further develop our product candidates or bring them to market.

We currently rely, and plan to rely in the future, on third parties to conduct and support our nonclinical studies and clinical trials. If these third parties do not properly and successfully carry out their contractual duties or meet expected deadlines, we may not be able to obtain regulatory approval of or commercialize our product candidates.

We have utilized and plan to continue to utilize and depend upon independent investigators and collaborators, such as medical institutions, CROs, contract testing labs and strategic partners, to conduct and support our nonclinical studies and clinical trials under agreements with us. We will rely heavily on these third parties over the course of our nonclinical studies and clinical trials, and we control only certain aspects of their activities. As a result, we will have less direct control over the conduct, timing and completion of these nonclinical studies and clinical trials and the management of data developed through nonclinical studies and clinical trials than would be the case if we were relying entirely upon our own staff. Nevertheless, we are responsible for ensuring that each of our studies and trials is conducted in accordance with the applicable protocol, legal, regulatory and scientific standards, and our reliance on these third parties does not relieve us of our regulatory responsibilities. We and our third-party contractors and CROs are required to comply with good laboratory practice ("GLP"), GCP and GVP regulations, which are regulations and guidelines enforced by the FDA and comparable foreign regulatory authorities for all of our programs in clinical development. If we or any of these third parties fail to comply with applicable GLP, GCP and GVP regulations, the nonclinical and clinical data generated in our nonclinical studies and clinical trials may be deemed unreliable and the FDA or comparable foreign regulatory authorities may require us to perform additional nonclinical and clinical trials before approving our marketing applications. We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our nonclinical studies and clinical trials comply with GLP, GCP and GVP regulations. In addition, our ~~nonclinical studies and~~ clinical trials must be conducted with products produced under cGMP regulations. Our failure to comply with these regulations may require us to repeat nonclinical studies and clinical trials, which would delay the regulatory approval process. Moreover, our business may be implicated if any of these third parties violates federal or state fraud and abuse or false claims laws and regulations or healthcare privacy and security laws.

Any third parties conducting our nonclinical studies and clinical trials will not be our employees and, except for remedies available to us under our agreements with such third parties, we cannot control whether they devote sufficient time and resources to our programs. These third parties may be involved in mergers, acquisitions or similar transactions and may have relationships with other commercial entities, including our competitors, for whom they may also be conducting nonclinical studies, clinical trials or other product development activities, which could negatively affect their performance on our behalf and the timing thereof and could lead to products that compete directly or indirectly with our current or future product candidates. If any of our relationships with these third parties, doincluding ~~not~~CMOs ~~successfully~~and ~~carry~~CROs, ~~out~~are ~~their~~terminated, ~~contractual~~we ~~duties~~may ornot ~~obligations~~be orable ~~meet~~to ~~expected~~enter ~~deadlines~~into arrangements with alternative CMOs, ifCROs ~~they~~or ~~need~~other third parties or to bedo ~~replaced~~so oron ifcommercially ~~the~~reasonable ~~quality~~terms. Switching or ~~accuracy~~adding ofadditional ~~the~~CMOs ~~clinical~~or ~~data~~CROs ~~they~~involves ~~obtain~~additional iscost ~~compromised~~and ~~due~~requires tocompany ~~the~~resources. ~~failure~~In toaddition, ~~adhere~~there tois ~~our~~a ~~nonclinical~~natural ~~and~~transition ~~clinical~~period ~~protocols~~when ora ~~regulatory~~new ~~requirements~~CMO or ~~for~~CRO ~~other~~begins ~~reasons~~work. As a result, delays may occur, which can materially impact our ~~nonclinical~~ability ~~studies~~to ~~and~~meet our desired clinical ~~trials~~development ~~may~~timelines. beThough ~~extended,~~we ~~delayed~~carefully ormanage ~~terminated~~our relationships with our CMOs and CROs, there can be no assurance that we ~~may~~will not beencounter ~~able~~similar tochallenges ~~complete~~or ~~development~~delays ~~of,~~in ~~obtain~~the ~~regulatory~~future ~~approval~~or ofthat these delays or ~~successfully~~challenges ~~commercialize~~will not have a material adverse impact on our ~~product~~business, ~~candidates~~financial condition and prospects.

InIf ~~addition~~these CMOs, weCROs ~~currently~~or ~~rely~~other onthird ~~foreign~~parties ~~CROs~~do ~~and~~not ~~CMOs,~~successfully ~~including~~carry ~~WuXi~~out ~~Biologics,~~their ~~and~~contractual ~~will~~duties ~~likely~~or ~~continue~~obligations or meet expected deadlines, if they need to ~~rely~~be onreplaced ~~foreign~~or ~~CROs~~if ~~and~~the ~~CMOs~~quality inor accuracy of the ~~future.~~clinical Wedata orthey obtain is compromised due to the ~~foreign~~failure ~~CROs~~(including by clinical sites or ~~CMOs~~investigators) weto ~~work~~adhere ~~with~~to our nonclinical and clinical protocols or regulatory requirements or for other reasons, our nonclinical studies and clinical trials may be ~~subject~~extended, delayed or terminated and we may not be able to Ucomplete development of, obtain regulatory approval of or successfully commercialize our product candidates.S. ~~legislation~~As a result, ~~including~~our results of operations and the ~~potential~~commercial ~~passing~~prospects offor anour ~~act~~product ~~similar~~candidates would be harmed, our costs could increase substantially and our ability to ~~the~~generate ~~previously~~revenues ~~proposed~~could be delayed significantly.

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In addition, we currently rely on foreign CROs and CMOs, including WuXi Biologics, and will likely continue to rely on foreign CROs and CMOs in the future. We or the foreign CROs or CMOs we work with may be subject to U.S. legislation, including the BIOSECURE Act included as part of the FY 2026 National Defense Authorization Act, sanctions, trade restrictions and other foreign regulatory requirements which could increase the cost or reduce the supply of material available to us, delay the procurement or supply of such material or have an adverse effect on our ability to secure significant commitments from governments to purchase our potential therapies or disrupt our supply chain. IfFor example, in April 2025, the United States government imposed significant tariffs on imports from China and other countries and may impose more restrictions on goods, including biologically derived substances, manufactured in or imported from China or impose other restrictions on companies’ ability to work with Chinese biotechnology companies. We are in the process of creating manufacturing capabilities with third parties outside of China, including within the United States, and have taken several measures to strengthen our supply chain in the event that our manufacturers are impacted; however, to the extent the aforementioned restrictions or future tariffs are applicable to the material we import from China and other countries or if we are not able to secure supply of our product candidates as a result of applicable legislation, ~~this~~our ~~could~~business ~~result~~and infinancial acondition ~~material~~could ~~adverse~~be ~~effect~~adversely onaffected despite our ~~Company~~mitigation efforts.

~~For example~~Further, the biopharmaceutical industry in China is strictly regulated by the Chinese government. Changes to Chinese regulations or government policies affecting biopharmaceutical companies are unpredictable and may have a material adverse effect on our collaborators in China which could have an adverse effect on our business, financial condition, results of operations and prospects. Evolving changes in China’s public health, economic, political, and social conditions and the uncertainty around China’s relationship with other governments, such as the United States and the UK, could also negatively impact our ability to manufacture our product candidates for our ongoing or planned clinical trials or have an adverse effect on our ability to secure government funding, which could adversely affect our financial condition and cause us to delay our clinical development programs.

We currently rely and expect to rely in the future on the use of manufacturing suites in third-party facilities or on third parties to manufacture our product candidates, and we may rely on third parties to produce and process our products, if approved. Our business could be adversely affected if we are unable to use third-party manufacturing suites or if the third-party manufacturers encounter difficulties in production.

We do not currently own any facility that may be used as our clinical or commercial manufacturing and processing facility and must currently rely on CMOs to manufacture our product candidates. We have not yet caused our product candidates to be manufactured on a commercial scale and may not be able to do so for any of our programs, if approved. We currently have a sole source relationship for our supply of the SPY001, SPY002 and SPY003 programs ~~and one of the molecules in our SPY002 program~~. If there should be any disruption in such supply arrangement, including any adverse events affecting our suppliers, it could have a negative effect on the clinical development of our programs and other operations while we work to identify and qualify alternate supply sources. We may not control the manufacturing process of, and may be completely dependent on, our contract manufacturing partners for compliance with cGMP requirements and any other regulatory requirements of the FDA or comparable foreign regulatory authorities for the manufacture of our product candidates. Beyond periodic audits, we have limited control over the ability of our CMOs to maintain adequate quality control, quality assurance and other qualified personnel. If the FDA or a comparable foreign regulatory authority does not approve these facilities for the manufacture of our product candidates or if it withdraws any approval in the future, we may need to find alternative manufacturing facilities, which would require the incurrence of significant additional costs and delays, and materially adversely affect our ability to develop, obtain regulatory approval for or market our product candidates, if approved. Similarly, our failure, or the failure of our CMOs, to comply with applicable regulations could result in sanctions being imposed on us, including fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of product candidates or drugs, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect supplies of our product candidates or drugs and harm our business and results of operations.

Moreover, our CMOs may experience manufacturing difficulties due to resource constraints, supply chain issues, proposed or actual legislative changes or requirements, or as a result of labor disputes or unstable political environments. If any CMOs on which we will rely fail to manufacture quantities of our product candidates at quality levels necessary to meet regulatory requirements and at a scale sufficient to meet anticipated demand at a cost that allows us to achieve profitability, ~~our~~including ~~business,~~tariffs ~~financial condition~~ and ~~prospects~~restrictions ~~could~~imposed beby ~~materially~~the ~~and~~United ~~adversely~~States ~~affected.~~or ~~In addition, our CMOs and~~ other ~~third~~foreign ~~parties~~governments ~~are~~on ~~responsible~~goods ~~for~~required ~~transporting temperature-controlled materials that can be inadvertently degraded during transport due to several factors, rendering certain batches unsuitable~~ for ~~trial use for failure to meet, among others, our integrity and purity specifications. We and any of our CMOs may also face product seizure or detention or refusal to permit~~ the ~~import~~operation ~~or export~~ of ~~products.~~their ~~Our~~ business could be materially adversely affected by business disruptions to our third-party providers that could materially adversely affect our anticipated timelines, potential future revenue and financial condition and increase our costs and expenses. ~~Each~~If ~~of these risks could delay or prevent the completion of our nonclinical studies and clinical trials or the approval of~~ any ofCMOs ~~our~~on ~~product~~which ~~candidates~~we bywill ~~the~~rely ~~FDA,~~fail ~~resulting~~to ~~in higher costs or adversely impact commercialization of our product candidates. See the section titled “Business – Manufacturing and Supply” in this Annual Report on Form~~

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10manufacture quantities of our product candidates at quality levels necessary to meet regulatory requirements and at a scale sufficient to meet anticipated demand at a cost that allows us to achieve profitability, our business, financial condition and prospects could be materially and adversely affected. In addition, our CMOs and other third parties are responsible for transporting temperature-Kcontrolled materials that can be inadvertently degraded during transport due to several factors, rendering certain batches unsuitable for trial use for failure to meet, among others, our integrity and purity specifications. We and any of our CMOs may also face product seizure or detention or refusal to permit the import or export of products or increased costs as a result of tariffs on imports imposed by the United States or other foreign governments. Our business could be materially adversely affected by business disruptions to our third-party providers that could materially adversely affect our anticipated timelines, potential future revenue and financial condition and increase our costs and expenses. Each of these risks could delay or prevent the completion of our nonclinical studies and clinical trials or the approval of any of our product candidates by the FDA, resulting in higher costs or adversely impact commercialization of our product candidates. See the section titled “Business – Manufacturing and Supply” in this Annual Report a more detailed description of our manufacturing plans and assumptions and the factors that may affect the success of our programs.

Risks Related to Employee Matters, Managing Growth and Other Risks Related to Our Business

In order to successfully implement our plans and strategies, we will need to grow the size of our organization and we may experience difficulties in managing this growth.

We expect to continue to experience significant growth in the number of our employees and the scope of our operations, particularly in the areas of ~~nonclinical and~~ clinical drug development, technical operations, clinical operations, regulatory affairs and, potentially, ~~sales~~commercial ~~and marketing~~operations. To manage our anticipated future growth, we must continue to implement and improve our managerial, operational and financial personnel and systems, ~~expand our facilities~~ and continue to recruit and train additional qualified personnel. Due to our limited financial resources and the ~~limited~~ experience of our management team, ~~working~~who have only worked together for a limited time in managing a public company with such anticipated growth, we may not be able to effectively manage the expansion of our operations or recruit and train additional qualified personnel.

We are highly dependent on our key personnel and anticipate hiring new key personnel. If we are not successful in attracting and retaining highly qualified personnel, we may not be able to successfully implement our business strategy.

We are a clinical stage biotechnology company with a limited operating history, and, as of December 31, ~~2024~~2025, we had 65102 employees. We have been and will continue to be highly dependent on the research and development, clinical and business development expertise of our executive officers, as well as the other principal members of our management, scientific and clinical team. Any such officers and other principal members may terminate their employment with us at any time. We do not maintain “key person” insurance for any of our executives or other employees.

Attracting and retaining qualified personnel will also be critical to our success, including with respect to any strategic transaction that we may pursue. The loss of the services of our executive officers or other key employees could impede the achievement of our research, development and commercialization objectives and seriously harm our ability to successfully implement our business strategy. Furthermore, replacing executive officers and key personnel may be difficult and may take an extended period of time because of the limited number of individuals in our industry with the breadth of skills and experience required to successfully develop, facilitate regulatory approval of and commercialize product candidates. Competition to hire from this limited pool is intense, and we may be unable to hire, train, retain or motivate these key personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for similar personnel. We also experience competition for the hiring of scientific and clinical personnel from universities and research institutions.

In addition, we rely on consultants and advisors, including scientific and clinical advisors, to assist us in formulating our discovery and nonclinical and clinical development and commercialization strategy. Our consultants and advisors may be employed by employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit their availability to us. If we are unable to continue to attract and retain high quality personnel, our ability to pursue our growth strategy will be limited.

~~Our future growth may depend, in part, on our ability to operate in foreign markets, where we would be subject to additional regulatory burdens and other risks and uncertainties.~~78

Our future growth may depend, in part, on our ability to develop and commercialize our product candidates in foreign markets for which we may rely on collaboration with third parties. We are not permitted to market or promote any of our product candidates before we receive regulatory approval from the applicable foreign regulatory authority, and may never receive such regulatory approval for any of our product candidates. To obtain separate regulatory approval in many other countries, we must comply with numerous and varying regulatory requirements of such countries regarding safety and efficacy and governing, among other things, clinical trials and commercial sales, pricing and distribution of our product candidates, and we cannot predict success in these jurisdictions. If we fail to comply with the regulatory requirements in international markets and receive applicable marketing approvals, our target market will be reduced and our ability to realize the full

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~~market~~Our ~~potential~~future ofgrowth ~~our~~may ~~product~~depend, ~~candidates~~in ~~will be harmed and our business will be adversely affected. Moreover~~part, ~~even~~on ~~if we obtain approval of~~ our ~~product~~ability ~~candidates~~to ~~and~~operate ~~ultimately commercialize our product candidates~~ in foreign markets, where we would be subject to ~~the~~additional ~~risks and uncertainties, including the burden of complying with complex and changing foreign~~ regulatory, ~~tax,~~burdens ~~accounting~~ and ~~legal~~other ~~requirements~~risks and ~~reduced protection of intellectual property rights in some foreign countries~~uncertainties.

Our future growth may depend, in part, on our ability to develop and commercialize our product candidates in foreign markets for which we may rely on collaboration with third parties. Recent and ongoing changes in the United States trade policy with foreign countries, including the continued uncertainty surrounding U.S. tariffs and retaliatory measures by foreign governments may disrupt the global supply chain for biopharmaceutical products. Any direct tariffs, if imposed on pharmaceutical products, may result in increased costs for raw materials and contract manufacturing services, reduced ability to source critical CMOs, and a delay in our development timelines.

We are not permitted to market or promote any of our product candidates before we receive regulatory approval from the applicable foreign regulatory authority, and may never receive such regulatory approval for any of our product candidates. To obtain separate regulatory approval in many other countries, we must comply with numerous and varying regulatory requirements of such countries regarding safety and efficacy and governing, among other things, clinical trials and commercial sales, pricing and distribution of our product candidates, and we cannot predict success in these jurisdictions. If we fail to comply with the regulatory requirements in international markets and receive applicable marketing approvals, our target market will be reduced and our ability to realize the full market potential of our product candidates will be harmed and our business will be adversely affected. Moreover, even if we obtain approval of our product candidates and ultimately commercialize our product candidates in foreign markets, we would be subject to the risks and uncertainties, including the burden of complying with complex and changing foreign regulatory, tax, accounting and legal requirements and reduced protection of intellectual property rights in some foreign countries.

Our estimates of market opportunity and forecasts of market growth may prove to be inaccurate, and even if the markets in which we compete achieve the forecasted growth, our business may not grow at similar rates, or at all.

Our market opportunity estimates and growth forecasts are subject to significant uncertainty and are based on assumptions and estimates which may not prove to be accurate. Our estimates and forecasts relating to size and expected growth of our target market may prove to be inaccurate. Even if the markets in which we compete meet our size estimates and growth forecasts, our business may not grow at similar rates, or at all. Our growth is subject to many factors, including our success in implementing our business strategy, which is subject to many risks and uncertainties.

Our revenue will be dependent, in part, upon the size of the markets in the territories for which we gain regulatory approval, the accepted price for the product, the ability to obtain coverage and reimbursement and whether we own the commercial rights for that territory. If the number of our addressable patients is not as significant as we estimate, the indication approved by regulatory authorities is narrower than we expect or the treatment population is narrowed by competition, physician choice or treatment guidelines, we may not generate significant revenue from sales of such products, even if approved.

Our employees, independent contractors, consultants, commercial collaborators, principal investigators, CROs, CMOs, suppliers and vendors may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements.

Despite our employee training and compliance programs, we are exposed to the risk that our employees, independent contractors, consultants, commercial collaborators, principal investigators, CROs, CMOs, suppliers and vendors acting for or on our behalf may engage in misconduct or other improper activities. We have adopted a code of conduct and ethics, policies, standard operating procedures and other compliance efforts but it is not always possible to identify and deter misconduct by these parties and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations.

Our internal information technology systems, oras well as those of any of our CROs, manufacturers, other contractors or consultants, third-party service providers, orand potential future collaborators, ~~may~~are ~~fail~~subject orto ~~suffer~~the risk of failure, security orbreaches, data privacy ~~breaches~~incidents, or other unauthorized or improper access to, use of, or destruction of our proprietary or confidential data, employee data or personal data, which could result in additional costs, loss of revenue, significant liabilities, harm to our brand and material disruption of our operations.

In the ordinary course of our business, we and the third parties upon which we rely collect, receive, store, process, generate, use, transfer, disclose, make accessible, protect, secure, dispose of, transmit, and share (collectively, process) proprietary, confidential, and sensitive data, including personal data, intellectual property, trade secrets, and other sensitive data (collectively, sensitive information).79

Despite the implementation of security measures in an effort to protect systems that store our information, given their size and complexity and the increasing amounts of information maintained on our internal information technology systems and those of our third-party CROs, other contractors (including sites performing our clinical trials), third-party service providers and supply chain companies, and consultants, these systems are potentially vulnerable to breakdown or other damage or interruption from service interruptions, system malfunction, natural disasters, terrorism, war and telecommunication and electrical failures, as well as security breaches from inadvertent or intentional actions by our employees, contractors, consultants, business partners and/or other third parties, or from cyber-attacks by malicious third parties, which may compromise our system infrastructure or lead to the loss, destruction, alteration or dissemination of, or damage to, our data.

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access to, use of, or destruction of proprietary, confidential, employee, or personal data, which could result in additional costs, loss of revenue, significant liabilities, harm to our brand, and material disruption to our business.

To achieve our business objectives, we depend on our own internal IT systems and networks, as well as those of third parties and their vendors. These systems are used to process and store sensitive data—including confidential research, business plans, financial information, intellectual property, trade secrets and various personal data that may be legally protected. They also play a critical role in maintaining the continuity of our supply chain and operations, and are integral to many of the products provided to customers.

Although we have implemented security measures designed to protect our information systems and the data they store, the size and complexity of these systems—and the increasing volume of information maintained on our internal IT systems and those of our third-party CROs, other contractors (including clinical trial sites), service providers, supply chain partners, and consultants—make them potentially vulnerable to a range of risks. These risks include breakdowns or other damage or interruption from service interruptions, system malfunction, natural disasters, terrorism, war and telecommunication and electrical failures, as well as security breaches from inadvertent or intentional actions by our employees, contractors, consultants, business partners and/or other third parties, or from cyber-attacks by malicious third parties. Such incidents could compromise our system infrastructure or lead to the loss, destruction, alteration or dissemination of, or damage to, our data. The evolving use of AI by malicious actors is expected to further intensify cybersecurity threats. For example, AI can be leveraged to develop adaptive malware, generate highly convincing phishing or impersonation attacks (such as deepfakes), or automate the discovery and exploitation of software vulnerabilities, thereby increasing the likelihood and sophistication of future attacks.

Some actors now engage and are expected to continue to engage in cyber-attacks, including without limitation nation-state actors for geopolitical reasons and in conjunction with military conflicts and defense activities. During times of war and other major conflicts, we, and the third parties upon which we rely, may be vulnerable to a heightened risk of these attacks, including retaliatory cyber-attacks, that could materially disrupt our systems and operations, supply chain, and ability to produce, sell and distribute our goods and services. In particular, severe ransomware attacks are becoming increasingly prevalent and can lead to significant interruptions in our operations, ability to provide our products or services, loss of sensitive data and income, reputational harm, and diversion of funds. Extortion payments may alleviate the negative impact of a ransomware attack, but we may be unwilling or unable to make such payments due to, for example, applicable laws or regulations prohibiting such payments.

To the extent that any disruption or security breach were to result in loss, destruction, unavailability, alteration or dissemination of, or damage to, our data or applications, or for it to be believed or reported that any of these occurred, we could incur liability and reputational damage and the development and commercialization of our product candidates could be delayed. Even prompt detection and response may not fully mitigate impacts, and remediation efforts could divert management attention and increase costs. The use of AI by attackers may also contribute to faster, more coordinated attacks that evade traditional detection methods, placing additional pressure on our security infrastructure and incident response capabilities. Further, our insurance policies may not be adequate to compensate us for the potential losses arising from any such disruption in, or failure or security breach of, our systems or third-party systems where information important to our business operations or commercial development is stored.

Our fully-remote workforce may create additional risks for our information technology systems and data because our employees work remotely and utilize network connections, computers, and devices working at home, while in transit and in public locations. Remote work may increase exposure to insecure networks, device loss, and compromised credentials. Additionally, business transactions (such as acquisitions or integrations) could expose us to additional cybersecurity risks and vulnerabilities, as our systems could be negatively affected by vulnerabilities present in acquired or integrated entities’ systems and technologies.

While we have implemented security measures designed to protect against security incidents, there can be no assurance that these measures will be effective. We may be unable in the future to detect vulnerabilities in our information technology systems because such threats and techniques change frequently, are often sophisticated in nature, and may not be detected until after a security incident has occurred. Further, we may experience delays in developing and deploying remedial measures designed to address any such identified vulnerabilities. Applicable data privacy and security obligations may require us to notify relevant stakeholders of ~~security incidents. Such disclosures are costly, and the disclosure or the failure to comply with such requirements could lead to adverse consequences.~~

We rely on third-party service providers and technologies to operate critical business systems to process sensitive information in a variety of contexts. Our ability to monitor these third parties’ information security practices is limited, and these third parties may not have adequate information security measures in place. If our third-party service providers experience a security incident or other interruption, we could experience adverse consequences. While we may be entitled to damages if our third-party service providers fail to satisfy their privacy or security-related obligations to us, any award may be insufficient to cover our damages, or we may be unable to recover such award. In addition, supply-chain attacks have increased in frequency and severity, and we cannot guarantee that third parties’ infrastructure in our supply chain or our third-party partners’ supply chains have not been compromised.80

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security incidents. Such disclosures are costly, and the disclosure or the failure to comply with such requirements could lead to adverse consequences. For further discussion of our evolving privacy and data security compliance obligations, see “Business - Government Regulation - Data Privacy and Cybersecurity Requirements (U.S.)” and “Regulation in the European Union - European Data and Security Laws.”

We rely on third-party service providers and technologies to operate critical business systems to process sensitive information in a variety of contexts. Certain third-party platforms or vendors may incorporate AI-driven automation or analytics into their offerings, which may expose us to new categories of risk, such as data being repurposed for AI training, unexplainable outputs generated by machine learning models, or unintended reliance on automated decision-making systems that lack transparency or auditability. Our ability to monitor these third parties’ information security practices is limited, and these third parties may not have adequate information security measures in place. If our third-party service providers experience a security incident or other interruption, we could experience adverse consequences. While we may be entitled to damages if our third-party service providers fail to satisfy their privacy or security-related obligations to us, any award may be insufficient to cover our damages, or we may be unable to recover such award. In addition, supply-chain attacks have increased in frequency and severity, and we cannot guarantee that third parties’ infrastructure in our supply chain or our third-party partners’ supply chains have not been compromised.

Internally, we are also evaluating and, in some cases, implementing AI-enabled technologies to support business operations, data analysis, and other workflow efficiencies. Although these tools offer potential benefits, they also present new and evolving risks, including exposure to biased outputs, regulatory uncertainty around AI governance, and the possibility that sensitive data could inadvertently be incorporated into AI model training datasets or disclosed through model inference. As global laws and guidance surrounding AI systems continue to evolve, noncompliance could result in restrictions on our use of AI, reputational consequences, or enforcement activity.

If we (or a third party upon whom we rely) experience a security incident or are perceived to have experienced a security incident, we may experience adverse consequences, such as government enforcement actions (for example, investigations, fines, penalties, audits, and inspections); additional reporting requirements and/or oversight; restrictions on processing sensitive information (including personal data); litigation (including class claims); indemnification obligations; negative publicity; reputational harm; monetary fund diversions; interruptions in our operations (including availability of data); financial loss; and other similar harms. Security incidents and attendant consequences may cause stakeholders (including investors and potential customers) to stop supporting our platform, deter new customers from products, and negatively impact our ability to grow and operate our business.

Our contracts may not ~~contain~~always include limitations of liability, and even ~~where~~when ~~they~~such doprovisions are present, there can be no assurance that ~~limitations~~they ofwill ~~liability~~be inadequate ~~our contracts are sufficient~~ to protect us from liabilities, damages, or claims ~~related~~arising tofrom our data privacy and security obligations. We ~~cannot~~can bealso ~~sure~~not guarantee that our cybersecurity insurance coverage will be ~~adequate or~~ sufficient to protect us from or to mitigate liabilities arising out of our privacy and security practices or that such coverage will continue to be available on commercially reasonable terms or at all. Moreover, even robust cybersecurity and privacy controls under frameworks such as the National Institute of Standards and Technology ("NIST") cannot eliminate all risk, and we have identified cybersecurity risks that, if realized, are reasonably likely to materially affect us.

69Our expanding use of AI exposes us to operational, regulatory, legal, and ethical risks that could adversely affect our business, reputation, financial condition, and results of operations.

We increasingly develop, procure, and deploy AI and machine learning (ML) tools across our operations. While these tools may create efficiencies, they also introduce material risks related to data quality and bias, transparency and explainability, validation and lifecycle management, cybersecurity, intellectual property, privacy, discrimination, liability, and third-party dependencies. Errors or bias in AI outputs, inadequate monitoring, or insufficient documentation could impair clinical development, pharmacovigilance, manufacturing quality, or commercial activities, resulting in delays, higher costs, product or batch actions, or reputational harm.

The emergence of AI and other technologies may exacerbate other risks, including those related to regulation, litigation, compliance issues, ethical concerns, confidentiality, and data privacy or security. For example, regulatory uncertainty related to AI or other emerging technologies may require significant resources

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~~practices,~~to ~~that~~adjust ~~such~~business ~~coverage~~practices ~~will continue~~ to becomply ~~available~~with ondeveloping ~~commercially~~laws. ~~reasonable~~Several ~~terms~~governmental orauthorities athave ~~all,~~already proposed or ~~that~~enacted ~~such~~laws ~~coverage~~and ~~will~~other ~~pay~~guidance ~~future~~governing ~~claims~~AI.

For example, in the United States, the FDA has outlined a risk based credibility framework for AI used to support drug and biologics development, signaling expectations for context of use validation, lifecycle maintenance, traceability, and explainability, and continues to oversee AI/ML enabled medical devices; these expectations could increase development costs and elongate review. These and other developing obligations may prevent or make it harder for us to conduct or enhance our business using AI, or lead to regulatory fines, penalties, or other liability. Further, use of AI technologies could lead to unintended consequences, such as data leakage, healthcare fraud and abuse, cybersecurity incidents, intellectual property infringement, or unintended biases. Our AI use must also comply with privacy regimes, including the UK GDPR and EU GDPR (e.g., restrictions on automated decision making and profiling, and stringent transparency and data subject rights). Divergent and evolving requirements across jurisdictions may require region specific controls, duplicated validation, or delayed deployments; failure to comply could lead to investigations, fines, injunctions, adverse regulatory outcomes, litigation, loss of market access, or reputational damage.

Our ability to use our net operating loss carryforwards and certain other tax attributes may be limited.

Under Sections 382 and 383 of the Internal Revenue Code of 1986, as amended ~~("the Code")~~, if a corporation undergoes an “ownership change,” ~~generally defined as a greater than 50% change (by value) in its equity ownership over a three-year period,~~ the corporation’s ability to use its pre-change net operating loss carryforwards, or ("NOLs"), and other pre-change tax attributes (such as research tax credits) to offset its post-change income or taxes may be limited. For these purposes, an ownership change generally occurs where the aggregate stock ownership of one or more stockholders or groups of stockholders who owns at least 5% of a corporation’s stock increases its ownership by more than 50 percentage points over its lowest ownership percentage over a 3-year period. Upon certain events since our conversion from a Delaware limited liability company to a Delaware corporation in 2015, it is possible that we may have triggered an “ownership change” limitation. We may also experience ownership changes in the future as a result of subsequent shifts in our stock ownership (some of which are outside of our control). As a result, if we earn net taxable income, our ability to use our pre-change NOLs and other pre-change tax attributes to offset U.S. federal taxable income or taxes may be subject to limitations, which could potentially result in increased future tax liability to us. In addition, at the state level, there may be periods during which the use of NOLs is suspended or otherwise limited, which could accelerate or permanently increase state taxes owed.

We are subject to stringent and changing laws, regulations and standards, and contractual obligations relating to privacy, data protection, and data security. The actual or perceived failure to comply with such obligations could lead to government enforcement actions (which could include civil or criminal penalties), fines and sanctions, private litigation and/or adverse publicity and could negatively affect our operating results and business.

We, and the third parties ~~who~~upon whom we ~~work with~~rely, are or may become subject to numerous domestic and foreign laws, regulations, and standards ~~relating~~governing to privacy, data protection, and ~~data~~information security, ~~the~~as ~~scope~~well as contractual and ethical obligations, many of which isoverlap ~~changing,~~or conflict and are subject to ~~differing~~changing ~~applications~~interpretations. ~~and~~As ~~interpretations~~noted, ~~and~~these ~~may~~include bethe ~~inconsistent~~HIPAA/HITECH ~~among~~framework ~~countries,~~for orprotected ~~conflict~~health ~~with~~information in certain contexts; the amended CCPA and approximately 19 other ~~rules~~comprehensive state privacy laws and their implementing regulations; state health data laws; federal and state consumer protection laws; data breach notification statutes; and the DOJ Bulk Data Rule. WeOutside ~~are~~the orUnited ~~may~~States, ~~become~~we are subject to the ~~terms~~GDPR, ofthe ~~contractual~~DPA 2018, DUAA, CTR, the ePrivacy Directive, among others. These regimes impose obligations ~~related~~such toas ~~privacy~~purpose limitation, data ~~protection~~minimization, security safeguards, vendor contracting, impact/risk assessments, transparency and ~~data~~individual ~~security~~rights, breach notification, and restrictions on automated decision-making and profiling. ~~Our~~New ~~obligations~~and ~~may~~proposed ~~also~~laws ~~change~~increasingly oremphasize ~~expand~~data aslocalization ~~our~~and ~~business~~restrictions ~~grows.~~on ~~The~~cross-border ~~actual~~transfers, and regulators have signaled heightened enforcement. Failure or perceived failure by us or our third parties ~~related~~ to ~~us to~~ comply with ~~such~~any ~~laws,~~of ~~regulations~~these ~~and~~requirements ~~obligations~~ could ~~increase~~result ~~our~~in ~~compliance~~investigations, ~~and~~enforcement ~~operational costs~~actions, ~~expose~~litigation us(including toclass ~~regulatory scrutiny~~claims), ~~actions,~~ fines and penalties, ~~result~~remedial ~~in reputational harm~~orders, ~~lead~~restrictions toon aprocessing, ~~loss~~reputational ~~of customers~~harm, ~~result~~increased incompliance ~~litigation~~ and ~~liability~~operational costs, and ~~otherwise~~other ~~cause~~adverse aconsequences ~~material~~that ~~adverse~~could ~~effect~~materially onand negatively affect our business, financial condition and results of operations. See the section titled “Business – Government Regulation – Data Privacy and ~~Security~~Cybersecurity Requirements (U.S.)" and related international data protection disclosures” in this Annual Report ~~on Form 10-K~~ for a more detailed description of the laws that may affect our ability to operate.

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If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could have a material adverse effect on the success of our business.

We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Our operations may involve the use of hazardous and flammable materials, including chemicals and biological and radioactive materials. In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. These current or future laws and regulations may impair our research, development or commercialization efforts. Failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions.

We may be subject to adverse legislative or regulatory tax changes that could negatively impact our financial condition.

The rules dealing with U.S. federal, state and local income taxation are constantly under review by persons involved in the legislative process and by the Internal Revenue Service and the U.S. Treasury Department. Changes to tax laws (which changes may have retroactive application) could adversely affect our stockholders or us. We assess the impact of various tax reform proposals and modifications to existing tax treaties in all jurisdictions where we have operations to determine the potential effect on our business and any assumptions we have made about our future taxable income. We cannot predict whether any specific proposals will be enacted, the terms of any such proposals or what effect, if any, such proposals would have on our business if they were to be enacted. For example, the United States enacted the Inflation Reduction Act of 2022, which implements, among other changes, a 1% excise tax on certain stock buybacks. In addition, beginning in 2022, the Tax Cuts and Jobs Act eliminated the previously available option to deduct research and development expenditures and requires taxpayers to amortize them generally over five years for research activities conducted in the United States and over 15 years for research activities conducted outside the United States. On July 4, 2025, the U.S. Congress enacted the One Big Beautiful Bill Act, which includes a provision restoring the immediate deductibility of domestic research and development expenditures. The impact of this newly enacted law on our tax position will depend on how the provision is implemented and interpreted by the Internal Revenue Service and other regulatory authorities. In addition, we have no assurance as to whether, when and how this provision may be subject to further amendment or repeal. Such changes, among others, may adversely affect our effective tax rate, results of operation and general business condition.

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business if they were to be enacted. For example, the United States enacted the Inflation Reduction Act of 2022, which implements, among other changes, a 1% excise tax on certain stock buybacks. In addition, beginning in 2022, the Tax Cuts and Jobs Act eliminated the previously available option to deduct research and development expenditures and requires taxpayers to amortize them generally over five years for research activities conducted in the United States and over 15 years for research activities conducted outside the United States. Such changes, among others, may adversely affect our effective tax rate, results of operation and general business condition.

We may acquire businesses or products, or form strategic alliances, in the future, and may not realize the benefits of such acquisitions.

We may acquire additional businesses or products, form strategic alliances, or create joint ventures with third parties that we believe will complement or augment our existing business. If we acquire businesses with promising markets or technologies, we may not be able to realize the benefit of acquiring such businesses if we are unable to successfully integrate them with our existing operations and company culture. We may encounter numerous difficulties in developing, manufacturing and marketing any new product candidates or products resulting from a strategic alliance or acquisition that delay or prevent us from realizing their expected benefits or enhancing our business. There is no assurance that, following any such acquisition, we will achieve the synergies expected in order to justify the transaction, which could result in a material adverse effect on our business and prospects.

We maintain our cash at financial institutions, often in balances that exceed federally-insured limits. The failure of financial institutions could adversely affect our ability to pay our operational expenses or make other payments.

Our cash held in non-interest-bearing and interest-bearing accounts exceeds the Federal Deposit Insurance Corporation ("FDIC") insurance limits. If such banking institutions were to fail, we could lose all or a portion of those amounts held in excess of such insurance limitations. ~~For example, the FDIC took control of Silicon Valley Bank on March 10, 2023. The Federal Reserve subsequently announced that account holders would be made whole.~~ However, the FDIC may not make all account holders whole in the event of future bank failures. In addition, even if account holders are ultimately made whole with respect to a future bank failure, account holders’ access to their accounts and assets held in their accounts may be substantially delayed. Any material loss that we may experience in the future or inability for a material time period to access our cash and cash equivalents could have an adverse effect on our ability to pay our operational expenses or make other payments, which could adversely affect our business.

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for a material time period to access our cash and cash equivalents could have an adverse effect on our ability to pay our operational expenses or make other payments, which could adversely affect our business.

Risks Related to Our Common Stock

The market price of our common stock has historically been volatile, and the market price of our common stock may decline in the future.

The market price of our common stock has been, and may continue to be, subject to significant fluctuations. Market prices for securities of ~~early~~clinical-stage pharmaceutical, biotechnology, and other life sciences companies have historically been particularly volatile. Some of the factors that may cause the market price of our common stock to fluctuate include:

•our ability to obtain regulatory approvals for our product candidates, and delays or failures to obtain such approvals;

•failure of any of our product candidates, if approved, to achieve commercial success;

•failure to maintain our existing third-party license and supply agreements;

•changes in laws or regulations applicable to our product candidates;

•any inability to obtain adequate supply of our product candidates or the inability to do so at acceptable prices;

•adverse regulatory authority decisions;

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•introduction of new products, services, or technologies by our competitors;

•failure to meet or exceed financial and development projections we may provide to the public and the investment community;

•the perception of the pharmaceutical industry by the public, legislatures, regulators, and the investment community;

•announcements of significant acquisitions, strategic collaborations, joint ventures, or capital commitments by us or our competitors;

•disputes or other developments relating to proprietary rights, including patents, litigation matters, and our ability to obtain patent protection for our technologies;

•additions or departures of key personnel;

•significant lawsuits, including patent or stockholder litigation;

•if securities or industry analysts do not publish research or reports about our business, or if they issue an adverse or misleading opinion regarding our business and stock;

•changes in the market valuations of similar companies;

•general market or macroeconomic conditions, including global inflationary pressures, rising interest rates, general economic slowdown or a recession, changes in tariff/trade and monetary ~~policy~~policies, instability in financial institutions and the prospect of a shutdown of the U.S. federal government;

•geopolitical instability and government actions, including the ongoing military conflict in Ukraine, ~~conflict~~conflicts ~~between~~in ~~Israel~~the ~~and~~Middle ~~various~~East, ~~other~~recent ~~parties~~events in Venezuela, geopolitical tensions between ~~China and~~ the United States and other countries, including China, and the implementation of measures that restrict international trade by the United States, China or other governments;

•sales of our common stock by us or our stockholders in the future;

•trading volume of our common stock;

•announcements by commercial partners or competitors of new commercial products, clinical progress or the lack thereof, significant contracts, commercial relationships, or capital commitments;

•the introduction of technological innovations or new therapies that compete with our potential products;

•changes in the structure of health care payment systems; and

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•period-to-period fluctuations in our financial results.

Moreover, the capital markets in general have experienced substantial volatility that has often been unrelated to the operating performance of individual companies. These broad market fluctuations may also adversely affect the trading price of our common stock. For example, escalating trade tensions, elevated interest rates and regulatory uncertainty have caused significant market volatility in recent months, and particularly in the biotechnology and biopharmaceutical industries. If the market price of our common stock does not exceed the price at which a stockholder purchases its shares, such stockholder may not realize any return on its investment in us and may lose some or all of its investment.

In the past, following periods of volatility in the market price of a company’s securities, stockholders have often instituted class action securities litigation against those companies. Such litigation, if instituted, could result in substantial costs and diversion of management attention and resources, which could significantly harm our profitability and reputation.

Anti-takeover provisions in our charter documents and under Delaware law and the terms of some of our contracts could make an acquisition of us more difficult and may prevent attempts by our stockholders to replace or remove our management.

Provisions in our Certificate of Incorporation and Bylaws may delay or prevent an acquisition or a change in management. These provisions include a prohibition on actions by written consent of our stockholders and the ability of our board of directors to issue preferred stock without stockholder approval. In addition, because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the Delaware General Corporation Law ("DGCL"), which prohibits stockholders owning in excess of 15% of our outstanding voting stock from merging or combining with us. Although we believe these provisions collectively will provide for an opportunity to receive higher bids by requiring potential acquirers to negotiate with our board of directors, they would apply even if the offer may be considered beneficial by some stockholders. In addition, these provisions may frustrate or prevent any attempts by our stockholders to replace or remove then current management by making it more difficult for stockholders to replace members of the board of directors, which is responsible for appointing the members of management.

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addition, because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the DGCL, which prohibits stockholders owning in excess of 15% of our outstanding voting stock from merging or combining with us. Although we believe these provisions collectively will provide for an opportunity to receive higher bids by requiring potential acquirers to negotiate with our board of directors, they would apply even if the offer may be considered beneficial by some stockholders. In addition, these provisions may frustrate or prevent any attempts by our stockholders to replace or remove then current management by making it more difficult for stockholders to replace members of the board of directors, which is responsible for appointing the members of management.

In addition, the Certificate of Designation of Preferences, Rights and Limitations of the Series A Preferred Stock (the “Series A Certificate of Designation”) relating to our Series A Preferred Stock may delay or prevent a change in control of our company. At any time while at least 30% of the originally issued Series A Preferred Stock remains issued and outstanding, we may not consummate a Fundamental Transaction (as defined in the Series A Certificate of Designation) or any merger or consolidation of the Company with or into another entity or any stock sale to, or other business combination in which our stockholders immediately before such transaction do not hold at least a majority of our capital stock immediately after such transaction, without the affirmative vote of the holders of a majority of the then outstanding shares of the Series A Preferred Stock. This provision of the Series A Certificate of Designation may make it more difficult for us to enter into any of the aforementioned transactions as it would require the separate consent of a majority of the holders of the Series A Preferred Stock.

Our Certificate of Incorporation and Bylaws provide that the Court of Chancery of the State of Delaware is the exclusive forum certain types of actions and proceedings that may be initiated by our stockholders, and our Bylaws designate the federal courts of the United States as the exclusive forum for actions arising under the Securities Act, each of which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers, employees or agents.

Our Certificate of Incorporation and Bylaws provide that, unless we consent in writing to an alternative forum, the Court of Chancery of the State of Delaware will be the sole and exclusive forum for any derivative action or proceeding brought on our behalf, any action asserting a claim of breach of a fiduciary duty owed by any of our directors, officers, employees or agents to us or our stockholders, any action asserting a claim arising pursuant to any provision of the DGCL, our Certificate of Incorporation or our Bylaws or any action asserting a claim that is governed by the internal affairs doctrine, in each case subject to the Court of Chancery having personal jurisdiction over the indispensable parties named as defendants therein and the claim not being one which is vested in the exclusive jurisdiction of a court or forum other than the Court of Chancery or for which the Court of Chancery does not have subject matter jurisdiction. Any person purchasing or otherwise acquiring any ~~interest in any shares of our capital stock shall be deemed to have notice of and to have consented to this provision of our Certificate of Incorporation and Bylaws.~~

Our Bylaws provide that the federal district courts of the United States of America will, to the fullest extent permitted by law, be the exclusive forum for resolving any complaint asserting a cause of action arising under the Securities Act (a “Federal Forum Provision”). Our decision to adopt a Federal Forum Provision followed a decision by the Supreme Court of the State of Delaware holding that such provisions are facially valid under Delaware law. While there can be no assurance that federal or state courts will follow the holding of the Delaware Supreme Court or determine that the Federal Forum Provision should be enforced in a particular case, application of the Federal Forum Provision means that suits brought by our stockholders to enforce any duty or liability created by the Securities Act must be brought in federal court and cannot be brought in state court. In addition, investors cannot waive compliance with the federal securities laws and the rules and regulations thereunder.85

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tointerest usin ~~than~~any toshares of our ~~stockholders.~~capital ~~Alternatively,~~stock ifshall abe ~~court~~deemed ~~were~~ to ~~find~~have ~~these~~notice ~~provisions~~ of ~~our~~and ~~governance~~to ~~documents~~have ~~inapplicable~~consented to, orthis ~~unenforceable~~provision ~~in respect~~ of, ~~one~~our orCertificate ~~more~~ of ~~the~~Incorporation ~~specified~~and types of actions or proceedings, we may incur additional costs associated with resolving such matters in other jurisdictions, which could have a material adverse effect on our business, financial condition or results of operationsBylaws.

These choice of forum provisions will not apply to claims brought to enforce a duty or liability created by the Exchange Act. These choice of forum provisions may limit our stockholders’ ability to bring a claim in a judicial forum that it finds favorable for disputes with us or our directors, officers, employees or agents, which may discourage such lawsuits against us and our directors, officers, employees and agents even though an action, if successful, might benefit our stockholders. Stockholders who do bring a claim in the specified courts could face additional litigation costs in pursuing any such claim. The specified courts may also reach different judgments or results than would other courts, including courts where a stockholder considering an action may be located or would otherwise choose to bring the action, and such judgments or results may be more favorable to us than to our stockholders. Alternatively, if a court were to find these provisions of our governance documents inapplicable to, or unenforceable in respect of, one or more of the specified types of actions or proceedings, we may incur additional costs associated with resolving such matters in other jurisdictions, which could have a material adverse effect on our business, financial condition or results of operations.

We do not anticipate that we will pay any cash dividends in the foreseeable future.

The current expectation is that we will retain our future earnings, if any, to fund the development and growth of our business. As a result, capital appreciation, if any, of our common stock will be your sole source of gain, if any, for the foreseeable future.

Future sales of shares by existing stockholders could cause our stock price to decline.

If our stockholders sell, or indicate an intention to sell, substantial amounts of our common stock in the public market after legal restrictions on resale lapse, the trading price of our common stock could decline. In addition, shares of our common stock that are subject to our outstanding options and restricted stock units will become eligible for sale in the public market to the extent permitted by the provisions of various vesting agreements and Rules 144 and 701 under the Securities Act.

Future sales and issuances of equity and debt could result in additional dilution to our stockholders.

We expect that we will need significant additional capital to fund our current and future operations, including to complete ongoing and potential preclinical and clinical trials for our product candidates. To raise capital, we may sell common stock, convertible securities, or other equity securities in one or more transactions at prices and in a manner we determine from time to time. As a result, our stockholders may experience additional dilution, which could cause our stock price to fall.

Pursuant to our equity incentive plans, we may grant equity awards and issue additional shares of our common stock to our employees, directors and consultants, and the number of shares of our common stock reserved for future issuance under certain of these plans will be subject to automatic annual increases in accordance with the terms of the plans. To the extent that new options or other stock-based equity awards are granted and, if applicable, exercised, or we issue additional shares of common stock in the future, our stockholders may experience additional dilution, which could cause our stock price to fall.

Our principal stockholders own a significant percentage of our stock and are able to exert significant control over matters subject to stockholder approval.

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Our directors, officers, 5% stockholders, and their affiliates currently beneficially own a substantial portion of our outstanding voting stock. Therefore, these stockholders have the ability and may continue to have the ability to influence us through this ownership position. These stockholders may be able to determine some or all matters requiring stockholder approval. For example, these stockholders, acting together, may be able to control elections of directors, amendments of organizational documents, or approval of any merger, sale of assets, or other major corporate transaction. This may prevent or discourage unsolicited acquisition proposals or offers for our common stock that you may believe are in your best interest as one of our stockholders.

General Risk Factors

We may become exposed to costly and damaging liability claims, either when testing our programs in the clinic or at the commercial stage, and our product liability insurance may not cover all damages from such claims.

We are exposed to potential product liability and professional indemnity risks that are inherent in the research, development, manufacturing, marketing and use of pharmaceutical products. While we currently have no products that have been approved for commercial sale, the use of our product candidates in clinical trials, and the sale of any approved products in the future, may expose us to liability claims. These claims may be made by participants or patients that use the product candidate or product, healthcare providers, pharmaceutical companies, or others selling such products. Any claims against us, regardless of their merit, could be difficult and costly to defend and could materially and adversely affect the market for our products or any prospects for commercialization of our products. Although we currently maintain adequate product liability insurance for our product candidates, it is possible that our liabilities could exceed our insurance coverage or that in the future we may not be able to maintain insurance coverage at a reasonable cost or obtain insurance coverage that will be adequate to satisfy any liability that may arise. If a successful product liability claim or series of claims is brought against us for uninsured liabilities or in excess of insured liabilities, our assets may not be sufficient to cover such claims and our business operations could be impaired.

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any prospects for commercialization of our products. Although we currently maintain adequate product liability insurance for our product candidates, it is possible that our liabilities could exceed our insurance coverage or that in the future we may not be able to maintain insurance coverage at a reasonable cost or obtain insurance coverage that will be adequate to satisfy any liability that may arise. If a successful product liability claim or series of claims is brought against us for uninsured liabilities or in excess of insured liabilities, our assets may not be sufficient to cover such claims and our business operations could be impaired.

Litigation costs and the outcome of litigation could have a material adverse effect on our business.

From time to time, we may be subject to litigation claims through the ordinary course of our business operations regarding, but not limited to, securities litigation, employment matters, security of patient and employee personal information, contractual relations with collaborators and licensors and intellectual property rights. Litigation to defend ourselves against claims by third parties, or to enforce any rights that we may have against third parties, could result in substantial costs and diversion of our resources, causing a material adverse effect on our business, financial condition, results of operations or cash flows.

We continue to incur significant costs and demands upon management as a result of complying with the laws and regulations regulating public companies.

As a public company, and particularly after December 31, 2024, when we ceased to be a “smaller reporting company” and “non-accelerated filer,” and became a “large accelerated filer,” we have and will continue to incur significant legal, accounting and other expenses associated with public company reporting requirements, including costs associated with corporate governance requirements, such as requirements under the Sarbanes-Oxley Act, the Dodd-Frank Wall Street Reform and Consumer Protection Act, as well as rules implemented by the SEC and Nasdaq. Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which may lead to additional compliance costs and impact (in ways we cannot currently anticipate) the manner in which we operate our business. In addition, changing laws, regulations, and standards relating to corporate governance and public disclosure, including those related to climate change and other environmental, social and governance focused disclosures, are creating uncertainty for public companies, increasing legal and financial compliance costs, and making some activities more time-consuming. These rules and regulations increase our legal and financial compliance costs and make some activities more time-consuming and costly. These rules and regulations may also make it difficult and expensive for us to obtain directors’ and officers’ liability insurance. Our management and other personnel will continue to devote a substantial amount of time to these compliance initiatives, and we will continue to incur increased legal and financial compliance costs. As a result, it may be more difficult for us to attract and retain qualified individuals to serve on our board of directors or as our executive officers, which may adversely affect investor confidence and could cause our business or stock price to suffer. In addition, the increased costs may require us to reduce costs in other areas of our business or increase the prices of our product candidates, once commercialized. Moreover, these rules and regulations are often subject to varying interpretations, in many cases due to their lack of specificity, and, as a result, their application in practice may evolve over time as new guidance is provided by regulatory and governing bodies. This could result in continuing uncertainty regarding compliance matters and higher costs necessitated by ongoing revisions to disclosure and governance practices.

We are no longer a “smaller reporting company” within the meaning of the Securities Act and as a result we are or will be subject to certain enhanced disclosure requirements which will require us to incur significant expenses and expend time and resources. 87

We are no longer a “smaller reporting company,” as of January 1, 2025 and, as a result, we are or will be required to comply with various disclosure and compliance requirements that did not previously apply, such as the auditor attestation requirements of Section 404(b) of the Sarbanes-Oxley Act, the requirement that we hold a nonbinding advisory vote on executive compensation and obtain stockholder approval of any golden parachute payments not previously approved, the requirement to provide full and more detailed executive compensation disclosure and the reduction in the amount of time for filing our periodic and annual reports. Compliance with these additional requirements increases our legal and financial compliance costs and causes management and other personnel to divert attention from operational and other business matters to these additional public company reporting requirements. In addition, if we are not able to comply with changing requirements in a timely manner, the market price of our stock could decline and we could be subject to

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~~delisting~~could ~~proceedings~~cause byour ~~the~~business or stock ~~exchange~~price onto ~~which~~suffer. In addition, the increased costs may require us to reduce costs in other areas of our ~~common~~business ~~shares~~or increase the prices of our product candidates, once commercialized. Moreover, these rules and regulations are ~~listed~~often subject to varying interpretations, orin ~~sanctions~~many orcases ~~investigations~~due byto ~~the~~their ~~SEC~~lack orof ~~other~~specificity, ~~regulatory~~and, ~~authorities~~as a result, ~~which~~their ~~would~~application ~~require~~in ~~additional~~practice ~~financial~~may evolve over time as new guidance is provided by regulatory and ~~management~~governing ~~resources~~bodies. This could result in continuing uncertainty regarding compliance matters and higher costs necessitated by ongoing revisions to disclosure and governance practices.

We are ~~not~~no ~~required~~longer toa ~~reflect~~“smaller ~~the~~reporting ~~change~~company” inwithin ~~our~~the ~~smaller~~meaning ~~reporting~~of ~~company~~the ~~status~~Securities Act and ~~comply~~as ~~with~~a ~~the~~result ~~increased~~we ~~disclosure~~are ~~obligations~~or ~~until~~will ~~our~~be ~~quarterly~~subject ~~report~~to ~~for~~certain ~~the~~enhanced ~~quarter~~disclosure ~~ending~~requirements ~~March~~which ~~31,~~will ~~2025,~~require ~~the~~us ~~first~~to ~~quarter~~incur insignificant ~~our~~expenses ~~fiscal~~and ~~year~~expend ~~ending~~time ~~December~~and ~~31, 2025~~resources.

We ~~will~~are ~~reassess~~no longer a “smaller reporting company,” as of ~~June~~January 301, 2025 and, ~~whether~~as a result, we ~~continue~~are required to ~~qualify~~comply with various disclosure and compliance requirements that did not previously apply, such as the auditor attestation requirements of Section 404(b) of the Sarbanes-Oxley Act, the requirement that we hold a ~~large~~nonbinding ~~accelerated~~advisory ~~filer~~vote on executive compensation and obtain stockholder approval of any golden parachute payments not previously approved, the requirement to provide full and more detailed executive compensation disclosure and the reduction in the amount of time for ~~filings~~filing ~~beyond~~our periodic and annual reports. Compliance with these additional requirements increases our legal and financial compliance costs and causes management and other personnel to divert attention from operational and other business matters to these additional public company reporting requirements. In addition, if we are not able to comply with changing requirements in a timely manner, the ~~fiscal~~market ~~year~~price ~~ending~~of ~~December~~our 31stock could decline and we could be subject to delisting proceedings by the stock exchange on which our common shares are listed, ~~2025~~or sanctions or investigations by the SEC or other regulatory authorities, which would require additional financial and management resources.

If equity research analysts do not publish research or reports, or publish unfavorable research or reports, about us, our business, or our market, our stock price and trading volume could decline.

The trading market for our common stock is influenced by the research and reports that equity research analysts publish about us and our business. Equity research analysts may elect not to provide research coverage of our common stock and such lack of research coverage may adversely affect the market price of our common stock. In the event we do have equity research analyst coverage, we will not have any control over the analysts or the content and opinions included in their reports. The price of our common stock could decline if one or more equity research analysts downgrade our stock or issue other unfavorable commentary or research. If one or more equity research analysts ceases coverage of us or fails to publish reports on us regularly, demand for our common stock could decrease, which in turn could cause our stock price or trading volume to decline.

If we fail to maintain proper and effective internal controls, our ability to produce accurate financial statements on a timely basis could be impaired, investors may lose confidence in the accuracy and completeness of our financial reports and the market price of our common stock may be negatively affected. For example, in the fourth quarter of 2024, we identified a material weakness in our internal control over financial reporting which resulted in restatements of our previously-issued financial statements to amend certain net loss per share disclosures.

We are subject to the reporting requirements of the Exchange Act, the Sarbanes-Oxley Act, and the rules and regulations of Nasdaq. The Sarbanes-Oxley Act requires, among other things, that we maintain effective disclosure controls and procedures and internal control over financial reporting. In addition to our management’s report on the effectiveness of our internal controls over financial reporting, our independent registered public accounting firm is required to attest to the effectiveness of our internal control over financial reporting pursuant to Section 404 of the Sarbanes-Oxley Act. The rules governing the standards that must be met for management to assess our internal control over financial reporting are complex and require significant documentation, testing, and possible remediation. We must perform system and process evaluation and testing of our internal control over financial reporting to allow management to report on the effectiveness of our internal controls over financial reporting in our annual report filing for that year, as required by Section 404 of the Sarbanes-Oxley Act. This requires that we incur substantial professional fees and internal costs to expand our accounting and finance functions and that we expend significant management efforts. We may experience difficulty in meeting these reporting requirements in a timely manner for each period.

We may or any subsequent testing by our independent registered public accounting firm may discover weaknesses in our system of internal financial and accounting controls and procedures that could result in a material misstatement of our financial statements. Our internal control over financial reporting will not prevent or detect all errors and all fraud. A control system, no matter how well designed and operated, can provide only reasonable, not absolute, assurance that the control system’s objectives will be met. Because of the inherent limitations in all control systems, no evaluation of controls can provide absolute assurance that misstatements due to error or fraud will not occur or that all control issues and instances of fraud will be detected. In addition, we may encounter problems or delays in completing the implementation of any requested improvements and receiving a favorable attestation in connection with the attestation provided by our independent registered public accounting firm.88

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If we are not able to comply with the requirements of Section 404 of the Sarbanes-Oxley Act, or if we are unable to maintain proper and effective internal controls, it could result in a material misstatement of our financial statements that would not be prevented or detected on a timely basis, which could require a restatement, cause us to be subject to sanctions or investigations by Nasdaq, the SEC, or other regulatory authorities, cause investors to lose confidence in our financial information, or cause our stock price to decline.

As A material weakness is a ~~public~~deficiency, ~~company~~or a combination of deficiencies, wein ~~incur~~internal ~~significant~~control ~~legal~~over financial reporting, ~~accounting~~such that there is a reasonable possibility that a material misstatement of our annual or interim consolidated financial statements will not be prevented or detected on a timely basis. As described in our Annual Report for the year ended December 31, ~~insurance~~2024, ~~and~~we ~~other~~identified ~~expenses~~a material weakness in our internal control over financial reporting in connection with our net earnings (loss) per share disclosures, ~~and~~which resulted in the restatement of our ~~management~~consolidated financial statements as of and ~~other~~for ~~personnel~~the year ended December 31, 2023, as well as the quarterly condensed consolidated financial information for the interim periods ended March 31, 2024, June 30, 2024, and September 30, 2024. We have implemented measures designed to improve our disclosure controls and ~~will~~procedures ~~need~~and internal control over financial reporting to ~~continue~~address the underlying causes of this material weakness, including enhancing the design of controls relevant to ~~devote~~the apreparation ~~substantial~~and ~~amount~~presentation of ~~time~~financial reporting matters related to ~~compliance~~net ~~initiatives~~earnings ~~resulting~~(loss) ~~from~~per ~~operating~~share ascalculations aand ~~public~~disclosures ~~company~~to ensure that economic substance beyond the legal form of our capital structure is considered when preparing disclosures related to net earnings (loss) per share.

WeIn ~~have~~addition, ~~identified a material weakness in~~ our internal control over financial reporting. Ifwill ~~our~~not ~~remediation~~prevent ofor ~~the~~detect ~~material~~all ~~weaknesses~~errors isand ~~not~~all ~~effective~~fraud. A control system, orno ifmatter wehow ~~experience~~well ~~additional~~designed ~~material~~and ~~weaknesses~~operated, orcan ~~otherwise~~provide ~~fail~~only toreasonable, ~~maintain~~not anabsolute, ~~effective~~assurance that the control system’s objectives will be met. Because of ~~internal~~the ~~controls~~inherent limitations in ~~the~~all ~~future~~control systems, weno ~~may~~evaluation ~~not~~of becontrols ~~able~~can provide absolute assurance that misstatements due to ~~accurately~~error ~~report~~or ~~our~~fraud ~~financial~~will ~~results~~not inoccur aor ~~timely~~that ~~manner,~~all control issues and weinstances orof ~~our~~fraud ~~independent~~will ~~registered~~be ~~public~~detected. ~~accounting~~In ~~firm~~addition, we may ~~conclude~~encounter ~~that~~problems ~~our~~or ~~internal~~delays ~~control~~in ~~over~~completing ~~financial~~the ~~reporting~~implementation isof ~~not~~any ~~effective,~~requested ~~which~~improvements ~~may~~and ~~adversely~~receiving ~~affect~~a ~~investor~~favorable ~~confidence~~attestation in usconnection ~~and~~with ~~materially~~the ~~and~~attestation ~~adversely~~provided ~~affect~~by our ~~business~~independent ~~and~~registered ~~operating~~public ~~results~~accounting firm.

~~Effective~~As ~~internal~~a ~~controls~~public ~~over financial reporting are necessary for us to provide reliable financial information and~~company, ~~together~~we ~~with~~incur ~~adequate~~significant ~~disclosure controls and procedures~~legal, ~~are designed to prevent fraud. Any failure to implement required new or improved controls~~accounting, ~~or difficulties encountered in their implementation~~insurance, ~~could~~and ~~cause~~other ~~us to fail to meet our reporting obligations. In addition~~expenses, ~~any~~and ~~testing by us conducted in connection with Section 404 of the Sarbanes-Oxley Act, or any subsequent testing by~~ our ~~independent~~management ~~registered~~and ~~public~~other ~~accounting~~personnel ~~firm,~~have ~~may~~and ~~reveal~~will ~~deficiencies~~need into ~~our~~continue ~~internal controls over financial reporting that are deemed~~ to bedevote ~~material~~a ~~weaknesses~~substantial oramount ~~that~~of ~~may~~time ~~require prospective or retroactive changes~~ to ~~our~~compliance ~~consolidated~~initiatives ~~financial~~resulting ~~statements~~from oroperating ~~identify~~as ~~other~~a ~~areas~~public ~~for further attention or improvement~~company. AWe ~~material~~may ~~weakness~~experience isdifficulty ~~a deficiency, or a combination of deficiencies,~~ in ~~internal~~meeting ~~control~~these ~~over financial~~ reporting, ~~such~~requirements ~~that~~in ~~there is~~ a ~~reasonable~~timely ~~possibility~~manner ~~that~~for aeach ~~material misstatement of our annual or interim consolidated financial statements will not be prevented or detected on a timely basis~~period.

AsOur ~~described~~business ~~elsewhere~~could inbe ~~this~~adversely ~~Annual~~affected ~~Report,~~by weeconomic ~~have~~downturns, ~~identified~~inflation, aincreases ~~material weakness~~ in ~~our~~interest ~~internal~~rates, ~~control~~natural ~~over~~disasters, ~~financial~~public ~~reporting~~health ~~related~~crises, topolitical ~~the~~crises, ~~Company’s~~U.S. ~~accounting~~elections, ~~and~~international ~~reporting~~or ofgeopolitical ~~complex financial instruments~~events, ~~resulting~~such inas ~~a determination that~~ the ~~Company’s~~conflict ~~issued~~between ~~preferred~~Russia ~~stock is common-like in nature~~ and ~~therefore~~Ukraine, werecent ~~should~~events ~~apply~~in ~~the~~Venezuela, ~~two-class method of calculating net loss per share~~ and ~~include~~conflicts ~~our issued Series A Preferred Stock and Series B Preferred Stock~~ in ~~such~~the ~~calculation~~Middle ~~for~~East, ~~our~~the ~~issued~~implementation ~~audited consolidated financial statements as~~ of ~~December~~measures ~~31,~~that ~~2023~~restrict ~~and~~international ~~for~~trade ~~the~~or ~~year~~other ~~then~~macroeconomic ~~ended~~conditions, ~~and~~which ~~our~~could ~~unaudited~~have ~~consolidated~~a ~~financial~~material ~~statements for the quarterly~~ and ~~year-to-date~~adverse ~~(as~~effect ~~applicable)~~on ~~periods~~our ~~ended~~results ~~June~~of ~~30,~~operations ~~2023, September 30, 2023, March 31, 2024, June 30, 2024~~ and ~~September~~financial ~~30, 2024 (collectively, the “Affected Periods”)~~condition.

WeThe ~~have~~global ~~implemented~~economy, ~~measures~~including ~~designed~~credit toand ~~improve~~financial ~~our~~markets, ~~disclosure~~has ~~controls~~experienced extreme volatility and ~~procedures~~disruptions, including, among other things, diminished liquidity and ~~internal~~credit ~~control~~availability, ~~over~~declines ~~financial~~in ~~reporting~~consumer toconfidence, ~~address~~declines ~~the~~in ~~underlying~~economic ~~causes~~growth, ofsupply ~~this~~chain ~~material~~shortages, ~~weakness~~increases in inflation rates, higher interest rates, and uncertainty about economic stability. Adverse macroeconomic conditions, including ~~enhancing~~inflation, ~~the~~slower ~~design~~growth ofor ~~controls~~recession, ~~relevant~~new toor ~~the~~increased ~~preparation~~tariffs and ~~presentation~~other barriers to trade, especially in light of ~~financial~~recent ~~reporting~~comments ~~matters~~and ~~related~~executive orders made by the Trump administration, changes to ~~net~~fiscal ~~earnings~~and monetary policy or government budget dynamics (~~loss~~particularly in the pharmaceutical and biotechnology areas), ~~per~~tighter ~~share~~credit, ~~calculations~~higher interest rates, volatility in financial markets, high unemployment, labor availability constraints, currency fluctuations and ~~disclosures~~other tochallenges ~~ensure~~in ~~that~~the ~~economic~~global ~~substance~~economy ~~beyond~~have in the ~~legal~~past ~~form~~adversely ofaffected, and may in the future adversely affect, us and our ~~capital~~business ~~structure~~partners isand ~~considered~~suppliers. ~~when~~The ~~preparing~~United ~~disclosures~~States ~~related~~has topreviously ~~net~~announced ~~earnings~~tariffs ~~(loss)~~on ~~per~~imports ~~share.~~from ~~These~~most ~~remediation~~countries, ~~measures~~including ~~may~~significant betariffs ~~time-consuming~~on ~~and~~imports ~~costly~~from Canada, Mexico and ~~there~~China. isHistorically, notariffs ~~assurance~~have ~~that~~led ~~these~~to ~~initiatives~~increased ~~will~~trade ~~ultimately~~and political tensions. In response to tariffs, other countries have ~~the~~implemented ~~intended~~retaliatory ~~effects~~tariffs on U.S. ~~While~~goods. wePolitical ~~believe~~tensions ~~that~~as ~~these~~a ~~efforts~~result ~~will~~of ~~improve~~trade ~~our~~policies ~~internal~~could ~~control~~reduce ~~over~~trade ~~financial~~volume, ~~reporting~~investment, ~~remediation~~technological ofexchange ~~the~~and other economic activities between major international economies, resulting in a material ~~weaknesses~~adverse ~~will~~effect ~~require~~on ~~validation~~global economic conditions and ~~testing~~the stability of ~~the~~global ~~design~~financial ~~and~~markets. ~~operating~~There ~~effectiveness~~is substantial uncertainty about the duration of ~~internal~~existing ~~controls~~tariffs ~~over~~and awhether ~~sustained~~additional ~~period~~tariffs ofmay ~~financial~~be ~~reporting~~imposed, ~~cycles~~modified or suspended. WeThe ~~cannot~~Federal ~~assure~~Reserve ~~you~~has ~~that~~raised ~~these~~interest ~~measures~~rates ~~will~~multiple ~~significantly~~times ~~improve~~in orresponse ~~remediate~~to ~~the~~concerns ~~material~~about ~~weaknesses~~inflation ~~described~~and ~~above~~it may raise them again. Higher interest rates, coupled with reduced

The material weakness resulted in the restatement of our financial statements for the Affected Periods. As a result of this material weakness, our management has concluded that our disclosure controls and procedures were not effective as of December 31, 2023 and 2024. See Part II, Item 9A. Controls and Procedures included in this Annual Report. While we are taking a number of measures to remediate the material weakness (as described above), if we identify additional material weaknesses, we may be unable to provide required financial information in a timely and reliable manner and we may incorrectly report financial information. Likewise, if our financial statements are not filed on a timely basis, we could be subject to sanctions or investigations by the stock exchange on which our shares of common stock are listed, the SEC or other regulatory authorities. The existence of material weaknesses in internal control over financial reporting could adversely affect our reputation or investor perceptions of us, which could have a negative effect on the trading 89

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~~price~~government ofspending ~~our~~and ~~stock~~volatility in financial markets, may increase economic uncertainty and affect consumer spending. WeSimilarly, ~~can~~geopolitical ~~give~~uncertainties, nointernational ~~assurance~~conflicts ~~that~~and ~~any~~government ~~additional~~actions, ~~material~~including ~~weaknesses~~the orongoing ~~restatements~~military ofconflicts ~~financial~~between ~~results~~Russia ~~will~~and ~~not~~Ukraine, ~~arise~~recent events in Venezuela, and conflicts in the ~~future~~Middle ~~due~~East toinvolving aIsrael ~~failure~~and tovarious ~~implement~~other parties, including Iran, Hamas and ~~maintain~~Hezbollah, ~~adequate~~as ~~internal~~well ~~control~~as ~~over~~other ~~financial~~conflicts ~~reporting~~in orthe ~~circumvention~~region, rising tensions with China and the implementation of ~~these~~tariffs, sanctions, export or import controls., ~~Even~~and ifother wemeasures ~~are~~that ~~successful~~restrict international trade by the United States, China or other governments, have created extreme volatility in ~~strengthening~~the ~~our~~global ~~controls~~capital markets and ~~procedures~~may have further global economic consequences, inincluding disruptions of the ~~future~~global ~~those~~supply ~~controls~~chain. Any such volatility and ~~procedures~~disruptions may ~~not~~adversely beaffect ~~adequate~~our tobusiness ~~prevent~~or the third parties on whom we rely. If the equity and credit markets deteriorate, including as a result of political unrest or ~~identify~~war, ~~irregularities~~it may make any necessary debt or ~~errors~~equity financing more costly, more dilutive, or more difficult to ~~facilitate~~obtain ~~the~~in ~~fair~~a ~~presentation~~timely ofmanner or on favorable terms, if at all. Increased inflation rates can adversely affect us by increasing our ~~financial~~costs, ~~statements~~including labor and employee benefit costs.

IfWe wemay ~~identify~~in ~~any~~the ~~new~~future ~~material~~experience ~~weaknesses~~disruptions inas ~~the~~a ~~future,~~result ~~any~~of such ~~newly~~macroeconomic ~~identified~~conditions, ~~material~~including ~~weakness~~delays ~~could~~or ~~limit~~difficulties ~~our~~in ~~ability~~initiating toor ~~prevent~~expanding clinical trials and manufacturing or ~~detect~~shipping asufficient ~~misstatement~~quantities of ~~our~~materials. ~~accounts~~Any one or ~~disclosures~~a ~~that~~combination ~~could~~of ~~result~~these inevents could have a material ~~misstatement~~and ofadverse effect on our ~~annual~~results orof ~~interim~~operations and financial ~~statements~~condition. InFor ~~such case~~example, weour business may be ~~unable~~generally exposed to ~~maintain~~the ~~compliance~~impact ~~with~~of ~~securities~~political ~~law~~or ~~requirements~~civil ~~regarding~~unrest ~~timely~~or ~~filing~~military ofaction. ~~periodic~~While ~~reports~~we do not have any employees or offices in ~~addition~~Ukraine, toVenezuela, ~~applicable~~Russia ~~stock~~or ~~exchange~~countries ~~listing~~in ~~requirements~~the Middle East, ~~investors~~including ~~may~~Israel, ~~lose~~we ~~confidence~~do have third-party partners with locations in ~~our~~Europe, ~~financial~~South ~~reporting~~America and the Middle East, which may be affected by the ongoing conflicts affecting such countries. In addition, we are pursuing sites for our ~~stock~~Phase ~~price~~2 platform trial in Israel and Ukraine. These sites may ~~decline~~be asmaterially aimpacted by the increasing military conflicts in Europe and the Middle East, could result in difficulties enrolling and retaining participants and/or delivering drug samples in such areas on schedule and cause delay in our clinical trials and/or increase trial costs. WeAny ~~cannot~~of ~~assure~~the ~~you~~foregoing ~~that~~could ~~any~~harm ~~measures~~our business and we ~~may~~cannot ~~take~~anticipate all of the ways in which the ~~future,~~current ~~will~~economic beor ~~sufficient~~political toclimate ~~avoid~~and ~~potential~~financial ~~future~~market ~~material~~conditions ~~weaknesses~~could adversely impact our business.

Our business could be adversely affected by economic downturns, inflation, increases in interest rates, natural disasters, public health crises, political crises, U.S. elections, international or geopolitical events, such as the conflict between Russia and Ukraine, and Israel and various other parties and other conflicts in the region, the implementation of measures that restrict international trade or other macroeconomic conditions, which could have a material and adverse effect on our results of operations and financial condition.

The global economy, including credit and financial markets, has experienced extreme volatility and disruptions, including, among other things, diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, supply chain shortages, increases in inflation rates, higher interest rates, and uncertainty about economic stability. For example, the COVID-19 pandemic resulted in widespread unemployment, economic slowdown and extreme volatility in the capital markets. The Federal Reserve has raised interest rates multiple times in response to concerns about inflation and it may raise them again. Higher interest rates, coupled with reduced government spending and volatility in financial markets, may increase economic uncertainty and affect consumer spending. Similarly, geopolitical uncertainties, international conflicts and government actions, including the ongoing military conflicts between Russia and Ukraine, and Israel and various other parties, including Iran, Hamas and Hezbollah, as well as other conflicts in the region, rising tensions with China and the implementation of tariffs, sanctions, export or import controls, and other measures that restrict international trade by the United States, China or other governments, have created extreme volatility in the global capital markets and may have further global economic consequences, including disruptions of the global supply chain. Any such volatility and disruptions may adversely affect our business or the third parties on whom we rely. If the equity and credit markets deteriorate, including as a result of political unrest or war, it may make any necessary debt or equity financing more costly, more dilutive, or more difficult to obtain in a timely manner or on favorable terms, if at all. Increased inflation rates can adversely affect us by increasing our costs, including labor and employee benefit costs.

We may in the future experience disruptions as a result of such macroeconomic conditions, including delays or difficulties in initiating or expanding clinical trials and manufacturing sufficient quantities of materials. Any one or a combination of these events could have a material and adverse effect on our results of operations and financial condition.

ITEM 1B. UNRESOLVED STAFF COMMENTS

None.

ITEM 1C. CYBERSECURITY

In the ordinary course of ~~our~~ business, we collect, use, store, and transmit digitally confidential, sensitive, proprietary, personal, and health-related information. The secure maintenance of this information and our information technology systems is important to our operations and business strategy. To this end, we have implemented processes using the cybersecurity risk framework published by the ~~National Institute of Standards and Technology ("~~NIST") designed to assess, identify, and manage risks from potential unauthorized occurrences on or through our information technology systems that may result in adverse effects on the confidentiality, integrity, and availability of these systems and the data residing therein. These processes are managed and monitored by a dedicated information technology team, which is led by our Vice President, Information Technology ("IT"), and include mechanisms, controls, technologies, systems, and other processes designed to prevent or mitigate data loss, theft, misuse, or other security incidents or vulnerabilities affecting the data and maintain a stable information technology environment. Our cybersecurity risk management processes also incorporate the use of automated and data-driven tools provided by third-party vendors to support threat detection, monitoring, and incident response, and are designed to address evolving cybersecurity threats, including those that may be enabled by artificial intelligence. Specific measures include regular penetration and vulnerability testing, data recovery testing, security audits, and ongoing risk assessments. We conduct due diligence on and audits of key technology vendors, contract research organizations (CROs), and other third-party contractors and suppliers. Additionally, we conduct employee training that covers identifying threats (phishing, social engineering), secure practices (strong passwords, multi-factor authentication, safe internet use, data handling), and incident response (reporting procedures), turning employees into the first line of defense through regular, engaging education on topics like malware, remote work security, physical security, cloud security, mobile devices, and social media risks. We also regularly consult with outside advisors and experts. Their assistance helps us assess, identify, and manage cybersecurity risks, anticipate future threats and trends, and understand their potential impact on our risk environment.

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~~managed~~Our ~~and~~Vice ~~monitored~~President, ~~by a dedicated information technology team~~IT, ~~which~~who isreports ~~led~~directly byto our ~~Senior~~Chief ~~Vice~~Financial ~~President~~Officer, ~~Operations~~has ~~and~~over ~~our~~26 ~~Vice~~years ~~President,~~of ~~Information~~experience ~~Technology~~managing ~~("IT"),~~information technology and ~~include~~cybersecurity ~~mechanisms,~~matters ~~controls,~~and ~~technologies,~~is ~~systems,~~certified ~~and~~as ~~other~~a ~~processes~~Certified ~~designed~~Information toSystems ~~prevent~~Security orProfessional. ~~mitigate~~Together ~~data~~with ~~loss,~~other ~~theft,~~members ~~misuse,~~of orour ~~other~~senior ~~security~~leadership ~~incidents~~team, orour ~~vulnerabilities~~Vice ~~affecting~~President, ~~the~~IT ~~data~~is ~~and~~responsible ~~maintain~~for aassessing ~~stable~~and ~~information~~managing ~~technology~~cybersecurity ~~environment~~risks. ~~Specific~~ ~~measures~~We ~~include~~consider ~~regular~~cybersecurity, ~~penetration~~along ~~and~~with ~~vulnerability~~other ~~testing,~~significant ~~data~~risks ~~recovery~~that ~~testing~~we face, ~~security~~within ~~audits,~~our ~~and~~overall ~~ongoing~~enterprise risk ~~assessments~~management framework. WeIn ~~conduct~~the ~~due~~last ~~diligence~~fiscal onyear, ~~and~~we ~~audits~~have ofnot ~~key~~identified ~~technology~~risks ~~vendors,~~from ~~contract~~known ~~research~~cybersecurity ~~organizations (CROs)~~threats, ~~and~~including ~~other~~as ~~third-party~~a ~~contractors~~result ~~and~~of ~~suppliers.~~any ~~Additionally,~~prior wecybersecurity ~~conduct~~incidents, ~~periodic employee training~~ that ~~covers~~have ~~cyber~~materially ~~and~~affected ~~information security~~us, ~~among~~but ~~other~~we ~~topics.~~face Wecertain ~~also~~ongoing ~~regularly~~cybersecurity ~~consult~~risks ~~with~~that, ~~outside~~if ~~advisors~~realized, ~~and~~are ~~experts.~~reasonably ~~Their~~likely ~~assistance~~to ~~helps~~materially affect us. ~~assess,~~Additional ~~identify,~~information ~~and~~on ~~manage~~ cybersecurity risks, ~~anticipate~~we ~~future~~face ~~threats~~is ~~and~~discussed ~~trends,~~in ~~and~~Part ~~understand~~I, ~~their~~Item ~~potential~~1A, ~~impact~~"Risk ~~on our risk environment~~Factors".

~~Our~~The ~~Vice~~Board ~~President,~~of ~~Information Technology~~Directors, ~~who~~as ~~reports~~a ~~directly~~whole toand ~~our~~at ~~Senior~~the ~~Vice~~committee ~~President~~level, ~~Operations,~~ has ~~over~~oversight 25for ~~years~~the ofmost ~~experience~~significant ~~managing~~risks ~~information~~facing ~~technology~~us and ~~cybersecurity~~for ~~matters and is certified as Certified Information Systems Security Professional. Together with~~ our ~~Senior~~processes ~~Vice~~to ~~President~~identify, ~~Operations~~prioritize, ~~and the other members of our senior leadership team~~assess, ~~our Vice President~~manage, ~~Information Technology is responsible for assessing~~ and ~~managing~~mitigate ~~cybersecurity~~those risks. We ~~consider~~The ~~cybersecurity,~~Audit ~~along with other significant risks that we face~~Committee, ~~within~~which ~~our~~is ~~overall~~comprised ~~enterprise~~solely ~~risk management framework. In the last fiscal year, we have not identified risks from known cybersecurity threats, including as a result~~ of ~~any~~independent ~~prior cybersecurity incidents~~directors, ~~that~~has ~~have~~been ~~materially~~designated ~~affected~~by ~~us,~~our ~~but~~Board weto ~~face~~oversee ~~certain ongoing~~ cybersecurity risks. ~~threats~~The ~~that,~~Audit ifCommittee ~~realized,~~receives ~~are~~regular ~~reasonably~~updates ~~likely to materially affect us. Additional information~~ on cybersecurity ~~risks~~and ~~we face is discussed in Part I, Item 1A, “Risk Factors,” under the heading “Our internal~~ information technology ~~systems,~~matters orand ~~those~~related ofrisk ~~any~~exposures offrom our ~~CROs,~~Vice ~~manufacturers~~President, ~~other contractors or consultants~~IT, ~~third-party~~as ~~service~~well ~~providers,~~as ~~or potential future collaborators, may fail or suffer security or data privacy breaches or~~ other ~~unauthorized~~members ~~or improper access to, use~~ of, orthe ~~destruction~~senior ofleadership ~~our~~team. ~~proprietary~~The orBoard ~~confidential~~also ~~data,~~receives ~~employee~~updates ~~data~~from ormanagement ~~personal~~and ~~data,~~the ~~which~~Audit ~~could~~Committee ~~result~~on incybersecurity ~~additional~~risks ~~costs,~~on ~~loss~~at ofleast ~~revenue,~~an ~~significant~~annual ~~liabilities, harm to our brand and material disruption of our operations~~basis.”

The Board of Directors, as a whole and at the committee level, has oversight for the most significant risks facing us and for our processes to identify, prioritize, assess, manage, and mitigate those risks. The Audit Committee, which is comprised solely of independent directors, has been designated by our Board to oversee cybersecurity risks. The Audit Committee receives regular updates on cybersecurity and information technology matters and related risk exposures from our Vice President, Information Technology, as well as other members of the senior leadership team. The Board also receives updates from management and the Audit Committee on cybersecurity risks on at least an annual basis.

ITEM 2. PROPERTIES

We do not maintain physical corporate offices. Our employees work remotely. We believe these arrangements support our current needs. We maintain a mailing address at 221 Crescent St., Building 23, Suite 105, Waltham, MA 02453. As we expand, we believe that suitable additional alternative spaces will be available in the future on commercially reasonable terms, if required.

ITEM 3. LEGAL PROCEEDINGS

From time to time, we may become involved in legal proceedings relating to claims arising from the ordinary course of business. Our management believes that there are currently no claims or actions pending against us, the ultimate disposition of which could have a material adverse effect on our results of operations, financial condition or cash flows.

ITEM 4. MINE SAFETY DISCLOSURES

Not applicable.

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PART II

ITEM 5. MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES

Market Information and Holders

Our common stock is traded on The Nasdaq Stock Market LLC under the symbol “SYRE.”

As of February 1912, ~~2025~~2026, there were approximately 2624 stockholders of record of our common stock based on information provided by our transfer agent. The actual number of stockholders is greater than this number of record holders, and includes stockholders who are beneficial owners, but whose shares are held in street name by brokers and other nominees. This number of holders of record also does not include stockholders whose shares may be held in trust by other entities.

Stock Price Performance Graph

This graph shall not be deemed “soliciting material” or be deemed “filed” for purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities under that Section, and shall not be deemed to be incorporated by reference into any of our filings under the Securities Act whether made before or after the date hereof and irrespective of any general incorporation language in any such filing.

The following stock performance graph compares our total stock return with the total return for (i) the Nasdaq Composite Index and the (ii) the Nasdaq Biotechnology Index for the period from December 31, 2020 through December 31, 2025. The figures represented below assume an investment of $100 in our common stock at the closing price of $196.75 on December 31, 2020 and in the Nasdaq Composite Index and the Nasdaq Biotechnology Index on December 31, 2020 and the reinvestment of dividends into shares of common stock. The comparisons in the table are required by the SEC and are not intended to forecast or be indicative of possible future performance of our common stock.

During 2023, the Company completed a reverse merger, which brought in an entirely new pipeline of product candidates targeting IBD, and refreshed the Board and executive team to lead development of this new pipeline and sunset legacy asset development. Additionally, the Company has since expanded its pipeline into RD. The graph below includes pre-reverse merger stock performance, which is not relevant to Spyre's current stock performance.

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Company/Index	2020		2021		2022	2023	2024	2025
Spyre Therapeutics, Inc. (SYRE)	$	100.00	$	60.36

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