UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

☒	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
OR
☐	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: 001-39712

OLEMA PHARMACEUTICALS, INC.

(Exact name of Registrant as specified in its charter)


Delaware		30-0409740
(State or other jurisdiction of incorporation or organization)		(I.R.S. Employer Identification No.)

780 Brannan Street

San Francisco, California 94103

(Address of principal executive offices and zip code)

Registrant’s telephone number, including area code: (415) 651-3316

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


Title of Each Class of Securities Registered	Trading Symbol	Name of Each Exchange on Which Registered
Common Stock, par value $0.0001 per share	OLMA	The Nasdaq Global Select Market

Securities registered pursuant to Section 12(g) of the 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 ☐ ☒ No ☒☐

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒

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 ☒ No ☐

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 ☒ No ☐

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. ☐

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. ☐

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. ☐

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). ☐

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b‑2 of the Act). Yes ☐ No ☒

The aggregate market value of common stock held by non-affiliates of the Registrant, based on the closing sales price for such stock on June 2830, ~~2024~~2025 as reported by The Nasdaq Global Select Market, was approximately $~~454~~243.31 million.

As of March 1311, ~~2025~~2026, the number of outstanding shares of the Registrant’s common stock was 6887,~~333~~156,~~065~~961. This number does not include 13,594,149 shares of common stock issuable upon the exercise of pre-funded warrants (which are immediately exercisable at an exercise price of $0.0001 per share of common stock, subject to beneficial ownership limitations) (See Notes 2 and 7 to the Registrant's consolidated financial statements).

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the registrant’s definitive Proxy Statement for the ~~2024~~2026 Annual Meeting of Stockholders to be filed with the U.S. Securities and Exchange Commission pursuant to Regulation 14A not later than 120 days after the end of the fiscal year covered by this Annual Report on Form 10‑K are incorporated by reference in Part III, Items 10‑14 of this Annual Report on Form 10‑K.

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OLEMA PHARMACEUTICALS, INC.

~~2024~~2025 ANNUAL REPORT ON FORM 10‑K

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		Page
PART I
Item 1.	Business.	7
Item 1A.	Risk Factors.	4854
Item 1B.	Unresolved Staff Comments.	~~112~~126
Item 1C.	Cybersecurity.	~~112~~126
Item 2.	Properties.	~~113~~128
Item 3.	Legal Proceedings.	~~113~~128
Item 4.	Mine Safety Disclosures.	~~114~~128
PART II
Item 5.	Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities.	~~115~~129
Item 6.	Reserved.	~~115~~129
Item 7.	Management’s Discussion and Analysis of Financial Condition and Results of Operations.	~~116~~130
Item 7A.	Quantitative and Qualitative Disclosures About Market Risk.	~~129~~143
Item 8.	Consolidated Financial Statements and Supplementary Data.	~~129~~144
Item 9.	Changes in and Disagreements with Accountants on Accounting and Financial Disclosure.	~~160~~179
Item 9A.	Controls and Procedures.	~~160~~179
Item 9B.	Other Information.	~~161~~180
Item 9C	Disclosure Regarding Foreign Jurisdictions that Prevent Inspections.	~~161~~180
PART III
Item 10.	Directors, Executive Officers and Corporate Governance.	~~162~~181
Item 11.	Executive Compensation.	~~162~~181
Item 12.	Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters.	~~162~~181
Item 13.	Certain Relationships and Related Transactions, and Director Independence.	~~162~~181
Item 14.	Principal Accountant Fees and Services.	~~162~~181
PART IV
Item 15.	Exhibit and Consolidated Financial Statement Schedules.	~~163~~182
Item 16.	Form 10‑K Summary.	~~167~~186
SIGNATURES		~~168~~187

Unless the context suggests otherwise, references in this Annual Report on Form 10‑K (the Annual Report), to “us,” “our,” “Olema,” “Olema Pharmaceuticals,” “we,” the “Company” and similar designations refer to Olema Pharmaceuticals, Inc. and, where appropriate, its ~~subsidiary~~subsidiaries.

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SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report contains forward-looking statements that involve risks, uncertainties and assumptions that, if they never materialize or prove incorrect, could cause our results to differ materially from those expressed or implied by such forward-looking statements. The statements contained in this Annual Report that are not purely historical are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended (the Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended (the Exchange Act). Forward-looking statements are often identified by the use of words such as, but not limited to, “anticipate,” “believe,” “could,” “estimate,” “expect,” “intend,” “may,” "might," “plan,” “potential,” “predict,” “~~project,” “~~should,” “will,” “would” or the negative of those terms, and similar expressions that convey uncertainty of future events or outcomes to identify these forward-looking statements. Any statements contained herein that are not statements of historical facts may be deemed to be forward-looking statements. Forward-looking statements in this Annual Report include, but are not limited to, statements about:

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our financial performance;

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the sufficiency of our existing cash to fund our future operating expenses and capital expenditure requirements;

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the accuracy of our estimates regarding expenses, future revenue, capital requirements, and needs for additional financing;

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the scope, progress, results and costs of developing palazestrant (OP‑1250), OP-3136, or any ~~other~~future product candidates we may develop, and conducting non-clinical studies and clinical trials, including for our OP-3136 Phase 1 clinical study and our palazestrant Phase 1/2 clinical studies and Phase 3 clinical trials;

•

the timing and costs involved in obtaining and maintaining regulatory approval of palazestrant, OP-3136, or any ~~other~~future product candidates we may develop, and the timing or likelihood of regulatory filings and approvals, including our expectation to seek special designations for our product candidates for various diseases;

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our plans relating to commercializing palazestrant, OP-3136, and any ~~other~~future product candidates we may develop, if approved, including the geographic areas of focus and our ability to grow a sales team;

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the implementation of our strategic plans for our business, palazestrant, OP-3136, or any ~~other~~future product candidates we may develop;

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the size of the market opportunity for palazestrant, OP-3136, or any ~~other~~future product candidates we may develop in each of the diseases we target;

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our reliance on third parties to conduct non-clinical research activities, and for the manufacture of palazestrant, OP-3136, and any ~~other~~future product candidates we may develop;

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the beneficial characteristics, safety, efficacy and therapeutic effects of palazestrant, OP-3136, and any ~~other~~future product candidates we may develop;

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our estimates of the number of patients in the United States who suffer from the diseases we target and the number of subjects that will enroll in our clinical trials;

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the progress and focus of our current and future clinical trials, and the reporting of data from those trials;

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our ability to advance product candidates into and successfully complete clinical trials;

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•

the ability of our clinical trials to demonstrate the safety and efficacy of palazestrant, OP-3136, and any ~~other~~future product candidates we may develop, and other positive results;

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developments relating to our competitors and our industry, including competing product candidates and therapies;

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our plans relating to the further development and manufacturing of palazestrant, OP-3136, and any ~~other~~future product candidates we may develop, including additional indications that we may pursue;

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existing regulations and regulatory developments in the United States and other jurisdictions;

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our potential and ability to successfully manufacture and supply palazestrant, OP-3136, and any ~~other~~future product candidates we may develop for clinical trials and for commercial use, if approved;

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the rate and degree of market acceptance of palazestrant, OP-3136, and any ~~other~~future product candidates we may develop, as well as the pricing and reimbursement of palazestrant, OP-3136, and any ~~other~~future product candidates we may develop, if approved;

•

our continued reliance on third parties to conduct additional clinical trials of palazestrant, OP-3136, and any ~~other~~future product candidates we may develop, and for the manufacture of our product candidates;

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our plans and ability to obtain and protect intellectual property rights, including the scope of protection we are able to establish and maintain for palazestrant, OP-3136, and any ~~other~~future product candidates we may develop;

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our ability to access capital resources on favorable terms, or at all; ~~and~~

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our ability to retain the continued service of our key personnel and to identify, hire, and then retain additional qualified personnel.; and

•

~~These statements are based on~~ the ~~beliefs~~impact ~~and assumptions~~ of ~~our~~the ~~management,~~above ~~which~~factors ~~are in turn based on information currently available to management. Such forward-looking statements are subject to risks, uncertainties~~ and other ~~important~~future ~~factors that could cause actual results and the timing of certain~~ events toon differ materially from future results expressed or implied by such forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to, those discussed in the ~~section~~market ~~entitled~~price ~~“Risk Factors” included under Part I, Item 1A below. Furthermore, such forward-looking statements speak only as~~ of ~~the~~our ~~date~~common ~~of this Annual Report~~stock. ~~Except as required by law, we undertake no obligation to update any forward-looking statements to reflect events or circumstances after the date of such statements.~~

These statements are based on the beliefs and assumptions of our management, which are in turn based on information currently available to management. Such forward-looking statements are subject to risks, uncertainties, and other important factors that could cause actual results and the timing of certain events to differ materially from future results expressed or implied by such forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to, those discussed in the section entitled “Risk Factors” included under Part I, Item 1A below. Furthermore, such forward-looking statements speak only as of the date of this Annual Report. Except as required by law, we undertake no obligation to update any forward-looking statements to reflect events or circumstances after the date of such statements.

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RISK FACTOR SUMMARY

Investing in our common stock involves numerous risks, including the risks described in “Part I, Item 1A. Risk Factors” of this Annual Report. Below are some of these risks, any one of which could materially adversely affect our business, financial condition, results of operations, and prospects.

•

We have no products approved for commercial sale, which may make it difficult for you to evaluate our current business and predict our future success and viability.

•

We require substantial additional capital to finance our operations. If we are unable to raise such capital when needed, or on acceptable terms, we may be forced to delay, reduce, and/or eliminate one or more of our research and drug development programs of our product candidates or future commercialization efforts.

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We have incurred net losses since inception, and we expect to continue to incur net losses for the foreseeable future. In addition, we may be unable to continue as a going concern over the long term.

•

We are substantially dependent on the success of our lead product candidate, palazestrant, which is currently in clinical development. If we are unable to complete development of, obtain regulatory approval for, and commercialize palazestrant in one or more indications and in a timely manner, our business, financial condition, results of operations, and prospects will be significantly harmed.

•

Clinical development is a lengthy and expensive process with an uncertain outcome, and results of earlier studies and trials may not be predictive of future trial results. Failure can occur at any stage of clinical development. We have never completed a pivotal clinical trial or submitted a New Drug Application (NDA), to the FDA or similar drug approval filings to comparable foreign authorities. If we are ultimately unable to obtain regulatory approval for palazestrant, or OP-3136, or any future product candidate we may develop, we will be unable to generate product revenue and our business, financial condition, results of operations, and prospects will be significantly harmed.

•

Even if approved, palazestrant or OP-3136 may not achieve adequate market acceptance among physicians, patients, healthcare payors, and others in the medical community necessary for commercial success.

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We face significant competition, and if our competitors develop and market technologies or products more rapidly than we do or that are more effective, safer, or less expensive than palazestrant, OP-3136, or any future product candidates we may develop ~~in the future~~, our commercial opportunities will be negatively impacted.

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We may be unable to obtain U.S. or foreign regulatory approvals and, as a result, may be unable to commercialize palazestrant, OP-3136, or any future product ~~candidate~~candidates we may develop.

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Unfavorable U.S. and global macroeconomic and geopolitical conditions could adversely affect our business, financial condition, ~~and~~ results of operations, and prospects.

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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.

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If our information technology systems, our data or those of the third parties with whom we work ~~or our data,~~ are or were compromised, we could experience adverse consequences resulting from such compromise, including but not limited to regulatory investigations or actions; litigation; fines and penalties; disruptions of our business operations; reputational harm; loss of revenue or profits; or other adverse consequences.

•

Our success depends on our ability to protect our intellectual property and our proprietary technologies.

We rely, and expect to continue to rely, on third parties, including independent clinical investigators and CROs to conduct certain aspects of our non-clinical studies and clinical trials. If these third parties do not successfully carry out their contractual duties, comply with applicable regulatory

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•

We rely, and expect to continue to rely, on third parties, including independent clinical investigators and CROs, to conduct certain aspects of our non-clinical studies and clinical trials. If these third parties do not successfully carry out their contractual duties, comply with applicable regulatory requirements or meet expected deadlines, we may not be able to obtain regulatory approval for or commercialize palazestrant, OP-3136, or future product candidates we may develop and our business, financial condition, results of operations, and prospects could be significantly harmed.

•

We qualify as a “smaller reporting company” within the meaning of the Exchange Act and may take advantage of certain exemptions from disclosure requirements available to smaller reporting companies, which could make our securities less attractive to investors and may make it more difficult to compare our performance to the performance of other public companies.

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Part I

Item 1. Business.

Overview

Olema is a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of next -generation targeted therapies for breast cancer and beyond. We are advancing our pipeline of novel therapies by leveraging our deep understanding of endocrine-driven cancers, nuclear receptors, and mechanisms of acquired resistance.

Our lead product candidate, palazestrant (formerly known as OP-1250), is a novel, orally-available small molecule with dual activity as both a complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD), currently being investigated in patients with recurrent, locally advanced or metastatic ER-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), breast cancer. In pre-clinical models, palazestrant binds and completely blocks ER-driven transcriptional activity in both wild-type and mutant forms of metastatic ER+ breast cancer. In clinical studies across more than 400 patients, palazestrant has demonstrated strong anti-tumor activity, attractive pharmacokinetics and prolonged drug exposure, favorable tolerability, and combinability with ~~CDK4~~cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) with no significant drug-drug interaction. Based on the clinical results we have achieved to date, we are advancing palazestrant through late-stage clinical development both as a monotherapy and in combination with other targeted agents.

In November 2023, we initiated OPERA-01, our pivotal Phase 3 clinical trial of palazestrant as a monotherapy in second/third-line ER+/HER2- metastatic breast cancer. We anticipate top-line results for this trial in the fall of 2026, expect to submit the NDA in 2027, and, if successful, anticipate potential U.S. Food and Drug Administration (FDA) approval and commercial launch in late 2027.

In combination, we are investigating palazestrant in multiple Phase 1/2 studies with CDK4/6 inhibitors (palbociclib or ribociclib), a phosphatidylinositol 3 kinase alpha (PI3Ka) inhibitor (alpelisib), ~~and~~a ~~with~~mechanistic antarget of rapamycin (mTOR) inhibitor (everolimus), and a CDK4 inhibitor (atirmociclib). In ~~March~~October ~~2024~~2025, at the European Society for Medical Oncology (ESMO), we ~~increased~~presented ~~the~~updated ~~size~~results offrom the ongoing Phase 11b/2 clinical ~~study~~trial of palazestrant in combination with ribociclib byin anpatients ~~additional~~with 15ER+/HER2- ~~patients~~advanced toor ~~explore~~metastatic 90breast mgcancer. ofThese data further support our thesis that palazestrant inpossesses ~~combination~~key ~~with~~characteristics ~~600~~to mgmake it a potential backbone endocrine therapy of ~~ribociclib.~~preference Wefor ER+/HER2- breast cancer, while also ~~initiated~~supporting ~~our~~the ongoing pivotal Phase ~~1b/2~~3 clinical ~~study~~trial of palazestrant in combination with anribociclib ~~mTOR~~in ~~inhibitor,~~front-line ~~everolimus~~ER+/HER2- metastatic breast cancer, incalled ~~the~~OPERA-02. ~~third~~The ~~quarter~~execution of ~~2024.~~OPERA-02 ~~Further~~is supported by our clinical trial collaboration and supply agreement with Novartis Pharma AG (Novartis), which was also announced in ~~October~~December 2024. Under the terms of the agreement, weNovartis ~~presented~~is ~~new~~providing ~~pre-clinical~~Olema ~~data~~with atribociclib drug supply for the ~~EORTC~~OPERA-~~NCI-AACR~~02 ~~Symposium~~trial, onwhich ~~Molecular~~we ~~Targets~~initiated ~~and~~in ~~Cancer~~2025. ~~Therapeutics~~We ~~showing~~anticipate ~~that~~top-line ~~the~~data ~~combination~~in of2028 ~~palazestrant~~and, ~~with~~if ~~both~~successful, ~~everolimus~~anticipate ~~and~~potential ~~capivasertib~~FDA ~~may~~approval beand ~~synergistic~~commercial ~~and~~launch ~~have~~in the ~~potential~~frontline toMBC ~~result~~setting in ~~significant~~the ~~tumor~~United ~~regression~~States in 2029.

~~Most~~Our ~~recently,~~second weproduct ~~presented~~candidate ~~updated~~in ~~results from the ongoing Phase 1b/2~~ clinical ~~trial~~development, ofcalled ~~palazestrant~~OP-3136, inis ~~combination~~a ~~with~~novel, ~~ribociclib~~orally-available insmall ~~patients~~molecule ~~with~~that ~~ER+/HER2-~~potently ~~advanced~~and orselectively ~~metastatic~~inhibits ~~breast~~KAT6, ~~cancer~~an atepigenetic ~~the~~target ~~San~~that ~~Antonio~~is ~~Breast~~dysregulated ~~Cancer~~in ~~Symposium~~breast ~~(SABCS)~~and inother ~~December 2024~~cancers. ~~These~~We ~~data~~believe ~~further~~OP-3136 ~~support~~presents ~~our thesis that palazestrant possesses key characteristics to make it~~ a potential ~~backbone~~best-in-class ~~endocrine~~KAT6 ~~therapy~~inhibitor ofin ~~preference~~breast ~~for~~and ~~ER+/HER2-~~other ~~breast~~solid ~~cancer,~~tumor ~~while~~cancers. ~~also~~In ~~providing~~October ~~the~~2024, ~~basis~~we ~~for~~presented a new ~~pivotal~~pre-clinical ~~Phase~~data 3at ~~clinical~~the ~~trial~~EORTC-NCI-AACR ofSymposium ~~palazestrant~~on inMolecular ~~combination~~Targets ~~with~~and ~~ribociclib~~Cancer inTherapeutics ~~front-line~~demonstrating ~~ER+/HER2~~OP-3136's ~~metastatic~~robust ~~breast cancer, called OPERA~~anti-~~02.~~tumor ~~The~~activity ~~execution~~as ofa ~~OPERA-02~~single ~~will~~agent, beas ~~supported~~well byas ~~our~~potential ~~new~~synergy ~~clinical~~and ~~trial~~enhanced ~~collaboration~~anti-tumor ~~and~~activity ~~supply~~in ~~agreement~~combination with ~~Novartis~~palazestrant. ~~Pharma~~The AGInvestigational New Drug (~~Novartis~~IND), ~~which~~application for OP-3136 was ~~also~~cleared ~~announced~~by FDA in ~~December~~late 2024., ~~Under~~ the ~~terms~~Phase of1 ~~the~~clinical ~~agreement,~~trial ~~Novartis~~is ~~will~~enrolling ~~provide~~patients, ~~Olema~~and ~~with~~we ~~ribociclib~~expect ~~drug~~to ~~supply~~present ~~for~~ the ~~OPERA-02~~first ~~trial,~~clinical ~~which~~data wefrom ~~expect~~this toprogram ~~initiate~~ in ~~2025~~the second quarter of 2026.

Our second product candidate in clinical development, called OP-3136, is a novel, orally-available small molecule that potently and selectively inhibits KAT6, an epigenetic target that is dysregulated in breast and other cancers. We believe OP-3136 presents a potential best-in-class KAT6 inhibitor in breast and other solid tumor cancers. In October 2024, we presented new pre-clinical data at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics demonstrating OP-3136's robust anti-tumor activity as a single agent, as well as potential synergy and enhanced anti-tumor activity in combination with palazestrant. The 7

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~~Table~~Since our inception, we have devoted substantially all of ~~Contents~~our resources to organizing and staffing our company, research and development activities, business planning, raising capital, establishing and maintaining our intellectual property portfolio, conducting non-clinical studies and clinical trials and providing general and administrative support for these operations.

~~Investigational~~We ~~New~~do ~~Drug~~not ~~(IND)~~have ~~application~~any product candidates approved for ~~OP-3136~~commercial ~~was~~sale, ~~cleared~~and bywe have not generated any revenue from product sales. Our ability to generate product revenue sufficient to achieve profitability, if ever, will depend on the Usuccessful development and eventual commercialization of one or more of our product candidates which we expect, if it ever occurs, will take a number of years.S ~~Food~~We also do not own or operate, and ~~Drug~~currently ~~Administration~~have ~~(FDA)~~no inplans ~~late~~to ~~2024~~establish, any manufacturing facilities. We rely, and expect to continue to rely, on third parties for the ~~Phase~~manufacture 1of our product candidates for non-clinical ~~trial~~and isclinical ~~now~~testing, ~~enrolling~~as ~~patients~~well as for commercial manufacturing if any of our product candidates obtain marketing approval. We believe that this strategy allows us to maintain a more efficient infrastructure by eliminating the need for us to invest in our own manufacturing facilities, equipment and personnel while also enabling us to focus our expertise and resources on the development of our product candidates.

~~Since~~Our our inception, we have devoted substantially all of our resources to organizing and staffing our company, research and development activities, business planning, raising capital, establishing and maintaining our intellectual property portfolio, conducting non-clinical studies and clinical trials and providing general and administrative support for these operations.Approach

We doare ~~not~~committed ~~have~~to ~~any~~transforming ~~product~~the ~~candidates~~standard ~~approved~~of care and improving outcomes for ~~commercial~~women ~~sale,~~living ~~and~~with wecancer. ~~have~~Breast ~~not~~cancer ~~generated~~represents ~~any~~approximately ~~revenue~~30% ~~from~~of ~~product~~all ~~sales~~new diagnoses of cancer in women. ~~Our~~The ~~ability~~American toCancer ~~generate~~Society ~~product~~(ACS) ~~revenue~~estimates ~~sufficient~~that toin ~~achieve~~2026 ~~profitability~~there will be approximately 321,910 ifnew ~~ever~~cases of invasive breast cancer diagnosed and approximately 42,140 ~~will~~deaths ~~depend~~from onbreast cancer in the ~~successful~~United ~~development~~States. ~~and~~Treatment ~~eventual~~decisions ~~commercialization~~are ofbased ~~one~~on ora ~~more~~combination of ~~our~~individual ~~product~~patient ~~candidates~~characteristics ~~which~~and wetumor ~~expect~~biology, ifmost itimportantly ~~ever~~the ~~occurs~~expression of three proteins: ER, ~~will~~progesterone ~~take~~receptor a(PR), ~~number~~and ofhuman ~~years~~epidermal growth factor receptor 2 (HER2). WeApproximately ~~also~~79% doof ~~not~~all ~~own~~breast orcancers ~~operate~~are ER+, and ~~currently~~approximately ~~have~~70% noare ~~plans~~ER+/HER2-, tohighlighting ~~establish,~~the ~~any~~central ~~manufacturing~~role ~~facilities~~of the ER in driving a large majority of breast cancer. WeApproximately ~~rely,~~6-10% ~~and~~of ~~expect~~breast tocancer ~~continue~~patients topresent ~~rely,~~with onmetastatic ~~third~~disease ~~parties~~at ~~for~~diagnosis ~~the~~and ~~manufacture~~a further 20-30% of ~~our~~patients ~~product~~initially ~~candidates~~diagnosed ~~for~~with ~~non~~early-~~clinical~~stage ~~and~~disease ~~clinical~~ultimately ~~testing,~~develop asmetastatic ~~well~~disease. asThe ~~for~~current ~~commercial~~five-year ~~manufacturing~~survival ifrate ~~any~~for ofpatients ~~our~~with ~~product~~ER+ ~~candidates~~metastatic ~~obtain~~breast ~~marketing~~cancer ~~approval~~is approximately 32%. WeBased on our internal estimates, we believe that ~~this~~the ~~strategy~~current ~~allows~~global usER+/HER2- tometastatic ~~maintain~~breast acancer ~~more~~market ~~efficient~~represents ~~infrastructure~~approximately by$20 ~~eliminating~~billion. In the ~~need~~U.S. ~~for~~and usE.U., towe ~~invest~~believe inthe ~~our~~market ~~own~~potential ~~manufacturing~~for ~~facilities,~~palazestrant ~~equipment~~is ~~and~~up ~~personnel~~to ~~while~~$5 ~~also~~billion ~~enabling~~in usthe tosecond- ~~focus~~and ~~our~~third-line ~~expertise~~settings and ~~resources~~up onto ~~the~~$10 ~~development~~billion ofin ~~our~~the ~~product~~first-line ~~candidates~~setting.

~~Our~~The ~~Approach~~ER is a nuclear receptor that functions as a ligand regulated transcription factor. When bound to estrogen, the ER directs the expression of genes that are essential for breast cancer cells’ survival and proliferation. For more than four decades, researchers have been developing new approaches and therapies to prevent activation of the ER pathway, thereby inhibiting the ability of the ER to drive tumor cell growth. In 1977, the first endocrine therapeutic, the anti-estrogen tamoxifen, was approved by the FDA for the treatment of breast cancer. Tamoxifen is still commonly used today but is challenged by the development of acquired drug resistance, which in some cases may be due to its partial agonist activity. In the search for a different mechanism to target the estrogen pathway, aromatase inhibitors (AIs), were developed in the 1990s to block the synthesis of estrogen and deprive the ER+ cells of its activating ligand. However, up to 50% of patients taking AIs develop arthralgia, leading to suspension of treatment in up to 15% of patients. Additionally, most patients with metastatic breast cancer have been shown to ultimately develop resistance to AIs, the most common of which is the development of a ligand-independent activating mutation in the estrogen receptor 1 (ESR1) gene. In pre-menopausal women, treatment with AIs must also be accompanied by ovarian suppression.

WeIn ~~are~~2002, ~~committed~~fulvestrant towas ~~transforming~~approved ~~the~~as ~~standard~~a oftreatment ~~care and improving outcomes~~ for ~~women~~HR+ ~~living~~metastatic ~~with~~breast cancer. ~~Breast~~patients ~~cancer~~and ~~represents~~is ~~approximately~~typically ~~30%~~used ofas ~~all~~a ~~new~~second- ~~diagnoses~~or ofthird-line ~~cancer~~endocrine ~~in women~~agent. ~~The~~Fulvestrant ~~American~~was ~~Cancer~~designed ~~Society~~to ~~(ACS), estimated that in 2025 there will~~ be ~~approximately~~a ~~319~~CERAN,~~750~~ ~~new cases of invasive breast cancer diagnosed~~ and ~~approximately~~later ~~42,680~~discovered ~~deaths~~to ~~from~~also ~~breast~~be ~~cancer in the United States. Treatment decisions are based on~~ a ~~combination~~SERD, ~~of individual patient characteristics~~ and ~~tumor~~represented ~~biology,~~a ~~most~~breakthrough ~~importantly~~for the ~~expression~~field ofwith ~~three~~improved ~~proteins:~~outcomes ~~ER,~~for ~~progesterone~~patients ~~receptor~~whose ~~(PR),~~disease ~~and~~had ~~human~~progressed ~~epidermal~~on ~~growth~~prior ~~factor~~endocrine ~~receptor 2 (HER2)~~therapy. ~~Approximately 79% of all breast cancers are ER+~~However, ~~and~~fulvestrant ~~approximately~~has ~~70%~~several ~~are ER+/HER2-~~limitations, ~~highlighting~~including ~~the~~its ~~central~~suboptimal ~~role~~drug ofexposure ~~the ER in driving a large majority of breast cancer. Approximately 6-10% of breast cancer patients present with metastatic disease at diagnosis~~ and aits ~~further~~route ~~20-30%~~ of ~~patients~~administration, ~~initially~~which ~~diagnosed~~requires ~~with~~two ~~early-stage~~monthly ~~disease~~intramuscular ~~ultimately develop metastatic disease~~injections. ~~The~~Despite ~~current~~these ~~five-year survival rate for patients with ER+ metastatic breast cancer is approximately 32%. Based on our internal estimates~~drawbacks, wefulvestrant ~~believe~~achieved ~~that~~worldwide ~~the~~sales ~~current~~of ~~global~~over ~~ER+/HER2- metastatic breast cancer market represents approximately~~ $~~20 billion~~1.1 ~~In the U.S. and E.U., we believe the market potential for palazestrant is up to $5~~ billion in ~~the second- and third-line settings and up to $10 billion in the first-line setting~~2019.

The ER is a nuclear receptor that functions as a ligand regulated transcription factor. When bound to estrogen, the ER directs the expression of genes that are essential for breast cancer cells’ survival and proliferation. For more than four decades, researchers have been developing new approaches and therapies to prevent activation of the ER pathway, thereby inhibiting the ability of the ER to drive tumor cell growth. In 1977, the first endocrine therapeutic, the anti-estrogen tamoxifen, was approved by the FDA for the treatment of breast cancer. Tamoxifen is still commonly used today but is challenged by the development of acquired drug resistance, which in some cases may be due to its partial agonist activity. In the search for a different mechanism to target the estrogen pathway, aromatase inhibitors (AIs), were developed in the 1990s to block the synthesis of estrogen and deprive the ER+ cells of its activating ligand. However, up to 50% of patients taking AIs develop arthralgia, leading to suspension of treatment in up to 15% of patients. Additionally, most patients with metastatic breast cancer have been shown to ultimately develop resistance to AIs, the most common of which is the development of a ligand-independent activating mutation in the estrogen receptor gene, ESR1. In pre-menopausal women, treatment with AIs must also be accompanied by ovarian suppression.8

InTable ~~2002,~~of fulvestrant was approved as a treatment for HR+ metastatic breast cancer patients and is typically used as a second- or third-line endocrine agent. Fulvestrant was designed to be a CERAN, and later discovered to also be a SERD, and represented a breakthrough for the field with improved outcomes for patients whose disease had progressed on prior endocrine therapy. However, fulvestrant has several limitations including its Contents

8More recently, the field has focused on the discovery and development of oral agents that have fulvestrant’s dual mechanism of action to completely inactivate and degrade the ER. Some of these oral SERD agents are CERANs, such as palazestrant, but others have partial agonist activity despite being SERDs and thus are not CERANs. These agents can be considered selective ER modulators (SERM) SERDs. SERM/SERDs reduce the levels of the ER but they do not entirely eliminate it. Notably, naturally-occurring estrogen itself leads to ER degradation when binding the ER.

~~Table~~We have spent a significant amount of ~~Contents~~time designing and optimizing our lead product candidate, palazestrant. We believe that the ability to function as a CERAN and a SERD, together with attractive pharmacokinetics and drug exposure, favorable tolerability, combinability with CDK4/6 inhibitors, and central nervous system (CNS) penetration, are important characteristics to enable the success of a next generation endocrine therapy. We believe that results from our pre-clinical and clinical studies demonstrate that palazestrant has shown properties supporting its potential to achieve these objectives, address an unmet need in the treatment of breast cancer, and improve upon standard of care.

~~suboptimal~~Based ~~drug~~on ~~exposure~~the ~~and~~clinical ~~route~~results ofwe ~~administration~~have achieved to date, we are advancing palazestrant through late-stage clinical development both as ~~two~~a ~~monthly~~monotherapy ~~intramuscular~~and ~~injections~~in combination with other targeted agents. ~~Despite~~We ~~these~~own ~~drawbacks~~worldwide development and commercialization rights to palazestrant. We believe palazestrant’s oral formulation and dual mechanism of action directly address the limitations of current endocrine therapies, such as fulvestrant, ~~achieved~~aromatase ~~worldwide~~inhibitors ~~sales~~and tamoxifen, and position palazestrant as a potential endocrine therapy of ~~over~~choice $1for the treatment of ER+ breast cancers.1 ~~billion~~We are also advancing OP-3136, our second product candidate in ~~2019~~clinical development, which targets KAT6. Taken together, we believe our product candidates have the potential to represent the future of breast cancer care.

~~More~~Our recently, the field has focused on the discovery and development of oral agents that have fulvestrant’s dual mechanism of action to completely inactivate and degrade the ER. Some of these oral SERD agents are CERANs, such as palazestrant, but others have partial agonist activity despite being SERDs and thus are not CERANs. These agents can be considered selective ER modulators (SERM) SERDs. SERM/SERDs reduce the levels of the ER but they do not entirely eliminate it. Notably, naturally-occurring estrogen itself leads to ER degradation when binding the ER.Strategy

WeOur ~~have~~goal ~~spent~~is ~~a significant amount of time designing and optimizing our lead product candidate, palazestrant. We believe that the ability~~ to ~~function both as a CERAN and a SERD~~discover, ~~together with attractive pharmacokinetics and drug exposure~~develop, ~~favorable tolerability, combinability with CDK4/6 inhibitors,~~ and ~~central~~commercialize ~~nervous system (CNS) penetration, are important characteristics to enable the success of a~~ next generation ~~endocrine~~targeted ~~therapy.~~therapies Wefor ~~believe~~breast ~~that results from our pre-clinical~~ and ~~clinical~~other ~~studies~~cancers. ~~demonstrate~~The ~~that~~key ~~palazestrant~~elements ~~has~~of ~~shown~~our ~~properties~~business ~~supporting~~strategy ~~its potential~~ to achieve ~~these~~this ~~objectives,~~goal ~~address an unmet need in the treatment of breast cancer, and improve upon standard of care.~~include:

•

~~Based~~Applying onour ~~the~~deep ~~clinical~~understanding ~~results~~of wenuclear ~~have~~receptors ~~achieved~~— toparticularly ~~date,~~the weER ~~are~~— ~~advancing~~and ~~palazestrant~~mechanisms ~~through~~of ~~late-stage~~resistance ~~clinical~~to ~~development~~develop ~~both~~novel astherapeutic aapproaches ~~monotherapy~~for ~~and~~endocrine-driven incancers. ~~combination~~Our ~~with~~team ~~other~~has ~~targeted~~spent ~~agents.~~over Wea ~~own~~decade ~~worldwide~~characterizing ~~development~~the structure and ~~commercialization~~function ~~rights~~of tothe ~~palazestrant.~~ER Weand ~~believe~~its ~~palazestrant’s~~role ~~oral~~in ~~formulation~~driving ~~and~~tumor ~~dual~~cell ~~mechanism~~proliferation ofin ~~action~~HR+ ~~directly~~breast ~~address~~cancer. ~~the~~Our ~~limitations~~knowledge of ~~current~~the ~~endocrine~~ER’s ~~therapies,~~functional ~~such~~domains ascombined ~~fulvestrant,~~with ~~aromatase~~our ~~inhibitors~~medicinal ~~and~~chemistry ~~tamoxifen,~~expertise ~~and~~has ~~position~~allowed ~~palazestrant~~us asto develop a ~~potential~~potent ~~endocrine~~and ~~therapy~~oral ofcompound ~~choice~~that ~~for~~both ~~the~~completely ~~treatment~~inactivates and strongly promotes degradation of the ER+ ~~breast~~in ~~cancers~~non-clinical studies. We ~~are~~believe ~~also~~palazestrant’s ~~advancing~~oral ~~OP-3136,~~formulation ~~our~~and ~~newest~~dual ~~product~~mechanism ~~candidate~~of inaction ~~clinical~~as ~~development~~a ~~targeting~~CERAN/SERD ~~KAT6.~~directly ~~Taken~~address ~~together~~the limitations of current endocrine therapies, wesuch ~~believe~~as ~~our~~fulvestrant, ~~product~~AIs, ~~candidates~~and ~~have~~tamoxifen, and has the potential to ~~represent~~drive ~~the~~deeper, ~~future~~more ofdurable ~~breast cancer care~~responses.

•

~~Our~~Rapidly ~~Strategy~~advancing our product candidates, including palazestrant, through late-stage clinical development for the treatment of ER+/HER2- metastatic breast cancer, and OP-3136 through early-stage clinical development in breast and other cancers. We are currently evaluating palazestrant in a pivotal Phase 3 trial, called OPERA-01, as a monotherapy in the second- and third-line setting of ER+/HER2- advanced or metastatic breast cancer. Patients are enrolling in OPERA-02, a pivotal Phase 3 trial evaluating palazestrant in combination with ribociclib in the frontline metastatic setting of ER+/HER2- breast cancer. OP-3136 is currently in a Phase 1 clinical trial being evaluated both as a monotherapy and in combination with fulvestrant and palazestrant.

~~Our goal is to discover, develop, and commercialize next generation targeted therapies for breast and other cancers. The key elements of our business strategy to achieve this goal include:~~9

~~Applying~~Table ~~our deep understanding~~ of nuclear receptors — particularly the ER — and mechanisms of resistance to develop novel therapeutic approaches for endocrine-driven cancers. Our team has spent over a decade characterizing the structure and function of the ER and its role in driving tumor cell proliferation in HR+ breast cancer. Our knowledge of the ER’s functional domains combined with our medicinal chemistry expertise has allowed us to develop a potent and oral compound that both completely inactivates and strongly promotes degradation of the ER in non-clinical studies. We believe palazestrant’s oral formulation and dual mechanism of action as a CERAN/SERD directly address the limitations of current endocrine therapies, such as fulvestrant, AIs, and tamoxifen, and has the potential to drive deeper, more durable responses.Contents

•

~~Rapidly~~Establishing ~~advancing~~palazestrant ~~our~~as ~~product~~the ~~candidates,~~endocrine ~~including~~therapy ~~palazestrant,~~of ~~through~~choice ~~late-stage~~with ~~clinical~~targeted ~~development~~therapy combinations for the treatment of metastatic ER+~~/HER2-~~ ~~metastatic~~ breast ~~cancer,~~cancers. ~~and~~We ~~OP-3136~~believe ~~through~~palazestrant’s ~~early-stage~~differentiated ~~clinical~~product ~~development~~profile inhas ~~breast~~the ~~and~~potential ~~other~~to ~~cancers.~~overcome Wemany ~~are~~of ~~currently~~the ~~evaluating~~limitations ~~palazestrant~~of incurrent aendocrine ~~pivotal~~therapy ~~Phase~~options. 3While ~~trial,~~targeted ~~called~~chemotherapy ~~OPERA-01,~~and asother atargeted ~~monotherapy~~anti-body indrug ~~the~~conjugates ~~second-~~continue ~~and~~to ~~third-line~~show ~~setting~~promising ofdata ~~ER+/HER2-~~and ~~advanced~~will orlikely ~~metastatic~~gain ~~breast~~further ~~cancer.~~favorability Weas ~~are~~a ~~also~~treatment ~~preparing~~option, towe ~~initiate~~believe ~~OPERA-02,~~these anew ~~pivotal~~treatment ~~Phase~~options 3will ~~trial~~replace ~~evaluating~~traditional ~~palazestrant~~chemotherapy, innot ~~combination~~endocrine ~~with~~therapies. ~~ribociclib~~Our ingoal ~~the~~is ~~frontline~~to ~~metastatic~~successfully ~~setting~~demonstrate ofimproved ~~ER+/HER2-~~efficacy ~~breast~~and ~~cancer.~~a ~~OP-3136~~favorable istolerability ~~currently~~profile in acombination ~~Phase~~with 1other ~~clinical~~targeted ~~trial being~~therapies ~~evaluated~~to ~~both~~position palazestrant as athe ~~monotherapy~~endocrine ~~and~~therapy of choice in ~~combination~~the ~~with~~first-line ~~fulvestrant~~setting ~~and~~for ~~palazestrant~~advanced or metastatic ER+/HER2- breast cancer.

•

~~Establishing~~Exploring additional clinical opportunities for palazestrant, asincluding metastatic breast cancer with brain metastases and other hormone sensitive tumors. Metastatic breast cancer is the ~~endocrine~~second ~~therapy~~most ofcommon ~~choice~~cancer associated with ~~targeted~~brain ~~therapy~~metastases ~~combinations~~in ~~for~~ the United States. The primary treatment for CNS metastases is typically surgery, radiation, or a combination of ~~metastatic~~both ~~ER+~~and these patients tend to have a poor prognosis. In pre-clinical studies, palazestrant demonstrated robust CNS penetration and, in an intracranial breast ~~cancers~~cancer brain metastases xenograft study, palazestrant demonstrated the ability to shrink tumors and improve survival in mice. We believe that combining palazestrant’s ~~differentiated~~with ~~product~~HER2-targeted ~~profile~~agents ~~has~~may ~~the~~represent ~~potential~~an opportunity to ~~overcome~~improve ~~many~~upon recent advancements in the treatment of CNS disease in patients that express both ER and HER2, as up to 50% of patients with metastatic ER+/HER2+ breast cancer develop CNS disease. In non-clinical studies, the ~~limitations~~addition of ~~current~~palazestrant to HER2 inhibitors improved tumor growth inhibition in ER+/HER2+ xenograft models.

•

9Expanding our portfolio of product candidates through both internal research activities and business development efforts. We are applying our internal drug discovery capabilities to identify and evaluate novel targeted therapies that can improve the lives of people living with cancer. We have an active discovery research team exploring additional opportunities for targeted therapies for breast cancer. We successfully identified KAT6 as a novel target and entered into a collaboration with Aurigene Oncology in 2022, which led to the discovery and development of OP-3136. We plan to continue to explore opportunities to acquire products and technologies that align with our core areas of expertise and complement our existing portfolio.

•

~~Table~~Continuing to evaluate opportunities to accelerate clinical development timelines and enhance the commercial potential of ~~Contents~~our programs through collaboration with third parties. We own full worldwide development and commercialization rights to both palazestrant and OP-3136. We have established clinical collaborations with both Novartis and Pfizer and we intend to continue evaluating opportunities to work with partners that meaningfully enhance our capabilities with respect to the development and commercialization of our product candidates. In addition, we intend to commercialize our product candidates in key markets either alone or with partners to maximize the worldwide commercial potential of our programs.

endocrine therapy options. While targeted chemotherapy and other targeted anti-body drug conjugates continue to show promising data and will likely gain further favorability as a treatment option, we believe these new treatment options will replace traditional chemotherapy - not endocrine therapies. Our goal is to successfully demonstrate improved efficacy and a favorable tolerability profile in combination with other targeted therapies to position palazestrant as the endocrine therapy of choice in the first-line setting for advanced or metastatic ER+/HER2- breast cancer.10

~~Exploring~~Table additional clinical opportunities for palazestrant, including metastatic breast cancer with brain metastases and other hormone sensitive tumors. Metastatic breast cancer is the second most common cancer associated with brain metastases in the United States. The primary treatment for CNS metastases is typically surgery, radiation, or a combination of both and these patients tend to have a poor prognosis. In pre-clinical studies, palazestrant demonstrated robust CNS penetration and, in an intracranial breast cancer brain metastases xenograft study, palazestrant demonstrated the ability to shrink tumors and improve survival in mice. We believe that combining palazestrant with HER2-targeted agents may represent an opportunity to improve upon recent advancements in the treatment of CNS disease in patients that express both ER and HER2, as up to 50% of patients with metastatic ER+/HER2+ breast cancer develop CNS disease. In non-clinical studies, the addition of palazestrant to HER2 inhibitors improved tumor growth inhibition in ER+/HER2+ xenograft models.Contents

~~Expanding~~As ~~our~~summarized ~~portfolio~~in ofthe ~~product~~figure ~~candidates~~below, ~~through both internal research activities and business development efforts. We are applying~~ our ~~internal~~plan ~~drug~~is ~~discovery capabilities~~ to ~~identify~~develop ~~and~~our ~~evaluate~~wholly-owned ~~novel~~lead ~~targeted~~product ~~therapies~~candidate, ~~that~~palazestrant, ~~can~~in ~~improve~~a ~~the~~number ~~lives~~ of ~~people~~ER+ ~~living~~breast ~~with~~ cancer. Weindications, ~~have~~both anas ~~active~~a ~~discovery~~monotherapy ~~research~~and ~~team~~in ~~exploring~~combination ~~additional~~with ~~opportunities~~approved ~~for~~ targeted therapies ~~for~~that ~~breast~~have ~~cancer.~~shown Weimproved ~~successfully~~outcomes ~~identified~~with ~~KAT6~~other asendocrine atherapies. ~~novel~~In ~~target~~addition, our ~~and~~KAT6 ~~entered into a collaboration with Aurigene Oncology in 2022~~program, ~~which led to the discovery and development of~~ OP-3136., Weentered ~~plan~~clinical todevelopment ~~continue~~in tolate ~~explore~~2024, ~~opportunities~~and towe ~~acquire~~are ~~products~~evaluating ~~and~~potential ~~technologies~~combination ~~that~~development ~~align~~ with ~~our~~both ~~core~~fulvestrant ~~areas of expertise~~ and ~~complement our existing portfolio~~palazestrant.

~~Continuing~~Figure ~~to evaluate opportunities to accelerate clinical development timelines and enhance the commercial potential of our programs through collaboration with third parties~~1. WeOlema own full worldwide development and commercialization rights to both palazestrant and OP-3136. We have established clinical collaborations with both Novartis and Pfizer and we intend to continue evaluating opportunities to work with partners that meaningfully enhance our capabilities with respect to the development and commercialization of our product ~~candidates. In addition, we intend to commercialize our product candidates in key markets either alone or with partners to maximize the worldwide commercial potential of our programs.~~pipeline

AsOur summarized in the figure below, our plan is to develop our wholly-owned lead product candidate, palazestrant, in a number of ER+ breast cancer indications, both as a monotherapy and in combination with approved targeted therapies that have shown improved outcomes with other endocrine therapies. In addition, Opportunity

10Epidemiology and classification of breast cancer

~~Table~~Breast cancer is the second-most common cancer worldwide, with nearly two million new diagnoses per year. The ACS estimates 1 in 8 women in the U.S. will be diagnosed with invasive breast cancer in her lifetime and that, in 2026, there will be approximately 321,910 new cases of ~~Contents~~female breast cancer and approximately 42,140 deaths in the United States, making it the second-leading cause of cancer death in women. Approximately 2,800 men are also diagnosed with breast cancer each year in the United States. Breast cancer is a heterogeneous disease which is grouped into several clinical subtypes based on the expression of three proteins: ER, PR and HER2. Both ER and PR are hormone receptors, and tumors that express either of these receptors are referred to as HR+. It is unusual for a tumor to express PR in the absence of the ER, therefore most tumors are referred to as either ER+ or ER-. Tumors that express HER2 are denoted HER2+, and tumors that do not express ER, PR, or HER2 are classified as triple negative breast cancer. Approximately 79% of all breast cancers are HR+, and approximately 70% are HR+/HER2-, highlighting the central role of ER signaling in driving a large majority of breast cancer.

~~our KAT6 program, OP-3136, entered clinical development in late 2024 with plans to explore its clinical development in combination with both fulvestrant and palazestrant.~~11

~~Figure~~Table 1.of ~~Olema product pipeline~~Contents

~~Our~~Treating ~~Opportunity~~breast cancer

~~Epidemiology~~Early-stage ~~and classification of~~ breast cancer

Breast cancer stage is ~~the~~determined ~~second-most~~by ~~common~~the ~~cancer~~size ~~worldwide,~~of ~~with~~the ~~nearly~~tumor ~~two~~and ~~million~~whether ~~new~~or ~~diagnoses~~not ~~per~~the ~~year.~~cancer ~~The~~has ~~ACS~~spread ~~estimates~~to 1lymph ~~in 8 women in the U~~nodes.S. ~~will~~A betumor ~~diagnosed with invasive breast cancer in her lifetime and~~ that, inis ~~2025,~~confined ~~there~~to ~~will~~the bebreast ~~approximately~~with ~~316,950~~or ~~new~~without ~~cases~~the involvement of ~~female breast cancer and approximately 42~~local,~~170~~ ~~deaths~~ipsilateral inlymph ~~the~~nodes ~~United~~is ~~States,~~considered ~~making it the second~~early-~~leading~~stage ~~cause~~breast of cancer ~~death in women~~. ~~Approximately~~Treatment ~~2,800~~for ~~men~~patients ~~are also diagnosed~~ with early-stage breast cancer ~~each~~involves ~~year~~two ~~in the United States~~components. ~~Breast~~First, ~~cancer~~there is alocal ~~heterogeneous~~treatment ~~disease~~of ~~which is grouped into several clinical subtypes based on~~ the ~~expression~~breast, ofchest ~~three proteins: ER~~wall, PR and ~~HER2.~~local ~~Both~~lymph ERnodes, ~~and~~if PRany, ~~are~~with ~~hormone receptors~~surgery, ~~and tumors that express~~ either ofa ~~these~~lumpectomy ~~receptors~~or ~~are~~mastectomy, ~~referred~~and topotentially ~~as HR+~~radiation. ItSecond, isbased ~~unusual~~on ~~for~~the abiology ~~tumor~~and tocharacteristics ~~express~~of ~~PR in~~ the ~~absence~~tumor, ofpatients ~~the~~may ~~ER,~~also ~~therefore~~be ~~most~~offered ~~tumors~~systemic ~~are~~therapy, referred to as ~~either~~adjuvant ~~ER+ or ER-. Tumors that express HER2 are denoted HER2+~~therapy, ~~and~~in ~~tumors~~order ~~that~~to dodecrease ~~not~~the ~~express~~risk ~~ER,~~of PRrecurrence orof ~~HER2 are classified as triple negative~~ breast cancer. ~~Approximately~~anywhere ~~79%~~in ofthe ~~all~~body. ~~breast~~Systemic ~~cancers~~therapy ~~are~~can ~~HR+,~~be ~~and~~given ~~approximately~~either ~~70%~~after ~~are~~surgery ~~HR+/HER2-~~(adjuvant), ~~highlighting~~prior ~~the~~to ~~central~~surgery ~~role~~(neoadjuvant), ofor ~~ER signaling in driving~~ a ~~large~~combination ~~majority~~ of ~~breast cancer~~both.

~~Treating~~The initial standard of care for patients with early-stage ER+ breast cancer is at least five years of adjuvant endocrine therapy. The endocrine treatment options for early-stage disease are AIs, such as anastrozole, exemestane or letrozole, or an ER antagonist such as a tamoxifen. For patients diagnosed with early-stage ER+ breast cancer who undergo surgical and adjuvant/neoadjuvant treatment, the five-year survival rate is over 90%.

~~Early-stage~~Metastatic breast cancer

~~Breast~~When cancer ~~stage is determined by the size of the tumor and whether or not the cancer~~ has spread tobeyond local lymph nodes., Aeither ~~tumor that is confined~~ to ~~the~~distant ~~breast~~lymph ~~with~~nodes, bones, or ~~without~~visceral ~~the involvement of local~~organs, ~~ipsilateral~~the ~~lymph~~cancer ~~nodes~~ is now considered ~~early~~metastatic. Approximately 6-~~stage~~10% of breast cancer. ~~Treatment for~~ patients present with ~~early-stage~~de ~~breast~~novo ~~cancer~~metastatic ~~involves two components. First~~disease, ~~there~~also isreferred ~~local~~to ~~treatment~~as ofstage ~~the~~IV ~~breast~~disease, ~~chest~~at ~~wall,~~initial ~~and~~diagnosis. ~~local~~In ~~lymph nodes~~addition, ifapproximately ~~any,~~30% ~~with~~of ~~surgery,~~patients ~~either~~diagnosed awith ~~lumpectomy~~early-stage orbreast ~~mastectomy,~~cancer ~~and~~will ~~potentially~~develop ~~radiation~~metastatic disease. ~~Second,~~In ~~based~~contrast onto the ~~biology~~goals ~~and characteristics~~ of ~~the~~adjuvant ~~tumor, patients may also be offered systemic~~ therapy, ~~referred~~treatments tofor asmetastatic ~~adjuvant~~disease ~~therapy,~~are inpalliative ~~order~~with ~~to decrease~~ the ~~risk~~desired ofoutcome ~~recurrence~~ of ~~breast~~controlling ~~cancer~~symptoms ~~anywhere~~and inextending ~~the~~survival ~~body.~~as ~~Systemic~~long ~~therapy~~as ~~can~~possible. beThe ~~given~~current ~~either~~five-year ~~after~~survival ~~surgery~~rate ~~(adjuvant),~~for ~~prior~~patients towith ~~surgery~~ER+ ~~(neoadjuvant),~~metastatic orbreast acancer ~~combination~~is ofapproximately ~~both~~32%.

11While there are national guidelines and recommendations for the treatment of metastatic breast cancer, the actual treatment decision is based on a combination of individual patient characteristics and tumor biology, including whether they received adjuvant therapy and, if so, how quickly the cancer recurred. There is significant overlap in the agents that are recommended, but guidelines vary in the sequence in which these agents are used. In the past five years, several new classes of targeted therapies have been approved to be used in combination with endocrine agents for the treatment of HR+/HER2‑ breast cancer. CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, used in combination with an AI or fulvestrant, led to significant increases in progression-free survival and overall survival. Everolimus, an mTOR inhibitor, was approved in 2012 for the treatment of postmenopausal women with advanced HR+/HER2- breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. Alpelisib, a PI3Ka inhibitor, was approved in 2019 in combination with fulvestrant for the treatment of HR+/HER2‑ breast cancers that have mutations in PIK3CA. Figure 2 shows the endocrine treatment options available for ER+ metastatic breast cancer, and an example of the sequence of treatments, by agent and line of therapy.

~~Table of Contents~~12

~~The~~Table ~~initial standard~~ of care for patients with early-stage ER+ breast cancer is at least five years of adjuvant endocrine therapy. The endocrine treatment options for early-stage disease are AIs, such as anastrozole, exemestane or letrozole, or an ER antagonist such as a tamoxifen. For patients diagnosed with early-stage ER+ breast cancer who undergo surgical and adjuvant/neoadjuvant treatment, the five-year survival rate is over 90%.Contents

~~Metastatic~~Figure 2. Available endocrine options and example of sequential alternating of endocrine based therapy in ER+ metastatic breast cancer

When ~~cancer~~moving ~~has~~a ~~spread~~patient ~~beyond~~from ~~local~~one ~~lymph~~line ~~nodes,~~of ~~either~~therapy to ~~distant~~the ~~lymph nodes~~next, ~~bones, or visceral organs,~~ the ~~cancer~~standard ~~is now considered metastatic. Approximately 6-10%~~ of ~~breast~~care ~~cancer~~is ~~patients~~to ~~present~~switch ~~with de novo metastatic disease, also referred~~ to asan ~~stage~~endocrine IVagent ~~disease,~~with ata ~~initial~~different ~~diagnosis.~~mechanism ~~In addition, approximately 30%~~ of ~~patients~~action ~~diagnosed~~depending ~~with~~upon ~~early-stage~~last ~~breast cancer will develop metastatic disease. In contrast to the goals of adjuvant~~ therapy, ~~treatments~~co-morbidities, ~~for metastatic disease are palliative with the desired outcome of controlling symptoms~~ and ~~extending~~individual ~~survival~~patient ~~as long as possible~~characteristics. ~~The current five-year survival rate for patients with ER+ metastatic breast cancer is approximately 32%.~~

~~While~~Metastatic ~~there are national guidelines and recommendations for the treatment of metastatic~~ breast cancer, ~~the actual treatment decision~~ is ~~based~~the onsecond amost ~~combination~~common ofcancer ~~individual~~associated ~~patient~~with ~~characteristics~~brain ~~and~~metastases ~~tumor~~in ~~biology,~~the ~~including~~United ~~whether~~States. ~~they~~About ~~received~~10% ~~adjuvant~~to ~~therapy~~15% ~~and,~~of ifwomen ~~so,~~with ~~how~~metastatic ~~quickly~~breast ~~the~~ cancer ~~recurred.~~develop ~~There~~brain ismetastases. ~~significant~~Brain ~~overlap~~metastases inpresent ~~the~~a ~~agents~~significant ~~that~~challenge ~~are~~to ~~recommended,~~systemic ~~but~~therapy ~~guidelines~~and ~~vary in~~ the ~~sequence~~primary intreatment ~~which~~for ~~these~~CNS ~~agents~~metastases ~~are~~is ~~used.~~typically Insurgical ~~the~~resection, ~~past five years~~radiation, ~~several~~or ~~new~~a ~~classes~~combination of ~~targeted~~both. ~~therapies~~Given ~~have~~the ~~been~~limited ~~approved~~treatment tooptions beavailable ~~used in combination with endocrine agents~~ for ~~the~~these ~~treatment of HR+/HER2‑ breast cancer. Inhibitors of CDK4/6~~patients, ~~such~~the asprognosis ~~palbociclib,~~remains ~~ribociclib and abemaciclib~~poor, ~~used~~making init ~~combination with~~ an AIarea orof ~~fulvestrant~~continued, ~~led~~high tounmet ~~significant~~medical ~~increases in progression-free survival and overall survival~~need. ~~Everolimus,~~In ~~an mTOR inhibitor~~addition, ~~was~~brain ~~approved~~metastases in ~~2012 for the treatment of postmenopausal women with advanced HR+/HER2-~~ breast cancer inpatients ~~combination~~are ~~with~~a ~~exemestane~~major ~~after~~cause ~~failure~~ of ~~treatment with letrozole or anastrozole. Alpelisib~~morbidity, aassociated ~~PI3Ka inhibitor, was approved in 2019 in combination~~ with ~~fulvestrant~~progressive ~~for~~neurologic ~~the~~deficits ~~treatment of HR+/HER2‑ breast cancers~~ that ~~have~~result ~~mutations~~ in ~~PIK3CA.~~a ~~Figure~~reduced 2quality ~~shows the endocrine treatment options available for ER+ metastatic breast cancer, and an example~~ of ~~the sequence of treatments, by agent and line of therapy~~life.

~~Figure~~ER 2.signaling ~~Available endocrine options and example of sequential alternating of endocrine based therapy~~ in ~~ER+ metastatic breast~~ cancer

12The ER is a nuclear receptor that functions as a ligand regulated transcription factor. When bound to estrogen, the ER directs the expression of genes that are essential for breast cancer cells’ survival and proliferation. The ER has three modular functional domains:

•

~~Table~~The amino terminal domain, which contains the activation function 1 (AF1), the activity of ~~Contents~~which can be increased by multiple cell proliferative signaling pathways;

•

~~When~~The ~~moving~~DNA abinding ~~patient~~domain, ~~from~~which ~~one~~directs ~~line of therapy to~~ the ~~next,~~ER ~~the standard of care is~~ to ~~switch~~bind to ~~an endocrine agent with~~ a ~~different~~specific ~~mechanism~~set of ~~action depending upon last therapy, co~~ER-~~morbidities,~~responsive ~~and~~genes; ~~individual patient characteristics.~~and

•

~~Metastatic~~The ~~breast~~ligand ~~cancer~~binding is the second most common cancer associated with brain metastases in the United States. About 10% to 15% of women with metastatic breast cancer develop brain metastases. Brain metastases present a significant challenge to systemic therapy and the primary treatment for CNS metastases is typically surgical resectiondomain, ~~radiation,~~which orcontains ~~a combination of both. Given~~ the ~~limited~~activation ~~treatment~~function ~~options~~2 ~~available for these patients~~(AF2), ~~the~~which ~~prognosis~~is ~~remains~~turned ~~poor,~~on ~~making~~when itbound anto ~~area of continued, high unmet medical need~~estrogen. ~~In addition, brain metastases in breast cancer patients are a major cause of morbidity, associated with progressive neurologic deficits that result in a reduced quality of life.~~

ERActivation ~~signaling~~of ineither AF1 or AF2 can drive transcription and cancer cell proliferation.

~~The~~Table ~~amino terminal domain, which contains the activation function 1 (AF1), the activity~~ of ~~which can be increased by multiple cell proliferative signaling pathways;~~Contents

~~The~~Figure ~~DNA~~3. ~~binding~~Growth ~~domain,~~and ~~which~~proliferation ~~directs~~mechanism ~~the~~driving ER+ tobreast ~~bind to a specific set of ER-responsive genes; and~~cancer

~~The~~Classes ~~ligand~~of ~~binding~~endocrine ~~domain,~~therapies ~~which~~and ~~contains~~their ~~the activation function 2 (AF2), which is turned on when bound to estrogen.~~limitations

~~Activation~~For ofmore ~~either~~than ~~AF1~~four ordecades, ~~AF2~~researchers ~~can~~have ~~drive~~been ~~transcription~~developing new approaches and ~~cancer~~therapies to prevent activation of the ER pathway, thereby inhibiting the ability of the ER to drive tumor cell ~~proliferation~~growth. The two major classes of endocrine therapies are AIs and ER antagonists.

~~Figure~~Antagonists 3.with ~~Growth~~partial ~~and~~agonist ~~proliferation mechanism driving ER+ breast cancer~~activity

13Although tamoxifen, the first endocrine therapy for the treatment of breast cancer, directly competes with estrogen and prevents activation of the AF2 transcription factor activation domain, it does not block AF1 activity and therefore does not completely inhibit ER function. As a consequence of this partial agonist activity, tamoxifen mimics estrogen in some circumstances and promotes proliferation. In addition, some breast cancers can develop resistance to these partial agonists by activation of upstream AF1 signaling pathways, such as mTOR, PI3K, MAPK, c-SRC, EGFR, FGFR and IGFR. Therefore, while tamoxifen is commonly used today, it is challenged by acquired drug resistance and a relatively short duration of response.

~~Table of Contents~~14

~~Classes~~Table of ~~endocrine therapies and their limitations~~Contents

~~For~~Figure ~~more~~4. ~~than~~Partial ~~four decades~~agonists, ~~researchers~~such ~~have~~as ~~been developing new approaches and therapies to prevent activation of the ER pathway~~tamoxifen, ~~thereby~~are ~~inhibiting~~unable ~~the ability of the ER~~ to ~~drive~~completely ~~tumor~~block ~~cell growth. The two major classes of endocrine therapies are AIs and~~ ER ~~antagonists.~~ activation

~~Antagonists~~In search of a different mechanism to target the estrogen pathway, AIs were developed in the 1990s to block the synthesis of estrogen and deprive the ER+ tumor of its activating ligand. However, most patients with ~~partial~~metastatic ~~agonist~~breast cancer have been shown to ultimately develop resistance to these therapies. Similar to tamoxifen, resistance to AIs, such as anastrozole, exemestane or letrozole, can develop by multiple mechanisms, including activation of the AF1 pathway and development of mutations. Mutations in ESR1 that confer estrogen-independent ER activity arise in up to 50% of patients receiving treatment with an AI in combination with a CDK4/6 inhibitor in the first-line metastatic setting.

Although tamoxifen, the first endocrine therapy for the treatment of breast cancer, directly competes with estrogen and prevents activation of the AF2 transcription factor activation domain, it does not block AF1 activity and therefore does not completely inhibit ER function. As a consequence of this partial agonist activity, tamoxifen mimics estrogen in some circumstances and promotes proliferation. In addition, some breast cancers can develop resistance to these partial agonists by activation of upstream AF1 signaling pathways, such as mTOR, PI3K, MAPK, c-SRC, EGFR, FGFR and IGFR. Therefore, while tamoxifen is commonly used today, it is challenged by acquired drug resistance and a relatively short duration of response.SERDs

~~Figure~~In 4.the ~~Partial~~search ~~agonists~~for more potent ER antagonists, ~~such~~researchers focused on another class of ER drugs that were described as SERDs. This classification arose from the observation that certain ligands bind tightly to ER leading to ER degradation. The field shifted drug discovery efforts to SERDs based on the hypothesis that degrading ER would be more efficacious than inhibiting it. However, similar to tamoxifen, many compounds with SERD activity are ~~unable~~not complete ER antagonists nor do they achieve complete degradation of the ER. Recent experiments conducted by us and third parties in non-clinical models of breast cancer suggest that ER degradation, as achieved by many SERDs, on its own is not sufficient to effectively treat tumors and that the ability to completely ~~block~~inhibit ER ~~activation~~function is best achieved through complete antagonism.

In search of a different mechanism to target the estrogen pathway, AIs were developed in the 1990s to block the synthesis of estrogen and deprive the ER+ tumor of its activating ligand. However, most patients with metastatic breast cancer have been shown to ultimately develop resistance to these therapies. Similar to tamoxifen, resistance to AIs, such as anastrozole, exemestane or letrozole, can develop by multiple mechanisms, including activation of the AF1 pathway and development of mutations. Mutations in ESR1 that confer estrogen-independent ER activity arise in up to 50% of patients receiving treatment with an AI in combination with a CDK4/6 inhibitor in the first-line metastatic setting.CERANs

~~SERDs~~A CERAN is a molecule that completely blocks the ability of both AF1 and AF2 to stimulate gene transcription. CERANs inhibit activation of the AF2 transcription factor activation domain and inactivate AF1 activity by recruiting nuclear receptor corepressors of the N-CoR/ SMRT family. Previous work by one of our co-founders identified specific interactions between fulvestrant-bound ER and N-CoR and that the strength of these interactions correlated with the ability of fulvestrant-bound ER to inactivate gene transcription through the transcription factor activating domain, AF1.

In the search for more potent ER antagonists, researchers focused on another class of ER drugs that were described as SERDs. This classification arose from the observation that certain ligands bind tightly to ER leading to ER degradation. The field shifted drug discovery efforts to SERDs based on the hypothesis that 15

14Table of Contents

~~Table~~Figure of5. ~~Contents~~Complete antagonists turn off AF2 and recruit N-CoR to inactivate AF1

~~degrading~~In ER2002, ~~would~~fulvestrant bewas ~~more~~approved ~~efficacious~~as ~~than~~a ~~inhibiting~~treatment ~~it.~~for ~~However,~~HR+ ~~similar~~metastatic tobreast ~~tamoxifen,~~cancer ~~many~~and ~~compounds~~is ~~with~~typically ~~SERD~~used ~~activity~~as ~~are~~a ~~not~~second- ~~complete~~or ERthird-line ~~antagonists~~endocrine ~~nor~~agent. doFulvestrant ~~they~~represented ~~achieve~~a ~~complete~~breakthrough ~~degradation~~for of the ~~ER.~~field ~~Recent~~based ~~experiments~~on ~~conducted~~its bydual- usmechanism ~~and~~of ~~third~~action ~~parties~~as ina ~~non-clinical~~CERAN ~~models~~and ofSERD ~~breast~~which ~~cancer~~led ~~suggest~~to ~~that~~improved ERefficacy ~~degradation,~~outcomes asfor ~~achieved~~patients. byHowever, ~~many SERDs~~fulvestrant, onthe ~~its~~only ~~own~~FDA-approved isanti-estrogen ~~not~~lacking ~~sufficient~~agonist-type toeffects ~~effectively~~in ~~treat~~in ~~tumors~~vivo ~~and~~uterotropic ~~that~~assays ~~the~~in ~~ability~~immature toor ~~completely~~ovariectomized ~~inhibit~~mice ERand ~~function~~rats, ishas ~~best~~several ~~achieved~~limitations ~~through complete antagonism.~~including:

•

~~CERANs~~Painful and inconvenient route of administration. Fulvestrant is a highly insoluble compound with poor oral bioavailability and therefore must be given intramuscularly. Fulvestrant is administered every 28 days in two 5 ml intramuscular injections into the buttocks. Injection site reactions occur in approximately 10% of patients and include sciatica, neuralgia, neuropathic pain, and peripheral neuropathy.

•

ASuboptimal ~~CERAN~~drug isexposure limits efficacy. In a ~~molecule~~non-clinical ~~that~~mouse ~~completely~~model, ~~blocks~~an increase in antitumor activity and ER degradation was observed as the ~~ability~~dose of ~~both~~fulvestrant ~~AF1~~was ~~and~~increased ~~AF2~~from to25 ~~stimulate~~mg/kg ~~gene~~to ~~transcription~~200 mg/kg. ~~CERANs~~However, ~~inhibit~~researchers ~~activation~~estimated ofthat ~~the~~achieving ~~AF2~~an ~~transcription~~equivalent ~~factor~~level ~~activation~~of ~~domain~~fulvestrant ~~and~~in ~~inactivate~~humans ~~AF1~~to ~~activity~~a by200 ~~recruiting~~mg/kg ~~nuclear~~dose ~~receptor~~in ~~corepressors~~mice ofwould ~~the~~require ~~N-CoR/~~a ~~SMRT~~dose ~~family.~~that ~~Previous~~is ~~work~~eight bytimes ~~one~~higher ofthan ~~our~~is ~~co-founders~~currently ~~identified~~clinically ~~specific~~achievable. ~~interactions~~Furthermore, ~~between~~xenograft ~~fulvestrant-bound~~models ERcreated ~~and~~using Npatient-~~CoR~~derived ~~and~~tumors ~~that~~containing ~~the~~ESR1 ~~strength~~mutations ofshow ~~these~~that ~~interactions~~even ~~correlated~~plasma ~~with~~levels ~~the~~substantially ~~ability~~higher ofthan ~~fulvestrant-bound~~those ERachievable toin ~~inactivate~~humans ~~gene~~at ~~transcription~~the ~~through~~approved ~~the~~dose ~~transcription~~fail ~~factor~~to ~~activating~~demonstrate ~~domain,~~optimal ~~AF1~~antitumor effect.

FigureOur 5.Lead CompleteProduct antagonistsCandidate: turn off AF2 and recruit N-CoR to inactivate AF1Palazestrant

InWe ~~2002,~~own ~~fulvestrant~~worldwide ~~was~~development ~~approved~~and ascommercialization arights ~~treatment~~to ~~for~~palazestrant. ~~HR+~~Our ~~metastatic~~plan ~~breast cancer and~~ is ~~typically~~to ~~used~~develop aspalazestrant ~~a second- or third-line endocrine agent. Fulvestrant represented a breakthrough~~ for the ~~field~~treatment ~~based on its dual- mechanism~~ of ~~action as~~ a ~~CERAN~~number ~~and~~of ~~SERD~~ER+ ~~which~~breast ~~led~~cancer ~~to improved efficacy outcomes for patients. However~~indications, ~~fulvestrant,~~both ~~the~~as ~~only~~monotherapy ~~FDA-approved~~and ~~anti-estrogen lacking agonist-type effects~~ in incombination ~~vivo~~with ~~uterotropic~~approved ~~assays~~targeted intherapies ~~immature~~that orhave ~~ovariectomized~~shown ~~mice~~improved ~~and~~outcomes ~~rats,~~with ~~has~~other ~~several~~endocrine ~~limitations including:~~therapies.

Painful and inconvenient route of administration. Fulvestrant is a highly insoluble compound with poor oral bioavailability and therefore must be given intramuscularly. Fulvestrant is administered every 28 days in two 5 ml intramuscular injections into the buttocks. Injection site reactions occur in approximately 10% of patients and include sciatica, neuralgia, neuropathic pain, and peripheral neuropathy.16

~~Suboptimal~~Table ~~drug exposure limits efficacy. In a non-clinical mouse model, an increase in antitumor activity and ER degradation was observed as the dose~~ of ~~fulvestrant was increased from 25 mg/kg to 200 mg/kg. However, researchers estimated that achieving an equivalent level of fulvestrant in humans~~ Contents

15Palazestrant is an oral small molecule clinical-stage product candidate for the treatment of endocrine-driven cancers. Palazestrant was designed by our scientific team based both on a detailed structural understanding of the ER and on known alterations to this structure induced by fulvestrant and other ER ligands. We have demonstrated in non-clinical studies that palazestrant functions both as a CERAN, inactivating both AF1 and AF2 transcriptional activation functions, and a SERD, promoting degradation of the ER. We believe palazestrant’s oral formulation and dual mechanism of action directly address the limitations of current endocrine therapies, such as fulvestrant and tamoxifen, and position palazestrant as a potential endocrine therapy of choice for the treatment of ER+ breast cancers.

~~Table~~In July 2022, palazestrant was granted Fast Track designation from the FDA in patients with ER+/HER2- metastatic breast cancer that has progressed following one or more lines of ~~Contents~~endocrine therapy with at least one line given in combination with a CDK4/6 inhibitor.

toOur apivotal ~~200~~Phase ~~mg/kg~~3 ~~dose~~monotherapy intrial: ~~mice would require a dose that is eight times higher than is currently clinically achievable. Furthermore, xenograft models created using patient~~OPERA-~~derived tumors containing ESR1 mutations show that even plasma levels substantially higher than those achievable in humans at the approved dose fail to demonstrate optimal antitumor effect.~~01

~~Our~~In ~~Lead~~November ~~Product~~2023, ~~Candidate~~we initiated our first pivotal Phase 3 trial of palazestrant, OPERA-01, which is a randomized Phase 3 trial evaluating palazestrant versus standard-of-care treatment for ER+/HER2- advanced or metastatic breast cancer. The trial is expected to enroll approximately 510 second/third-line metastatic breast cancer patients randomized one-to-one with either palazestrant or standard-of-care endocrine therapy. Key inclusion criteria for the trial include evaluable disease and prior exposure to endocrine therapy in combination with a CDK4/6 inhibitor in the advanced setting. One additional line of endocrine therapy in the advanced or metastatic setting is permitted. The trial consists of two parts: ~~Palazestrant~~a three-arm dose selection part followed by assessment of the selected dose (90 mg) of palazestrant versus standard of care. Top-line results from the trial are expected in the fall of 2026.

WeFigure ~~own worldwide development and commercialization rights to palazestrant~~6. ~~Our~~OPERA-01 ~~plan~~study is to develop palazestrant for the treatment of a number of ER+ breast cancer indications, both as monotherapy and in combination with approved targeted therapies that have shown improved outcomes with other endocrine therapies.design

~~Palazestrant~~Phase is2 anmonotherapy ~~oral small molecule~~ clinical~~-stage~~ product candidate for the treatment of endocrine-driven cancers. Palazestrant was designed by our scientific team based both on a detailed structural understanding of the ER and on known alterations to this structure induced by fulvestrant and other ER ligands. We have demonstrated in non-clinical studies that palazestrant functions both as a CERAN, inactivating both AF1 and AF2 transcriptional activation functions, and a SERD, promoting degradation of the ER. We believe palazestrant’s oral formulation and dual mechanism of action directly address the limitations of current endocrine therapies, such as fulvestrant and tamoxifen, and position palazestrant as a potential endocrine therapy of choice for the treatment of ER+ breast cancers.study

InWe ~~July~~presented ~~2022,~~positive ~~palazestrant~~Phase ~~was~~2 ~~granted~~monotherapy ~~Fast~~clinical ~~Track~~results ~~designation~~in ~~from~~an ~~the~~oral ~~FDA~~presentation at ESMO in October 2023. As of the data cut-off of July 7, 2023, 86 patients with recurrent, locally advanced or metastatic ER+/HER2- ~~metastatic~~ breast cancer ~~that~~were ~~has~~treated ~~progressed~~at ~~following~~the ~~one~~recommended Phase 2 dose (RP2D) of 120 mg. The group was heavily pretreated with 42% of patients being fourth-line or later at study entry, 65% of patients having received two or more prior lines of endocrine therapy ~~with~~for atmetastatic ~~least~~disease, ~~one~~and ~~line~~31% ~~given~~having inreceived ~~combination~~prior chemotherapy. Almost all patients (97%) received prior treatment with a CDK4/6 inhibitor, and 66% received prior treatment with fulvestrant. Of 75 patients whose circulating tumor DNA (ctDNA), was assessed, 48% had activating mutations in ESR1 at baseline.

~~Our pivotal Phase 3 monotherapy trial: OPERA-01~~17

InTable ~~November 2023, we initiated our first pivotal Phase 3 trial~~ of palazestrant, OPERA-01, which is a randomized Phase 3 trial evaluating palazestrant versus standard-of-care treatment for ER+/HER2- advanced or metastatic breast cancer. The trial is expected to enroll approximately 510 second/third-line metastatic breast cancer patients randomized one-to-one with either palazestrant or standard-of-care endocrine therapy. Key inclusion criteria for the trial include evaluable disease and prior exposure to endocrine therapy in combination with a CDK4/6 inhibitor in the advanced setting. One additional line of endocrine therapy in the advanced or metastatic setting is permitted. The trial consists of two parts: a three-arm dose selection part followed by assessment of the selected dose of palazestrant versus standard of care. Top-line results from the trial are expected in 2026. Contents

~~Figure 6. OPERA-01 study design~~Pharmacokinetics

16Palazestrant demonstrated favorable pharmacokinetics characterized by high oral bioavailability, dose proportional exposure and a long half-life of eight days, with steady-state plasma levels showing minimal peak-to-trough variability, enabling consistent inhibition of the ER for the full dosing interval.

~~Table~~Safety ofand ~~Contents~~tolerability profile

~~Phase~~Treatment with palazestrant at the RP2D of 120 mg was well tolerated with no dose-limiting toxicities, and the maximum tolerated dose (MTD), was not reached. The majority of treatment-emergent adverse events (TEAEs), were Grade 1 or 2. ~~monotherapy~~Of ~~clinical~~the ~~study~~86 patients treated, events of Grade 4 neutropenia were observed in six patients, occurring approximately 4–6 weeks into therapy. Of these patients, three had a dose interruption with recovery and subsequent dose reduction (two continued at 90 mg and one continued at 60 mg) without any recurrence, and three had dose discontinuation followed by recovery. All six patients had prior exposure to CDK4/6 inhibitors.

WeEfficacy presented positive Phase 2 monotherapy clinical results in an oral presentation at ESMO in October 2023. As of the data cut-off of July 7, 2023, 86 patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer were treated at the recommended Phase 2 dose (RP2D) of 120 mg. The group was heavily pretreated with 42% of patients being fourth-line or later at study entry, 65% of patients having received two or more prior lines of endocrine therapy for metastatic disease, and 31% having received prior chemotherapy. Almost all patients (97%) received prior treatment with a CDK4/6 inhibitor, and 66% received prior treatment with fulvestrant. Of 75 patients whose circulating tumor DNA (ctDNA), was assessed, 48% had activating mutations in ESR1 at baseline.profile

~~Pharmacokinetics~~Across all 86 patients, the median progression-free survival (PFS) was 4.6 months and the clinical benefit rate (CBR), was 40% with a 6-month PFS rate of 38%. In patients with an ESR1 mutation, the median PFS was 5.6 months and the CBR was 52% with a 6-month PFS rate of 46%. In ESR1 wild-type patients, the median PFS was 3.5 months and the CBR was 32% with a 6-month PFS rate of 35%.

~~Palazestrant~~In ~~demonstrated~~a ~~favorable~~subset ~~pharmacokinetics~~analysis ~~characterized~~of by49 ~~high~~patients ~~oral~~that ~~bioavailability~~received palazestrant as a second- or third-line therapy with or without prior chemotherapy, ~~dose~~the ~~proportional~~median ~~exposure~~PFS was 7.2 months and athe ~~long~~CBR ~~half~~was 48% across all patients with a 6-~~life~~month PFS rate of ~~eight~~54%. ~~days~~In patients with an ESR1 mutation, the median PFS was 7.3 months and CBR was 59% with ~~steady~~a 6-~~state~~month ~~plasma~~PFS ~~levels~~rate ~~showing~~of ~~minimal~~62%. ~~peak~~In ESR1 wild-~~to-trough~~type ~~variability,~~patients ~~enabling~~the ~~consistent~~median ~~inhibition~~PFS ofwas ~~the~~5.5 ERmonths ~~for~~and the ~~full~~CBR ~~dosing~~was ~~interval~~38% with a 6-month PFS rate of 44%.

~~Safety~~Anti-tumor activity was observed in this heavily pretreated population, with 40% of patients demonstrating reduction in target lesions and ~~Tolerability~~evidence ~~Profile~~of activity in both ESR1 wild-type and ESR1-mutant patients. Given the advanced and heavily pretreated nature of the patients, many of these patients are expected to be resistant to monotherapy endocrine treatment.

~~Treatment~~Palazestrant ~~with~~Phase palazestrant at the RP2D of 120 mg was well tolerated with no dose-limiting toxicities, and the maximum tolerated dose (MTD), was not reached. The majority of treatment-emergent adverse events (TEAEs), were Grade 1 or 1b/2. Ofstudy ~~the 86 patients treated, events of Grade 4 neutropenia were observed~~ in ~~six~~combination ~~patients, occurring approximately 4–6 weeks into therapy. Of these patients, three had a dose interruption~~ with recovery and subsequent dose reduction (two continued at 90 mg and one continued at 60 mg) without any recurrence, and three had dose discontinuation followed by recovery. All six patients had prior exposure to CDK4/6 inhibitors.ribociclib

~~Efficacy~~In ~~Profile~~October 2025, we announced data from our clinical study of palazastrant in combination with ribociclib at ESMO in Berlin, Germany. As of July 8, 2025, 72 patients were enrolled across the 90 mg and 120 mg palazestrant dose cohorts. 56 patients received 120 mg once-daily palazestrant and 16 patients received 90 mg once-daily palazestrant, all with the approved dose of ribociclib for metastatic breast cancer of 600 mg daily. 45 (63%) patients had prior treatment with CDK4/6i with endocrine therapy for advanced disease. 33% (15/45) of patients who had prior treatment with CDK4/6i in the advanced setting (2/3L) had an ESR1 mutation at baseline.

~~Across~~Efficacy all 86 patients, the median progression-free survival (PFS) was 4.6 months and the clinical benefit rate (CBR), was 40% with a 6-month PFS rate of 38%. In patients with an ESR1 mutation, the median PFS was 5.6 months and the CBR was 52% with a 6-month PFS rate of 46%. In ESR1 wild-type patients, the median PFS was 3.5 months and the CBR was 32% with a 6-month PFS rate of 35%.profile

In athe ~~subset~~90 ~~analysis~~mg ofpalazestrant 49dose ~~patients~~cohort, ~~that~~with ~~received palazestrant as~~ a ~~second-~~median ~~or third~~follow-~~line~~up ~~therapy~~of ~~with~~10.8 ~~or without prior chemotherapy~~months, ~~the~~ median progression-free survival (PFS) was 7not reached.2 ~~months~~In ~~and~~ the ~~CBR~~120 ~~was~~mg ~~48%~~palazestrant ~~across~~dose ~~all~~cohort, ~~patients~~ with a 6median follow-~~month~~up ~~PFS~~of ~~rate~~more ofthan ~~54%~~19 months, median PFS are mature. InMedian ~~patients~~PFS ~~with~~was an15.5 ~~ESR1~~months ~~mutation,~~for ~~the~~all ~~median~~patients. Median PFS was 712.32 months ~~and~~for ~~CBR~~those ~~was~~who ~~59%~~received prior treatment with aCDK4/6i, ~~6-month~~including ~~PFS~~9.2 ~~rate~~months offor ~~62%.~~patients Inwith ESR1 wild-type ~~patients~~tumors ~~the~~and ~~median PFS was 5~~13.58 months ~~and~~for ~~the~~patients ~~CBR~~with ~~was~~tumors ~~38%~~ with aESR1 ~~6-month PFS rate of 44%~~mutations.

~~Anti-tumor~~Safety ~~activity~~profile ~~was observed in this heavily pretreated population, with 40% of patients demonstrating reduction in target lesions~~ and evidence of activity in both ESR1 wild-type and ESR1-mutant patients. Given the advanced and heavily pretreated nature of the patients, many of these patients are expected to be resistant to monotherapy endocrine treatment.pharmacokinetics

~~Palazestrant Phase 1b/2 study in combination with ribociclib~~18

InTable ~~December 2023, we presented Phase 1b/2 data from our clinical study~~ of palazastrant in combination with ribociclib at SABCS. With a data cutoff of November 1, 2023, across 19 patients who had completed at least one cycle of treatment as of the data cutoff date, the combination of up to 120 mg of palazestrant with 600 mg of ribociclib daily was well tolerated, with no safety signals or enhancement of toxicity and an overall safety profile consistent with the expected safety profile of ribociclib plus an endocrine therapy.Contents

~~Palazestrant~~Across ~~did~~72 ~~not~~patients ~~affect~~treated, 90 mg or 120 mg of palazestrant combined with 600 mg of ribociclib ~~drug~~daily ~~exposure~~was well tolerated with no new safety signals or increase in ~~patients,~~toxicity. Palazestrant and ribociclib ~~had~~did nonot ~~clinically~~demonstrate ~~meaningful~~any ~~effect~~drug-drug oninteractions ~~palazestrant~~and ~~drug~~the ~~exposure~~overall safety profile was consistent with the established safety profile of ribociclib plus an endocrine therapy. ~~There~~The ~~were~~majority noof ~~dose~~treatment-~~limiting~~emergent ~~toxicities~~adverse events were grade 1 or 2, and the ~~maximum~~severity ~~tolerated~~and ~~dose~~incidence ~~was~~of ~~not~~adverse events were consistent with the expected safety profile of each drug.

17Conclusions

~~Table~~These data support the ongoing Phase 3 OPERA-02 study evaluating 90 mg QD palazestrant in combination with ribociclib for the first-line treatment of ~~Contents~~ER+/HER2- advanced breast cancer.

~~reached,~~Our ~~and~~pivotal ~~the~~Phase ~~majority~~3 ofcombination ~~treatment-emergent~~trial adverse events were grade 1 or 2, with no grade 4 events observed. Neutropenia was reversible in all patients, and the timing was generally consistent with ribociclib-related neutropenia. Findings from this study support the continued use of palazestrant ~~at the RP2D of 120 mg~~ in combination with ~~600mg of~~ ribociclib,: ~~and enrollment of sixty patients in the dose~~OPERA-~~expansion portion of the study has been completed.~~02

In ~~May 2024, we presented interim results from this combination clinical trial at~~ the ~~ESMO~~third ~~Breast~~quarter ~~Cancer~~of ~~Annual Congress in Berlin~~2025, ~~Germany.~~we Asinitiated ~~of the data cut~~OPERA-~~off date of March 13~~02, ~~2024,~~ the ~~combination~~pivotal ofPhase ~~the~~3 ~~palazestrant~~clinical ~~RP2D~~trial of ~~120~~palazestrant mg in combination with ~~the~~ribociclib ~~full~~in ~~FDA-approved~~patients ~~label~~with ~~dose~~frontline ofadvanced ~~600~~or mgmetastatic ofER+/HER2- ~~ribociclib~~breast ~~was~~cancer. ~~well~~The ~~tolerated~~trial ~~with~~is nocurrently ~~new~~enrolling, ~~safety~~and ~~signals~~is orexpected ~~enhancement~~to ofenroll ~~toxicity~~approximately ~~and~~1,000 ~~palazestrant~~patients, ~~did~~half ~~not~~of ~~affect~~whom ~~ribociclib~~will ~~drug~~receive ~~exposure~~palazestrant ~~while~~plus ribociclib; ~~had~~the noother ~~clinically~~half ~~meaningful~~will ~~effect~~receive onletrozole, ~~palazestrant~~a ~~drug~~standard-of-care ~~exposure.~~aromatase ~~Furthermore~~inhibitor, ~~the~~plus ~~results~~ribociclib. ~~for~~The ~~the~~trial ~~maturing~~is ~~dataset~~enrolling ~~showed anti~~first-~~tumor~~line ~~activity~~patients ~~and~~who ~~prolonged~~have ~~disease~~received ~~stabilization,~~no ~~and~~prior asystemic ~~CBR~~therapy offor ~~85%~~the ~~across~~treatment 13of ~~CBR-eligible~~advanced ~~patients.~~or ~~These~~metastatic ~~data~~breast ~~further~~cancer. ~~supported~~Progression ~~our~~free ~~thesis~~survival ~~that~~is ~~palazestrant~~the ~~possesses~~primary ~~key~~endpoint, ~~characteristics~~and tooverall ~~make~~survival itis a ~~potential~~key ~~backbone~~secondary ~~endocrine therapy of preference for ER+/HER2- breast cancer~~endpoint.

InFigure ~~December 2024, we presented updated clinical results from this study at SABCS 2024 as of a data cut-off date of November 22, 2024~~7. Palazestrant, in combination with ribociclib, demonstrated promising clinical activity, a safety profile consistent with ribociclib and endocrine therapy, and favorable tolerability in patients with ER+/HER2OPERA-02 ~~advanced~~study ~~or metastatic breast cancer.~~ design

~~Enrollment~~Palazestrant Phase 1b/2 study in combination with palbociclib

62We ~~patients~~presented ~~with~~Phase ~~advanced or metastatic ER+~~1b/~~HER2-~~2 ~~breast~~data ~~cancer~~from ~~were~~our ~~treated~~clinical ~~with~~study ~~palazestrant (n=56 at the RP2D~~ of ~~120~~palazastrant mgin ~~once~~combination ~~daily)~~with ~~plus~~palbociclib ~~ribociclib~~at ~~(600~~SABCS ~~mg once daily; three weeks~~ on ~~treatment~~December ~~followed~~7, by2023. ~~one~~With ~~week~~a ~~off~~data ~~treatment).~~cutoff ~~The majority~~ of ~~participants~~September ~~(48~~15, ~~(77%))~~2023, ~~were~~across ~~2/3+~~46 ~~line~~ patients; 48as ~~(77%)~~of ~~patients~~the ~~received~~cutoff ~~prior~~date ~~endocrine~~of ~~therapy~~September ~~for~~15, ~~metastatic breast cancer~~2023, 46the ~~(74%)~~combination ~~patients received prior treatment~~ of ~~endocrine~~palazestrant ~~therapy with CDK4/6i, 12~~ (~~19%~~120 mg) ~~received two prior lines of treatment~~ with ~~CDK4/6i,~~palbociclib ~~and 11~~ (~~18%)~~125 ~~patients received chemotherapy for metastatic breast cancer. 36 (58%~~mg) ~~patients~~daily ~~had~~was ~~visceral~~well ~~disease;~~tolerated, 42with ~~(68%)~~an ~~patients~~overall ~~had~~safety ~~measurable~~profile ~~disease~~consistent atwith ~~baseline.~~the Ofexpected 60safety ~~patients~~profile ~~whose~~of ~~ctDNA~~palbociclib ~~was~~plus ~~assessed,~~an ~~28%~~endocrine ~~had activating mutations in ESR1 at baseline~~therapy.

~~Efficacy~~There ~~Profile~~was no observed drug-drug interaction between palazestrant and palbociclib, and there was no induced metabolism or increase in exposure of either palbociclib or palazestrant when administered in combination. Most treatment-emergent adverse events were grade 1 or 2. Neutropenia incidence was similar to the PALOMA-3 study; it was reversible in all patients and the timing was generally consistent with the palbociclib-related neutropenia.

Palazestrant combined with ribociclib showed promising clinical activity including tumor responses, prolonged disease stabilization, and progression-free survival in patients with ESR1 wild-type and ESR1 activating mutations at baseline and in those previously treated with one or two lines of CDK4/6i. Efficacy data continue to mature; 30 (48%) patients remained on treatment, and the longest duration on treatment is approximately 18 months (79 weeks) and was ongoing as of the data cutoff date of November 11, 2024. With a median follow-up of 12 months, the median PFS was not reached as of the data cutoff date. Across all patients, the 6-month PFS rate was 73%. In those who received prior treatment with a CDK4/6i plus an endocrine therapy, the 6-month PFS rate was 68%. The 6-month PFS rate in ESR1 mutant patients was 81% and in ESR1 wild-type patients it was 70%. In those who were clinical benefit rate (CBR)1-eligible, the CBR was 76% (37/49) in all patients, 81% (13/16) in patients with ESR1 mutations, and 74% (23/31) in ESR1 wild-type patients. In patients with prior CDK4/6i treatment, the CBR was 71% (25/35), 81% (13/16) in patients with ESR1 mutations, and 65% (11/17) in ESR1 wild-type patients. As of the data cutoff date, there were 11 responses (two confirmed complete responses, eight confirmed partial responses, and one unconfirmed partial response). Among 37 response-evaluable patients with measurable disease, the ORR was 27% (10/37). 60% of the 37 had a reduction in target lesion size.19

~~Safety~~Table ~~and~~of ~~Tolerability Profile~~Contents

~~Across~~Tumor 62responses ~~treated~~and ~~patients,~~prolonged ~~the~~disease ~~combination~~stabilization ofwere upobserved toin ~~120~~this mgpatient ofgroup, ~~palazestrant~~including ~~with~~in ~~the~~those ~~approved~~previously ~~dose~~exposed ~~for~~to ~~metastatic~~CDK4/6 ~~disease~~inhibitors, ofin ~~600~~both mgESR1 ofmutant ~~ribociclib~~and ~~daily~~ESR1 ~~was~~wild-type ~~well~~tumors. ~~tolerated~~Partial responses were observed in seven patients, with notwo ~~new~~confirmed ~~safety~~partial ~~signals~~responses orand ~~increase~~five inunconfirmed ~~toxicity~~partial responses. The ~~overall~~clinical ~~safety~~benefit ~~profile~~rate was ~~consistent~~46% ~~with~~in ~~the~~all ~~established~~patients ~~safety~~and ~~profile~~60% ofin ~~ribociclib~~patients ~~600~~with mgan ~~plus~~ESR1 anmutation ~~endocrine~~at ~~therapy~~baseline. ~~Treatment~~In ~~with~~patients ~~palazestrant~~naïve up to ~~120~~prior mgCDK4/6 ~~combined~~inhibitor ~~with~~treatment, ~~ribociclib~~the ~~(600~~CBR ~~mg)~~ was ~~well~~71%. 53% of patients had any reduction in target lesion size.

18Twenty-two (48%) patients remained on treatment, and efficacy data were still maturing. Findings from this study were consistent with previously reported data and support the ongoing clinical development of palazestrant in combination with CDK4/6 inhibitors for the treatment of ER+/HER2− metastatic breast cancer. Enrollment of sixty patients in the Phase 2 portion of the palazestrant-palbociclib combination clinical study is complete.

~~Table~~Additional ofpalazestrant ~~Contents~~pre-clinical combination data

~~tolerated~~In ~~with~~October no2024, ~~dose~~we presented new pre-~~limiting~~clinical ~~toxicities.~~data ~~The~~at ~~majority~~the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics showing that the combination of ~~TEAEs~~palazestrant ~~were~~with ~~Grade~~both 1everolimus orand 2,capivasertib are synergistic and have the ~~severity~~potential to result in significant tumor regression. Palazestrant and ~~incidence~~everolimus ofdemonstrated ~~adverse~~synergy ~~events~~in ~~were~~vitro ~~consistent~~and ~~with~~in ~~the~~vivo ~~expected~~and ~~safety~~resulted ~~profile~~in greater anti-proliferative activity than either agent alone; this combination also caused gene signature transcriptional changes, downregulating cell cycle progression and upregulating apoptosis. Palazestrant and capivasertib in combination worked synergistically to inhibit proliferation of ~~ribociclib~~multiple ~~plus~~ER+ ~~endocrine~~breast ~~therapy~~cancer models, both in vitro and in vivo.

~~Pharmacokinetics~~Clinical development plan for palazestrant and additional clinical opportunities

~~Palazestrant~~Everolimus, ~~did~~an ~~not~~mTOR ~~affect~~inhibitor, ~~ribociclib~~is ~~drug~~a ~~exposure~~targeted ~~when~~therapy ~~compared~~that is often used by oncologists in the treatment of advanced breast or other cancers. Clinical studies evaluating everolimus in combination with ~~published~~endocrine ~~exposure~~therapies ~~data~~has demonstrated clinical results that indicate a potential benefit for ~~single~~patients in later-~~agent~~line ~~ribociclib~~settings. ~~Steady-state~~In ~~trough~~the ~~values~~third ~~showed~~quarter noof ~~clinically~~2024, ~~significant~~we ~~difference~~initiated ~~between~~evaluation of palazestrant in combination with everolimus in a Phase 1b/2 clinical study. Our primary objectives are to determine the safety, tolerability, and PK profile of the combination with palazestrant, and ~~single~~secondarily to determine efficacy and duration of response in patients with ER+/HER2-~~agent~~ ~~palazestrant~~metastatic breast cancer.

~~Conclusions~~In September 2025, we announced a new clinical trial collaboration and supply agreement with Pfizer, Inc. to evaluate, in a Phase 1b/2 study, the safety and combinability of palazestrant plus atirmociclib, Pfizer’s investigational, highly selective-CDK4 inhibitor, in patients with ER+/HER2- metastatic breast cancer.

~~Findings~~Furthermore, ~~from~~though ~~this~~we ~~study~~are ~~support~~currently ~~the~~evaluating ~~advancement of~~ palazestrant in ~~combination~~patients with ~~ribociclib~~ER+/HER2- ~~into~~breast ~~clinical~~cancer, ~~development~~we believe that there is an opportunity for ~~the~~us ~~first-line~~to ~~treatment~~study ofpalazestrant in patients with ER+/HER2-+ ~~advanced~~breast orcancer, which represents approximately 11% of breast cancer patients and more than 50% of the patients with HER2+ breast cancer. In particular, up to 50% of patients with metastatic HER2+ breast cancer develop CNS disease. We believe that combining palazestrant with HER2 targeted agents may represent an opportunity to improve upon recent advancements in the treatment of CNS disease in patients that express both ER and HER2.

InWhile ~~March~~our ~~2025~~initial studies are focused on treating breast cancer patients with metastatic disease, we ~~disclosed~~believe ~~updated~~that ~~median~~if ~~PFS~~palazestrant ~~(mPFS)~~is ~~from~~determined to be safe and effective in this ~~study~~population, atthere ~~the~~is TDpotential ~~Cowen~~for ~~45th~~it ~~Annual~~to ~~Health~~be ~~Care~~used ~~Conference.~~in Asearlier ofstage adisease. ~~data~~Based ~~cutoff~~on ~~date~~our ofextensive ~~February~~non-clinical 18studies, ~~2025~~including certain head-to-head studies, ~~the~~we ~~mPFS~~believe ~~was~~that 13palazestrant could have superior PK properties and improved clinical outcomes than fulvestrant.8 ~~months~~If proven in 56the ~~patients~~clinic, ~~treated~~we ~~with~~believe ~~120~~that mgpalazestrant ofhas ~~palazestrant~~the ~~and~~potential ~~600~~to mgnot ofonly ~~ribociclib~~replace ~~daily.~~fulvestrant 40but ofto become the 56endocrine ~~patients~~treatment ~~had~~of ~~received~~choice ~~prior~~for the treatment of aboth ~~CDK4~~advanced/6imetastatic ~~plus~~ER+ anbreast ~~ET;~~cancer ~~the~~as ~~mPFS~~well as ultimately in ~~this~~early-stage ~~population~~ER+ ~~was~~breast ~~13.1~~cancer ~~months~~in the adjuvant setting.

~~Our pivotal Phase 3 combination trial of palazestrant in combination with ribociclib: OPERA-02~~20

~~Following~~Table the entry into our new clinical trial collaboration and supply agreement with Novartis and our positive data presentation at SABCS in December 2024, we announced our intention to initiate a new pivotal Phase 3 clinical trial of palazestrant in combination with ribociclib in patients with frontline advanced or metastatic ER+/HER2- breast cancer. The trial is expected to enroll approximately 1,000 patients, half of whom will receive palazestrant plus ribociclib; the other half will receive letrozole, a standard-of-care aromatase inhibitor, plus ribociclib. The trial will enroll first-line patients who have received no prior systemic therapy for the treatment of advanced or metastatic breast cancer. Progression free survival will be the primary endpoint; overall survival is a key secondary endpoint. We expect OPERA-02 to initiate in 2025.Contents

FigureOur 7.Second OPERA-02Product studyCandidate: designOP-3136

~~Palazestrant~~In October 2023, we presented new pre-clinical data regarding the discovery of novel compounds targeting KAT6, an epigenetic target that is dysregulated in breast and other cancers at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. In January 2024, we nominated a development candidate for this program, OP-3136 and in late 2024, the IND application for OP-3136 was cleared by the FDA and we initiated a Phase ~~1b/2~~1 ~~study~~clinical trial evaluating OP-3136 in ~~combination~~patients with ~~palbociclib~~ER+/HER2- metastatic breast cancer and other cancers.

WeIn ~~presented~~a ~~Phase 1b/2 data from our~~ non-clinical ~~study~~xenograft ~~of palazastrant in combination with palbociclib at SABCS on December 7~~model, ~~2023.~~OP-3136 ~~With~~caused adose-dependent ~~data~~tumor ~~cutoff~~growth ofinhibition ~~September~~and ~~15,~~tumor ~~2023,~~regression ~~across~~comparable 46to ~~patients~~or asbetter ofthan ~~the~~a ~~cutoff~~positive-control ~~date~~patented ofKAT6 ~~September~~inhibitor ~~15,~~and ~~2023,~~demonstrated ~~the~~synergy in combination ~~of palazestrant (120 mg)~~ with ~~palbociclib~~CDK4/6 ~~(125~~inhibitors ~~mg)~~or ~~daily was well~~ palazestrant.

19KAT6 is a clinically validated target and its overexpression has been shown to be correlated with worse clinical outcomes in ER+ breast cancer. KAT6 inhibition downregulates genes involved in estrogen receptor signaling and other signaling pathways.

~~Table~~Figure 8. Schematic of ~~Contents~~KAT6 biology and impact of OP-3136 inhibition

~~tolerated~~In KAT6-amplified and overexpressing ER+ breast cancer cell lines, ~~with~~OP-3136 anstrongly ~~overall~~inhibited ~~safety~~cell ~~profile~~proliferation ~~consistent~~whereas ~~with~~KAT6-low cell lines were insensitive to the ~~expected~~compounds. ~~safety~~In ~~profile~~a ofnon-clinical ~~palbociclib~~xenograft ~~plus~~model, OP-3136 caused dose-dependent tumor growth inhibition and tumor regression comparable to or better than a positive-control patented KAT6 inhibitor and demonstrated synergy in combination with CDK4/6 inhibitors or an endocrine therapy, palazestrant. In addition, OP-3136 demonstrated activity in both ESR1 wild-type and mutant breast cancer cell lines.

There was no observed drug-drug interaction between palazestrant and palbociclib, and there was no induced metabolism or increase in exposure of either palbociclib or palazestrant when administered in combination. Most treatment-emergent adverse events were grade 1 or 2. Neutropenia incidence was similar to the PALOMA-3 study; it was reversible in all patients and the timing was generally consistent with the palbociclib-related neutropenia.21

~~Tumor~~Table responses and prolonged disease stabilization were observed in this patient group, including in those previously exposed to CDK4/6 inhibitors, in both ESR1 mutant and ESR1 wild-type tumors. Partial responses were observed in seven patients, with two confirmed partial responses and five unconfirmed partial responses. The clinical benefit rate was 46% in all patients and 60% in patients with an ESR1 mutation at baseline. In patients naïve to prior CDK4/6 inhibitor treatment, the CBR was 71%. 53% of ~~patients had any reduction in target lesion size.~~Contents

~~Twenty-two~~Figure ~~(48%) patients remained on treatment, and efficacy data were still maturing~~9. ~~Findings~~Impact ~~from~~of ~~this~~OP-3136 ~~study were consistent with previously reported data~~ and ~~support~~positive ~~the~~control ~~ongoing~~on ~~clinical~~tumor ~~development~~volume ~~of palazestrant~~ in ~~combination~~a ~~with CDK4/6 inhibitors for the treatment of ER+/HER2− metastatic breast cancer. Enrollment of sixty patients in the Phase 2 portion of the palazestrant~~25-~~palbociclib~~day ~~combination~~mouse ~~clinical~~xenograft ~~study is complete.~~model

~~Additional~~In ~~palazestrant~~October 2024, we presented compelling new pre-clinical data at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics demonstrating OP-3136's robust anti-tumor activity as a single agent, as well as potential synergy and enhanced anti-tumor activity in combination ~~data~~with palazestrant. OP-3136 inhibited cell proliferation and synergized with anti-estrogens (fulvestrant and palazestrant) and a CDK4/6 inhibitor (ribociclib) in a breast cancer cell line. OP-3136 led to either tumor growth inhibition or tumor regression in vivo in xenograft models across all treatment groups. In combination with OP-3136, palazestrant was consistently superior to fulvestrant and led to improved anti-tumor activity and tumor regression; OP-3136 also showed robust synergistic anti‑tumor activity when combined with fulvestrant or palazestrant as doublet therapy in breast cancer models.

In ~~October~~April ~~2024~~2025, we ~~presented~~announced ~~new~~preclinical ~~pre-clinical~~ data atdemonstrating the ~~EORTC~~anti-~~NCI-AACR~~tumor ~~Symposium~~activity onof ~~Molecular~~OP-3136 ~~Targets~~in ~~and~~prostate, ~~Cancer~~ovarian, ~~Therapeutics~~and ~~showing~~non-small ~~that~~cell ~~the~~lung ~~combination~~cancer of(NSCLC) ~~palazestrant~~models ~~with~~at ~~both~~the ~~everolimus~~American ~~and~~Association ~~capivasertib~~for ~~are~~Cancer ~~synergistic~~Research ~~and~~(AACR) ~~have~~Annual ~~the~~Meeting ~~potential to result~~ in ~~significant~~Chicago, ~~tumor regression~~Illinois. ~~Palazestrant~~OP-3136 ~~and~~showed ~~everolimus~~potent ~~demonstrated~~anti-proliferative ~~synergy~~activity in ~~vitro~~multiple ~~and~~ovarian, inNSCLC, ~~vivo~~ and ~~resulted~~prostate incell ~~greater~~lines ~~anti-proliferative~~in ~~activity~~vitro ~~than~~as ~~either~~well ~~agent~~as ~~alone;~~activity ~~this~~that ~~combination~~was ~~also~~independent ~~caused~~of ~~gene~~KAT6 ~~signature~~amplification ~~transcriptional~~or ~~changes,~~over ~~downregulating~~expression. ~~cell~~As ~~cycle~~a ~~progression~~monotherapy, ~~and~~OP-3136 ~~upregulating~~demonstrated ~~apoptosis.~~anti-tumor ~~Palazestrant~~activity ~~and~~in ~~capivasertib~~ in ~~combination~~vivo ~~worked~~xenograft ~~synergistically~~models ~~to inhibit proliferation~~ of ~~multiple~~ovarian ~~ER+~~(OVCAR3), ~~breast~~NSCLC ~~cancer models~~(LCLC-97TM1), ~~both in vitro~~ and inprostate ~~vivo~~(22Rv1) cancers.

~~Clinical development plan for palazestrant and additional clinical opportunities~~22

~~Everolimus,~~Table ~~an mTOR inhibitor, is a targeted therapy that is often used by oncologists in the treatment~~ of advanced breast or other cancers. Clinical studies evaluating everolimus in combination with endocrine therapies has demonstrated clinical results that indicate a potential benefit for patients in later-line settings. In the third quarter of 2024, we initiated evaluation of palazestrant in combination with everolimus in a Phase 1b/2 clinical study. Our primary objectives are to determine the safety, tolerability, and PK profile of the combination with palazestrant, and secondarily to determine efficacy and duration of response in patients with ER+/HER2- metastatic breast cancer.Contents

~~Furthermore,~~Figure ~~though~~10. ~~we are currently evaluating palazestrant in patients with ER+/HER2~~OP-3136 ~~breast~~demonstrates ~~cancer,~~synergistic weactivity ~~believe that there is an opportunity for us to study palazestrant~~ in patients with ER+/HER2+ breast cancer, which represents approximately 11% of breast cancer patients and more than 50% of the patients with HER2+ breast cancer. In particular, up to 50% of patients with metastatic HER2+ breast cancer develop CNS disease. We believe that combining palazestrant with HER2 targeted agents may represent an opportunity to improve upon recent advancements in the treatment of CNS disease in patients that express both ER and HER2. combination

~~While~~In ~~our~~December ~~initial studies are focused on treating breast cancer patients with metastatic disease~~2024, we ~~believe~~announced that ifthe ~~palazestrant~~FDA iscleared ~~determined~~our toIND beapplication ~~safe and effective in this population, there is potential~~ for ~~it to be used in earlier stage disease~~OP-3136. ~~Based~~The onPhase ~~our~~1 ~~extensive non-~~clinical ~~studies,~~trial ~~including~~is ~~certain~~enrolling ~~head-to-head studies~~patients, and we ~~believe~~expect ~~that~~to ~~palazestrant~~present ~~could~~initial ~~have superior PK properties and improved~~ clinical ~~outcomes~~data ~~than~~from ~~fulvestrant.~~this Ifprogram ~~proven~~ in the ~~clinic,~~second wequarter ~~believe~~of ~~that palazestrant has the potential to not only replace fulvestrant but to become~~ 2026.

20Figure 11. OP-3136 Phase 1 clinical trial

~~Table of Contents~~23

~~the~~Table ~~endocrine treatment~~ of ~~choice for the treatment of both advanced/metastatic ER+ breast cancer as well as ultimately in early-stage ER+ breast cancer in the adjuvant setting.~~Contents

OurClinical SecondCollaboration Productand Candidate:Supply OP-3136Agreement with Novartis

In ~~October~~July ~~2023~~2020, we ~~presented~~entered ~~new~~into ~~pre~~a non-~~clinical~~exclusive ~~data~~Clinical ~~regarding~~Collaboration and Supply Agreement (as amended from time to time, the ~~discovery~~2020 ofNovartis ~~novel~~Agreement) ~~compounds~~with ~~targeting~~Novartis ~~KAT6~~Institutes for BioMedical Research, Inc. (Novartis). On January 13, 2022, we entered into an ~~epigenetic~~Amended ~~target~~and ~~that~~Restated Clinical Collaboration and Supply Agreement with Novartis, and on October 9, 2023, we entered into Amendment No. 1 to Amended and Restated Clinical Collaboration and Supply Agreement with Novartis. The collaboration is ~~dysregulated~~focused on the evaluation of the safety, tolerability and efficacy of palazestrant in ~~breast~~combination with Novartis’ proprietary CDK4/6 inhibitor KISQALI® (ribociclib) and/or ~~other~~Novartis’ ~~cancers~~proprietary atphosphatidylinositol 3-kinase inhibitor PIQRAY® (alpelisib), or collectively the Novartis Study Drugs, as part of our planned Phase 1b clinical study of palazestrant in patients with metastatic ER+ breast cancer. The October 2023 ~~AACR-NCI-EORTC~~Amendment ~~International~~No. ~~Conference~~1 onexpanded ~~Molecular~~the ~~Targets~~size of the ongoing ribociclib and ~~Cancer~~palazestrant ~~Therapeutics~~study cohort to a total of approximately 60 patients. In ~~January~~March 2024, we ~~nominated~~entered ainto ~~development~~Amendment ~~candidate~~No. ~~for~~2 ~~this~~to ~~program~~Amended and Restated Clinical Collaboration and Supply Agreement with Novartis, ~~OP-3136~~which amended the agreement and expanded the collaboration to explore 90mg of palazestrant in ~~late~~combination ~~2024~~with ribociclib, bringing the ~~IND~~total ~~application~~enrollment to approximately 75 patients. We are responsible for ~~OP-3136~~the ~~was~~conduct ~~cleared~~of bythe clinical studies for the ~~FDA~~combined ~~and~~therapies wein ~~initiated~~accordance with a ~~Phase~~mutually 1agreed ~~clinical~~development ~~trial~~plan. ~~evaluating~~As ~~OP-3136~~part inof ~~patients~~the ~~with~~collaboration, ~~ER+/HER2~~the parties granted to each other a non-exclusive, ~~metastatic~~royalty-free ~~breast~~license ~~cancer~~under certain of the parties’ respective background patent rights and other ~~cancers~~technology to use the parties’ respective study drugs in research and development, solely to the extent reasonably needed for the other party’s activities in the collaboration. All inventions and data developed in the performance of the clinical studies for the combined therapies (other than those specific to each component study drug), are jointly owned by the parties.

InWe aare ~~non-clinical~~responsible ~~xenograft~~for ~~model~~manufacturing, ~~OP-3136~~packaging ~~caused~~and ~~dose-dependent~~labeling ~~tumor~~palazestrant, ~~growth~~and ~~inhibition~~for packaging and ~~tumor~~labeling ~~regression~~all ~~comparable~~drugs toused orin ~~better~~the clinical studies for the combined therapies (other than athe ~~positive-control~~Novartis ~~patented~~Study ~~KAT6~~Drugs). ~~inhibitor~~Novartis is responsible for manufacturing and ~~demonstrated~~delivering ~~synergy~~to us the Novartis Study Drugs in ~~combination~~such quantities as reasonably needed for the clinical studies for the combined therapies. In accordance with ~~CDK4/6~~an ~~inhibitors~~agreed orbudget, ~~palazestrant~~Novartis is reimbursing us for a portion of the direct outside costs, but no more than an amount in the low single digit millions of U.S. dollars, that we incur related to conducting the activities under the agreed development plan in conducting the clinical trials for the combined therapies.

~~KAT6~~The is2020 aNovartis ~~clinically~~Agreement ~~validated~~will ~~target~~terminate upon completion of all activities outlined in the development plan and ~~its~~the ~~overexpression~~relevant ~~has~~protocols. ~~been~~Either ~~shown~~party may terminate the 2020 Novartis Agreement for the uncured material breach or insolvency of the other party, if it reasonably deems it necessary in order to beprotect ~~correlated~~the ~~with~~safety, ~~worse~~health or welfare of subjects enrolled in the clinical ~~outcomes~~studies for the combined therapies due to the existence of a material safety issue, or in ~~ER+~~certain ~~breast~~circumstances ~~cancer~~for an unresolved clinical hold with respect to either the Novartis Study Drugs or palazestrant. ~~KAT6~~In ~~inhibition~~addition, ~~downregulates~~Novartis ~~genes~~may ~~involved~~terminate inthe ~~estrogen~~2020 ~~receptor~~Novartis ~~signaling~~Agreement if certain disputes between the parties are not resolved after following the applicable dispute resolution procedures, and we may terminate the 2020 Novartis Agreement in the event we terminate all clinical studies of the combined therapies other ~~signaling~~than ~~pathways~~due to a material safety issue or upon a clinical hold.

~~Figure~~The 8.2020 ~~Schematic~~Novartis Agreement does not grant any right of ~~KAT6~~first ~~biology~~negotiation to participate in future clinical trials, and ~~impact~~each of ~~OP-3136~~the ~~inhibition~~parties retains all rights and ability to evaluate their respective compounds in any studies or clinical trials, either as a monotherapy or in combination with any other product or compound, in any therapeutic area. The parties retain their independent rights to commercialize their respective therapies both alone or with other parties.

InClinical ~~KAT6-amplified~~Trial ~~and~~Collaboration overexpressing ER+ breast cancer cell lines, OP-3136 strongly inhibited cell proliferation whereas KAT6-low cell lines were insensitive to the compounds. In a non-clinical xenograft model, OP-3136 caused dose-dependent tumor growth inhibition and ~~tumor~~Supply ~~regression~~Agreement ~~comparable to or better than a positive-control patented KAT6 inhibitor and demonstrated synergy in combination~~ with ~~CDK4/6 inhibitors or an endocrine therapy, palazestrant. In addition, OP-3136 demonstrated activity in both ESR1 wild-type and mutant breast cancer cell lines.~~Novartis

~~Figure~~In 9.November ~~Impact~~2024, ofwe ~~OP-3136~~entered into a Clinical Trial Collaboration and ~~positive~~Supply ~~control~~Agreement on(the ~~tumor~~2024 ~~volume~~Novartis Agreement), with Novartis. Pursuant to the 2024 Novartis Agreement, Novartis is providing us with ribociclib drug supply for our ongoing Phase 3 OPERA-02 trial of palazestrant in acombination 25with ribociclib in ER+/HER2-~~day~~ ~~mouse~~frontline ~~xenograft~~advanced ~~model~~or metastatic breast cancer.

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InUnder ~~October~~the 2024 Novartis Agreement, we ~~presented~~supply ~~compelling~~(including ~~new~~manufacturing, ~~pre-clinical~~packaging ~~data~~and atlabeling) palazestrant and letrozole for the ~~EORTC~~OPERA-~~NCI-AACR~~02 ~~Symposium~~trial. onNovartis ~~Molecular~~manufactures ~~Targets~~ and ~~Cancer~~supplies ~~Therapeutics~~(including ~~demonstrating~~primary ~~OP-3136's~~packaging) ~~robust~~a ~~anti-tumor~~specified ~~activity~~amount asof aribociclib, ~~single~~which ~~agent,~~amount asis ~~well~~expected asto ~~potential~~be ~~synergy~~sufficient ~~and~~for ~~enhanced~~the ~~anti~~OPERA-~~tumor~~02 ~~activity~~trial. inThe ~~combination~~parties ~~with~~have ~~palazestrant.~~granted OPeach other a non-~~3136~~exclusive, ~~inhibited~~royalty-free ~~cell~~license ~~proliferation~~under ~~and~~certain ~~synergized~~of ~~with~~the ~~anti-estrogens~~parties’ ~~(fulvestrant~~respective ~~and~~background ~~palazestrant)~~patent rights and aother ~~CDK4/6~~technology ~~inhibitor~~to ~~(ribociclib)~~use inthe aparties’ ~~breast~~respective ~~cancer~~study ~~cell~~drugs ~~line.~~in ~~OP-3136~~research ~~led~~and development, solely to ~~either~~the ~~tumor~~extent ~~growth~~reasonably ~~inhibition~~needed orfor ~~tumor~~the ~~regression~~other party’s activities in ~~vivo~~the collaboration. Any inventions developed in ~~xenograft~~the ~~models~~performance ~~across~~of ~~all~~the ~~treatment~~clinical ~~groups~~studies for the combined therapies (other than those specific to each component study drug) will be jointly owned by the parties. InExcept ~~combination~~as ~~with~~otherwise ~~OP-3136~~specified, ~~palazestrant~~the ~~was~~2024 ~~consistently~~Novartis ~~superior~~Agreement todoes ~~fulvestrant~~not ~~and~~grant ~~led~~any right of first negotiation to ~~improved~~participate ~~anti-tumor~~in ~~activity~~future clinical trials, and ~~tumor~~each ~~regression;~~party ~~OP-3136~~retains ~~also~~all ~~showed~~rights ~~robust~~and ~~synergistic~~ability ~~anti‑tumor~~to ~~activity~~evaluate ~~when~~their ~~combined~~respective ~~with~~compounds ~~fulvestrant~~in any studies or ~~palazestrant~~clinical trials, either as ~~doublet~~a ~~therapy~~monotherapy or in ~~breast~~combination ~~cancer~~with ~~models~~any other product or compound, in any therapeutic area. The parties retain their independent rights to commercialize their respective therapies both alone and with third parties.

~~Figure~~We 10granted Novartis a right of first negotiation with respect to (a) the grant to any person or entity any right, license or sublicense to exploit palazestrant, in any field or territory, other than to third party service providers, or (b) the sale or other transfer to any person or entity of palazestrant and any related assets, each referred to herein as an Olema Compound Transaction. ~~OP-3136~~If ~~demonstrates~~we ~~synergistic~~desire ~~activity~~to or do, at any time, (a) solicit or entertain any third party proposal or indication of interest with respect to an Olema Compound Transaction, or (b) negotiate (including in ~~combination~~response to any proposal or indication of interest received by the Company), enter into or perform under, in each case, any written definitive agreement with a third party with respect to or that contemplates an Olema Compound Transaction, then we must provide written notice to Novartis regarding such Olema Compound Transaction, along with certain other specified information. Novartis will have 30 days after receipt of such notice to elect to enter into exclusive good faith negotiations with respect to such Olema Compound Transaction for a period of up to 120 days.

22If our board of directors (or a duly authorized board committee) determines that we should pursue or explore a change of control or sale of all or substantially all of the assets of the Company (an Olema Change of Control Transaction), other than in response to an unsolicited bona fide acquisition proposal (a Proposed Sale), we must promptly notify Novartis of such determination. In the event Novartis elects to engage in negotiations with us in respect of such Proposed Sale, then from the date such notice is given until 45 days after the later of (a) the date on which the foregoing notice is given to Novartis, (b) the date on which Novartis is given notice that a data room has been populated as required by the 2024 Novartis Agreement, and (c) entry by us and Novartis into a customary nondisclosure agreement, Novartis will have the exclusive right (but no obligation) to conduct due diligence on us and our business and negotiate with us the definitive terms and conditions of the Proposed Sale.

~~Table~~If the Company or its affiliates receive an unsolicited bona fide acquisition proposal from a third party, the Company must promptly notify its board of ~~Contents~~directors (or a duly authorized board committee) of the receipt thereof and request that they consider the merits of such acquisition proposal. If, after such consideration, the Company’s board of directors (or authorized committee) authorizes the Company to engage in negotiations with regard to such acquisition proposal, then the Company must notify Novartis in writing within 24 hours of receipt of such authorization. To the extent possible in light of any confidentiality obligations, such notice must include a summary of the key structural, non-financial terms of such acquisition proposal.

~~In December 2024, we announced that the FDA cleared our IND application for OP-3136. The Phase 1 clinical trial initiated thereafter and is now enrolling patients.~~25

~~Figure~~Table ~~11.~~of ~~OP-3136 Phase 1 clinical trial~~Contents

~~Clinical~~In ~~Collaboration~~the ~~and~~event ~~Supply~~of an Olema Compound Transaction or Olema Change of Control involving a third party other than Novartis (the first to occur, referred to as a Repayment Trigger Event), the Company must promptly pay, or procure the payment of, the Repayment Amount (as defined below) to Novartis. Notwithstanding the foregoing, if the 2024 Novartis Agreement is terminated as a result of certain patient safety issues, lack of product efficacy, regulatory issues or clinical hold issues prior to the consummation of the Olema Compound Transaction or Olema Change of Control, then the Company shall not be obligated to pay the Repayment Amount unless (a) the Olema Change of Control or Olema Compound Transaction occurs after such termination and (b) prior to the fifth anniversary of such Olema Change of Control or Olema Compound Transaction (as applicable), the Company or its affiliates (or the applicable acquirer, successor, licensee or option holder of the Company or its affiliates) enrolls a subject in any clinical study involving the combination of palazestrant and ribociclib (the Olema Combination) or submits any filing with any regulatory authority relating to the Olema Combination. The Repayment Amount is the proportion of approximately $275 million that is represented by the number of units of ribociclib actually supplied to the Company under the 2024 Novartis Agreement as of immediately prior to the Repayment Trigger Event as compared to the total number of units that could be supplied under the 2024 Novartis Agreement.

InThe ~~July~~foregoing ~~2020,~~rights weof ~~entered~~first ~~into~~negotiation, afirst ~~non-exclusive~~offer ~~Clinical~~and ~~Collaboration~~notice and ~~Supply~~repayment ~~Agreement~~obligations ~~(the~~remain ~~Novartis~~in ~~Agreement)~~effect ~~with~~until ~~Novartis~~the ~~Institutes~~first ~~for~~to ~~BioMedical~~occur ~~Research,~~of: ~~Inc.~~ (~~Novartis~~a). Onthe ~~January~~date ~~13,~~that ~~2022,~~is we120 ~~entered~~days ~~into~~after anfiling ~~Amended~~of ~~and~~the ~~Restated~~New ~~Clinical~~Drug ~~Collaboration~~Application ~~and~~for ~~Supply~~the ~~Agreement~~Olema ~~with Novartis~~Combination, ~~and~~(b) onone ~~October~~year 9,after ~~2023,~~any weexpiration ~~entered~~or ~~into~~termination ~~Amendment~~of ~~No. 1 (~~the 2024 Novartis ~~Amendment)~~Agreement, ~~to Amended~~ and ~~Restated~~(c) ~~Clinical~~such ~~Collaboration~~time ~~and Supply Agreement with Novartis (~~as ~~amended,~~ the 2024 Novartis Agreement). ~~The collaboration~~ is ~~focused~~terminated onby the ~~evaluation~~Company ofdue ~~the~~to ~~safety, tolerability and efficacy of palazestrant in combination with~~ Novartis’ ~~proprietary~~material ~~CDK4/6~~breach. ~~inhibitor KISQALI® (ribociclib) and/or Novartis’ proprietary phosphatidylinositol 3-kinase inhibitor PIQRAY® (alpelisib)~~However, ~~or collectively the Novartis Study Drugs, as part of our planned Phase 1b clinical study of palazestrant~~ in ~~patients with metastatic ER+ breast cancer. The Novartis Amendment expanded~~ the ~~size~~event of the ~~ongoing~~2024 ~~ribociclib~~Novartis ~~and~~Agreement ~~palazestrant~~is ~~study~~terminated ~~cohort~~due to acertain ~~total~~patient ofsafety ~~approximately~~issues, 60lack ~~patients.~~of Inproduct ~~March 2024~~efficacy, weregulatory ~~further~~issues ~~amended~~or ~~the~~clinical ~~agreement~~hold ~~and~~issues ~~expanded~~prior ~~the collaboration~~ to ~~explore~~the ~~90mg~~consummation of ~~palazestrant~~an inOlema ~~combination~~Change ~~with~~of ~~ribociclib,~~Control ~~bringing~~or ~~the~~Olema ~~total~~Compound ~~enrollment~~Transaction, tothen ~~approximately 75 patients. We are responsible for~~ the ~~conduct~~Repayment ofObligation ~~the~~shall ~~clinical~~survive ~~studies~~until ~~for~~ the ~~combined~~fifth ~~therapies~~anniversary inof ~~accordance~~such ~~with~~Olema aChange ~~mutually agreed development plan. As part~~ of ~~the~~Control ~~collaboration,~~or ~~the~~Olema ~~parties~~Compound ~~granted~~Transaction to(as ~~each~~applicable) ~~other a non-exclusive~~or, ~~royalty-free~~if ~~license~~payment ~~under certain~~ of the ~~parties’~~Repayment ~~respective~~Amount ~~background~~is ~~patent rights and other technology to use the parties’ respective study drugs in research and development~~required, ~~solely~~until to the ~~extent~~next ~~reasonably~~business ~~needed~~day ~~for~~after the ~~other~~Repayment ~~party’s~~Amount ~~activities~~has inbeen ~~the~~received ~~collaboration. All inventions and data developed in the performance of the clinical studies for the combined therapies (other than those specific to each component study drug), are jointly owned~~ by ~~the parties~~Novartis.

WeThe ~~are~~2024 ~~responsible~~Novartis ~~for~~Agreement ~~manufacturing,~~will ~~packaging~~terminate ~~and~~on ~~labeling~~the fifth anniversary of the date on which the first dose of palazestrant, ~~and~~is ~~for~~administered ~~packaging~~to ~~and~~the ~~labeling~~first ~~all~~study ~~drugs~~subject. ~~used~~Either inparty may terminate the ~~clinical~~2024 ~~studies~~Novartis Agreement for the ~~combined~~uncured ~~therapies~~material ~~(other~~breach ~~than~~or insolvency of the ~~Novartis~~other ~~Study~~party, ~~Drugs).~~for ~~Novartis~~failure isto ~~responsible~~comply ~~for~~with ~~manufacturing~~certain ~~and~~anti-corruption ~~delivering~~obligations, toin usthe event of a change of control of the ~~Novartis~~other ~~Study~~party, ~~Drugs~~if it reasonably deems it necessary in ~~such~~order ~~quantities~~to asprotect ~~reasonably~~the ~~needed~~safety, ~~for~~health or welfare of subjects enrolled in the clinical studies for the combined therapies. Indue ~~accordance~~to ~~with~~the anexistence ~~agreed~~of ~~budget~~a material safety issue, ~~Novartis~~if the parties jointly decide that the Olema Combination is ~~reimbursing~~not usachieving ~~for~~sufficiently asuperior ~~portion~~levels of efficacy, if any regulatory authority action prevents a party (or the ~~direct~~Letrozole ~~outside~~supplier) ~~costs~~from supplying its product, ~~but~~in nothe ~~more~~event ~~than~~of an ~~amount~~unresolved force majeure event, or in ~~the~~certain ~~low~~circumstances ~~single~~for ~~digit~~an ~~millions~~unresolved clinical hold with respect to ribociclib, palazestrant or letrozole (or the combination of Uribociclib and palazestrant or ribociclib and letrozole).S. ~~dollars~~In addition, ~~that~~Novartis wemay ~~incur~~terminate ~~related~~the 2024 Novartis Agreement if the Company has failed to ~~conducting~~commence the ~~activities~~OPERA-02 ~~under~~trial on or prior to March 31, 2026 or if the ~~agreed~~Company ~~development~~consummates ~~plan~~an inOlema ~~conducting~~Compound Transaction, and the ~~clinical~~Company ~~trials~~may ~~for~~terminate the ~~combined~~2024 ~~therapies~~Novartis Agreement if the Company terminates the OPERA-02 trial other than due to a material safety issue, efficacy issue, regulatory action or upon a clinical hold.

TheClinical NovartisTrial Agreement willwith terminate upon completion of all activities outlined in the development plan and the relevant protocols. Either party may terminate the Novartis Agreement for the uncured material breach or Pfizer

23In November 2020, we entered into a non-exclusive clinical trial agreement with Pfizer (the Pfizer Agreement) to evaluate the safety and tolerability of palazestrant in combination with Pfizer’s proprietary CDK4/6 inhibitor IBRANCE® (palbociclib) in patients with recurrent, locally advanced or metastatic ER+/HER2‑ breast cancer in a clinical trial. Under the terms of the non-exclusive agreement, we are responsible for conducting the clinical study for the combined therapies and Pfizer is responsible for supplying IBRANCE® to us at no cost to us. As part of the collaboration, the parties granted to each other a non-exclusive, royalty- free license under certain of the parties’ respective patent rights in the combination of IBRANCE® and palazestrant to use the parties’ respective study drugs in research and development, solely to the extent reasonably needed for the other party’s activities in the collaboration. All inventions and data developed in the performance of the clinical trials for the combined therapies (other than those specific to each component study drug), are jointly owned by the parties.

~~Table of Contents~~26

~~insolvency~~Table of the other party, if it reasonably deems it necessary in order to protect the safety, health or welfare of subjects enrolled in the clinical studies for the combined therapies due to the existence of a material safety issue, or in certain circumstances for an unresolved clinical hold with respect to either the Novartis Study Drugs or palazestrant. In addition, Novartis may terminate the Novartis Agreement if certain disputes between the parties are not resolved after following the applicable dispute resolution procedures, and we may terminate the Novartis Agreement in the event we terminate all clinical studies of the combined therapies other than due to a material safety issue or upon a clinical hold.Contents

~~The~~We ~~Novartis~~are ~~Agreement~~responsible ~~does~~for ~~not~~manufacturing, ~~grant~~packaging ~~any~~and ~~right~~labeling ~~of first negotiation to participate in future clinical trials~~palazestrant, and ~~each~~for ofpackaging ~~the~~and ~~parties~~labeling ~~retains~~ all ~~rights~~drugs ~~and~~used ~~ability to evaluate their respective compounds~~ in ~~any~~the ~~studies or~~ clinical trials, ~~either~~for asthe acombined ~~monotherapy~~therapies or(other inthan ~~combination~~IBRANCE® ~~with~~(palbociclib)). ~~any~~Pfizer ~~other~~is ~~product~~responsible orfor ~~compound,~~manufacturing inand ~~any~~delivering ~~therapeutic~~to ~~area.~~us ~~The~~IBRANCE® ~~parties~~(palbociclib) ~~retain~~in ~~their~~such ~~independent~~quantities ~~rights~~as toreasonably ~~commercialize~~needed ~~their~~for ~~respective~~the ~~therapies~~clinical ~~both~~studies ~~alone~~for orthe ~~with~~combined ~~other parties~~therapies.

~~New~~The ~~Clinical~~Pfizer ~~Trial~~Agreement ~~Collaboration~~will terminate upon completion of all activities outlined in the study plan and ~~Supply~~the relevant protocols. Either party may terminate the Pfizer Agreement for the uncured material breach or insolvency of the other party, if it reasonably deems it necessary in order to protect the safety, health or welfare of subjects enrolled in the clinical studies for the combined therapies due to the existence of a material safety issue, or in certain circumstances for an unresolved clinical hold with ~~Novartis~~respect to either the IBRANCE® (palbociclib) or palazestrant. In addition, either party may terminate the Pfizer Agreement if certain disputes between the parties are not resolved after following the applicable dispute resolution procedures or if either party determines to discontinue clinical development for medical, scientific, legal or other reasons.

InThe ~~November~~Pfizer ~~2024,~~Agreement wedoes ~~entered~~not ~~into~~grant aany ~~Clinical~~right ~~Trial~~of ~~Collaboration~~first ~~and~~negotiation ~~Supply~~to ~~Agreement~~participate ~~(the~~in ~~NovartisPharma~~future ~~Agreement),~~clinical ~~with Novartis. Pursuant to the Novartis PharmaAgreement~~studies, ~~Novartis~~and ~~will~~each ~~provide us with ribociclib drug supply for our planned Phase 3 OPERA-02trial~~ of ~~palazestrant~~the inparties ~~combination~~retains ~~with~~all ~~ribociclib~~rights inand ~~ER+/HER2-~~ability ~~frontline~~to ~~advanced~~evaluate ortheir ~~metastatic~~respective ~~breastcancer~~compounds.

~~Under~~Clinical ~~the~~Trial ~~Novartis~~Collaboration ~~Pharma Agreement, we will supply (including manufacturing, packaging~~ and ~~labeling)palazestrant~~Supply and letrozole for the OPERA-02 trial. Novartis will manufacture and supply (includingprimary packaging) us with a specified amount of ribociclib, which amount is expected to be sufficient for theOPERA-02 trial. The parties granted to each other a non-exclusive, royalty-free license under certain of theparties’ respective background patent rights and other technology to use the parties’ respective study drugs inresearch and development, solely to the extent reasonably needed for the other party’s activities in thecollaboration. Any inventions developed in the performance of the clinical studies for the combined therapies(other than those specific to each component study drug) are jointly owned by the parties. Except asotherwise specified, the Agreement does not grant any right of first negotiation to participate in future clinicaltrials, and each party retains all rights and ability to evaluate their respective compounds in any studies orclinical trials, either as a monotherapy or in combination with ~~any other product or compound, in anytherapeutic area. The parties retain their independent rights to commercialize their respective therapies bothalone and with third parties.~~Pfizer

WeIn ~~granted~~September ~~Novartis~~2025, awe ~~right~~announced ofthat ~~first~~we ~~negotiation~~entered ~~with~~into ~~respect to (~~a) ~~the~~non-exclusive ~~grant~~clinical totrial ~~any~~collaboration ~~person~~and orsupply ~~entity~~agreement ~~any~~with ~~right,license~~Pfizer or(the ~~sublicense~~2025 toPfizer ~~exploit palazestrant~~Agreement), into ~~any~~evaluate ~~field~~the orsafety ~~territory,~~and ~~other~~tolerability ~~than~~of topalazestrant ~~third~~in ~~party~~combination ~~service~~with ~~providers,or~~Pfizer’s ~~(b)~~proprietary ~~the~~investigative ~~sale~~selective orCDK4 ~~other~~inhibitor ~~transfer~~atirmociclib toin ~~any~~patients ~~person~~with ormetastatic ~~entity~~ER+/HER2- ofbreast ~~palazestrant~~cancer ~~and~~in ~~any~~a ~~related~~Phase ~~assets,~~1b/2 ~~each~~clinical ~~referred~~trial. toUnder ~~herein~~the asterms anof ~~Olema~~the ~~Compound~~2025 ~~Transaction.~~Pfizer IfAgreement, we ~~desire~~are toresponsible orfor ~~do,~~conducting atthe ~~any~~clinical ~~time,~~trial ~~(a)~~for ~~solicit~~the orcombined ~~entertain~~therapies ~~any~~and ~~third~~Pfizer ~~party~~is ~~proposal~~responsible orfor ~~indication~~supplying ofatirmociclib ~~interest~~to ~~with~~us ~~respect~~at tono ancost. ~~Olema~~As ~~Compound~~part ~~Transaction,~~of orthe ~~(b)~~collaboration, ~~negotiate(including~~the inparties ~~response~~granted to ~~any~~each ~~proposal~~other ora ~~indication~~non-exclusive, ofroyalty-free ~~interest~~license ~~received~~under bycertain of the ~~Company),~~parties’ ~~enter~~respective ~~into~~patent orrights ~~perform under,~~ in ~~each~~the ~~case,~~combination ~~any~~of ~~written~~atirmociclib ~~definitive~~and ~~agreement~~palazestrant ~~with~~to ause ~~third~~the ~~party~~parties’ ~~with~~respective ~~respect~~study todrugs orin ~~that~~research ~~contemplates~~and ~~an Olema Compound Transaction~~development, ~~then~~solely ~~we must provide written notice~~ to ~~Novartis~~the ~~regarding~~extent ~~such~~reasonably ~~Olema~~needed ~~Compound~~for ~~Transaction,~~the ~~along~~other ~~with~~party’s ~~certain~~activities ~~other~~in ~~specified~~the ~~information~~collaboration. ~~Novartis~~All ~~will~~inventions ~~have~~and 30data ~~days~~developed ~~after~~in ~~receipt~~the performance of ~~such~~the ~~notice~~clinical totrials ~~elect~~for tothe ~~enter~~combined ~~into~~therapies ~~exclusive~~(other ~~good~~than ~~faith~~those ~~negotiations~~specific ~~with respect~~ to ~~such~~each ~~Olema~~component ~~Compound~~study ~~Transaction~~drug), ~~for~~will abe ~~period~~jointly ofowned upby tothe ~~120 days~~parties.

IfWe ~~our~~are ~~board~~responsible offor ~~directors~~manufacturing, ~~(or~~packaging aand ~~duly~~labeling ~~authorized~~palazestrant, ~~board~~and ~~committee)~~for ~~determines~~packaging ~~that~~and welabeling ~~should pursue or explore a change of control or sale of~~ all ordrugs ~~substantially~~used ~~all~~in of the ~~assets~~clinical oftrials for the ~~Company~~combined ~~(an~~therapies. ~~Olema~~Pfizer ~~Change~~is ~~ofControl~~responsible ~~Transaction),~~for ~~other~~manufacturing ~~than~~and indelivering ~~response~~ to anus ~~unsolicited~~atirmociclib ~~bona fide acquisition proposal (a ProposedSale), we must promptly notify Novartis of such determination. In the event Novartis elects toengage~~ in ~~negotiations with us in respect of~~ such ~~Proposed~~quantities ~~Sale,~~as ~~then~~reasonably ~~from~~needed ~~the~~for ~~date such notice is given until45 days after~~ the ~~later~~clinical oftrials ~~(a)~~for the ~~date~~combined ~~on which the foregoing notice is given to Novartis, (b) the dateon which Novartis is given notice that a data room has been populated as required by the Novartis~~ therapies.

24The 2025 Pfizer Agreement will terminate upon completion of all activities outlined in the study plan and the relevant protocols. Either party may terminate the 2025 Pfizer Agreement for the uncured material breach of the other party, if it reasonably deems it necessary in order to protect the safety, health or welfare of subjects enrolled in the clinical trials for the combined therapies due to the existence of a material safety issue, or in certain circumstances for an unresolved clinical hold with respect to either atirmociclib or palazestrant. In addition, Pfizer may terminate the 2025 Pfizer Agreement if Pfizer reasonably and in good faith believes that atirmociclib is being used in an unsafe manner, and either party may terminate the 2025 Pfizer Agreement if either party determines to discontinue clinical development for medical, scientific, legal or other reasons. The 2025 Pfizer Agreement does not grant any right of first negotiation to participate in future clinical trials, and each of the parties retains all rights and ability to evaluate their respective compounds.

~~Table~~License ofAgreement ~~Contents~~with Aurigene

~~Pharma~~In ~~Agreement~~June 2022, ~~and~~we ~~(c)~~entered ~~entry by us and Novartis~~ into aan ~~customary nondisclosure agreement,Novartis will have the~~ exclusive ~~right~~global ~~(but~~license noagreement ~~obligation)~~with Aurigene, to ~~conduct~~research, ~~due~~develop ~~diligence on us~~ and ~~ourbusiness~~commercialize ~~and~~novel ~~negotiate~~small ~~with~~molecule usinhibitors ~~the~~of ~~definitive~~an ~~terms~~undisclosed ~~and~~oncology ~~conditions~~target of (the ~~Proposed~~Aurigene ~~Sale~~Agreement).

If the Company or its affiliates receive an unsolicited bona fide acquisition proposal from a third party, theCompany must promptly notify its board of directors (or a duly authorized board committee) of the receiptthereof and request that they consider the merits of such acquisition proposal. If, after such consideration, theCompany’s board of directors (or authorized committee) authorizes the Company to engage in negotiationswith regard to such acquisition proposal, then the Company must notify Novartis in writing within 24 hours ofreceipt of such authorization. To the extent possible in light of any confidentiality obligations, such notice mustinclude a summary of the key structural, non-financial terms of such acquisition proposal.27

InTable ~~the event~~ of an Olema Compound Transaction or Olema Change of Control involving a third party otherthan Novartis (the first to occur, a “Repayment Trigger Event”), the Company must promptly pay, or procurethe payment of, the Repayment Amount (as defined below) to Novartis. Notwithstanding the foregoing, if theAgreement is terminated as a result of certain patient safety issues, lack of product efficacy, regulatory issuesor clinical hold issues prior to the consummation of the Olema Compound Transaction or Olema Change ofControl, then the Company shall not be obligated to pay the Repayment Amount unless (a) the Olema Change of Control or Olema Compound Transaction occurs after such termination and (b) prior to the fifth anniversary of such Olema Change of Control or Olema Compound Transaction (as applicable), the Company or its affiliates (or the applicable acquirer, successor, licensee or option holder of the Company or its affiliates) enrolls a subject in any clinical study involving the combination of palazestrant and ribociclib (the Olema Combination) or submits any filing with any regulatory authority relating to the Olema Combination. The “Repayment Amount” is the proportion of approximately $275 million that is represented by the number ofunits of ribociclib actually supplied to the Company under the Supply Agreement as of immediately prior to theRepayment Trigger Event as compared to the total number of units that could be supplied under the Agreement.Contents

~~The~~Under ~~foregoing~~the ~~rights~~terms of ~~first~~the ~~negotiation~~Aurigene Agreement, ~~first~~Aurigene ~~offer~~provides ~~and~~to ~~notice~~us ~~and~~an ~~repayment~~exclusive ~~obligations~~license ~~remain~~to inits ~~effect~~portfolio ~~untilthe~~of ~~first~~novel tosmall ~~occur~~molecule inhibitors of: ~~(a)~~ the ~~date~~target. ~~that~~Financial isterms ~~120~~of ~~days~~the ~~after~~Aurigene ~~filing~~Agreement ofinclude ~~the~~a ~~New~~$8.0 ~~Drug~~million ~~Application~~upfront ~~for~~payment ~~the~~from ~~OlemaCombination,~~us ~~(b)~~for ~~one~~rights ~~year~~to ~~after~~a ~~any~~pre-existing ~~expiration~~Aurigene orprogram ~~termination~~and ofremaining ~~the~~potential ~~Agreement,~~future ~~and~~milestone ~~(c)~~payments ~~such~~of ~~time~~up asto ~~theAgreement~~$45.0 ismillion ~~terminated~~in byclinical ~~the~~development ~~Company~~and ~~due~~regulatory tomilestones, ~~Novartis’~~and ~~material~~up ~~breach~~to $370.0 ~~However,~~million in ~~the~~commercial ~~event~~milestones. ~~theAgreement~~Aurigene is ~~terminated~~also ~~due~~eligible to ~~certain~~receive ~~patient~~mid-single-digit ~~safety~~to ~~issues,~~low ~~lack~~double-digit royalties as percentages of product ~~efficacy~~sales, ~~regulatory~~if ~~issues~~any. ~~orclinical~~During ~~hold~~the ~~issues~~years ~~prior~~ended toDecember ~~the~~31, ~~consummation~~2025 ofand an2024, ~~Olema~~we ~~Change~~made one-time milestone payments to Aurigene of ~~Control~~$10.0 ormillion ~~Olema~~and ~~CompoundTransaction~~$5.0 million, ~~then~~respectively, ~~the~~pursuant ~~Repayment~~to ~~Obligation~~the ~~shall~~Aurigene ~~survive~~Agreement. ~~until~~During the ~~fifth~~research ~~anniversary~~term, ofwe ~~such~~contribute ~~Olema~~funding ~~Change~~to ~~ofControl~~Aurigene orto ~~Olema~~facilitate ~~Compound~~Aurigene’s ~~Transaction~~ongoing ~~(as~~discovery ~~applicable)~~efforts. orWe and Aurigene jointly direct further pre-clinical work and, if ~~payment~~successful, ofwe ~~the~~will ~~Repayment~~lead ~~Amount~~clinical isdevelopment ~~required,until~~as ~~the~~well ~~next~~as ~~business~~regulatory ~~day~~and ~~after~~commercial ~~the~~activities. ~~Repayment~~We ~~Amount~~and ~~has~~Aurigene ~~been~~jointly ~~received~~own bycollaboration ~~Novartis~~compounds and rights to any inventions made during the research term.

The ~~Agreement~~term ~~will terminate on the fifth anniversary~~ of the ~~date~~Aurigene onAgreement ~~which~~will ~~the~~continue ~~first~~until ~~dose of palazestrant isadministered to~~ the ~~first~~expiration ~~study subject. Either party may terminate the Agreement for the uncured materialbreach or insolvency~~ of the ~~other party, for failure~~ last-to ~~comply with certain anti~~-~~corruption~~expire ~~obligations, in theevent~~ of aall ~~change~~payment ofobligations ~~control~~with ofrespect ~~the~~to ~~other~~all ~~party,~~licensed ifproducts ~~it reasonably deems it necessary in order to protect thesafety~~thereunder, ~~health~~unless orterminated ~~welfare~~earlier ~~of subjects enrolled~~ in ~~the~~accordance ~~clinical~~with ~~studies for~~ the ~~combined~~terms ~~therapies due to theexistence~~ of ~~a material safety issue, if~~ the ~~parties~~Aurigene ~~jointly~~Agreement. ~~decide~~The ~~that~~Aurigene ~~the~~Agreement ~~Olema~~may ~~Combination~~be isterminated ~~not achievingsufficiently superior levels of efficacy, if any regulatory authority action prevents a party~~ (~~or the Letrozolesupplier~~a) ~~from~~by ~~supplying~~us ~~its~~for ~~product~~convenience, in ~~the~~our ~~event~~sole ~~of an unresolved force majeure event~~discretion, orupon inprior ~~certaincircumstances~~written ~~for~~notice ~~an unresolved clinical hold with respect~~ to ~~ribociclib~~Aurigene, ~~palazestrant or letrozole~~ (orb) ~~thecombination~~by ofeither ~~ribociclib~~us ~~and palazestrant~~ or ~~ribociclib~~Aurigene ~~and~~in ~~letrozole).~~connection Inwith ~~addition, Novartis may terminate theAgreement if~~ the ~~Company~~other ~~has~~party’s ~~failed~~uncured tomaterial ~~commence~~breach ~~the OPERA-02 trial on~~ or ~~prior~~(c) toby ~~March~~either ~~31,~~us ~~2026~~ or ifAurigene ~~theCompany~~in ~~consummates~~connection anwith ~~Olema Compound Transaction, and~~ the ~~Company~~insolvency ~~may~~of ~~terminate~~ the ~~Agreementif the Company terminates the OPERA-02 trial~~ other ~~than due to a material safety issue, efficacy issue,regulatory action or upon a clinical hold~~party.

25Other Licensing Agreements

~~Table~~On October 17, 2024, we signed an out-license of ~~Contents~~our de-prioritized TRPM4 targeted research program to Black Shadow Therapeutics LLC in exchange for potential single-digit royalties on world-wide net sales should a product be approved by regulatory authorities.

ClinicalIntellectual Trial Agreement with PfizerProperty

InOur ~~November~~success ~~2020~~depends, wein ~~entered~~part, ~~into~~on aour ~~non-exclusive~~ability ~~clinical trial agreement with Pfizer (the Pfizer Agreement)~~ to ~~evaluate~~obtain, ~~the~~maintain ~~safety~~ and ~~tolerability~~protect ofour ~~palazestrant~~intellectual inproperty ~~combination~~and ~~with~~other ~~Pfizer’s~~ proprietary ~~CDK4/6~~rights ~~inhibitor~~for ~~IBRANCE® (palbociclib) in patients with recurrent~~palazestrant, ~~locally advanced or metastatic ER+/HER2‑ breast cancer in a clinical trial. Under the terms of the non~~OP-~~exclusive agreement~~3136, weand ~~are~~any ~~responsible~~future ~~for~~product ~~conducting~~candidates ~~the~~and ~~clinical~~other ~~study~~discoveries, ~~for~~inventions, ~~the~~trade ~~combined~~secrets, ~~therapies~~ and ~~Pfizer~~know-how isthat ~~responsible~~are ~~for~~critical ~~supplying IBRANCE®~~ to usour atbusiness ~~no cost to us~~operations. AsOur ~~part~~success ofalso ~~the~~depends ~~collaboration,~~in ~~the~~part ~~parties~~on ~~granted~~our ability to ~~each~~operate ~~other~~without ~~a non-exclusive~~infringing, ~~royalty-~~misappropriating ~~free~~or ~~license~~otherwise ~~under~~violating ~~certain of~~ the ~~parties’~~intellectual ~~respective~~property ~~patent~~and proprietary rights ~~in the combination~~ of ~~IBRANCE®~~others, and ~~palazestrant~~in topart, ~~use~~on ~~the~~our ~~parties’~~ability ~~respective~~to ~~study~~prevent ~~drugs~~others infrom ~~research and development~~infringing, ~~solely~~misappropriating toor ~~the~~otherwise ~~extent~~violating ~~reasonably~~our ~~needed~~intellectual ~~for~~property ~~the~~and ~~other~~proprietary ~~party’s activities in the collaboration~~rights. ~~All~~A ~~inventions~~comprehensive ~~and~~discussion ~~data~~on ~~developed~~risks inrelating ~~the~~to ~~performance~~intellectual ofproperty ~~the~~is ~~clinical~~provided ~~trials~~under ~~for~~ the ~~combined~~section ~~therapies~~titled ~~(other~~“Risk ~~than~~Factors—Risks ~~those~~related ~~specific~~ to ~~each~~our ~~component~~intellectual ~~study drug), are jointly owned by the parties~~property.”

WeIntellectual ~~are~~property ~~responsible~~rights ~~for~~relevant ~~manufacturing,~~to ~~packaging~~pharmaceutical ~~and~~companies ~~labeling~~typically ~~palazestrant,~~include ~~and~~a ~~for~~combination ~~packaging~~of ~~and~~patent ~~labeling~~rights, ~~all~~trademark ~~drugs~~rights, ~~used~~and intrade ~~the~~secret ~~clinical~~protection. ~~trials~~Our ~~for~~success ~~the~~depends, ~~combined~~in ~~therapies~~part, ~~(other~~on ~~than~~our ~~IBRANCE®~~ability ~~(palbociclib)).~~to ~~Pfizer~~secure ~~is responsible for manufacturing~~ and ~~delivering~~enforce toeach usof ~~IBRANCE®~~these ~~(palbociclib)~~types inof ~~such~~intellectual ~~quantities~~property ~~as reasonably needed for the clinical studies for the combined therapies~~rights.

The ~~Pfizer~~patent ~~Agreement~~positions ~~will~~of ~~terminate~~companies ~~upon~~like ~~completion~~ours ofare ~~all~~generally ~~activities~~uncertain ~~outlined~~and ininvolve ~~the~~complex ~~study~~legal ~~plan~~ and ~~the~~factual ~~relevant protocols~~questions. ~~Either~~No ~~party~~consistent ~~may~~policy ~~terminate~~regarding the ~~Pfizer~~scope ~~Agreement~~of ~~for~~claims ~~the~~allowable ~~uncured~~in ~~material~~patents ~~breach~~in orthe ~~insolvency~~field of biotechnology has emerged in the United States and in Europe, among other ~~party~~countries. Changes in the patent laws and rules, ifeither itby ~~reasonably~~legislation, ~~deems~~judicial itdecisions, ~~necessary~~or inregulatory ~~order~~interpretation may diminish our ability to protect ~~the~~our ~~safety~~inventions and enforce our intellectual property rights, ~~health~~and ormore ~~welfare~~generally could affect the value of ~~subjects~~our ~~enrolled~~intellectual inproperty. ~~the~~In ~~clinical~~particular, ~~studies~~our ~~for~~ability ~~the~~to ~~combined~~stop ~~therapies~~third ~~due~~parties from making, using, selling, offering to ~~the~~sell, ~~existence~~importing ofor aotherwise ~~material~~commercializing ~~safety~~any ~~issue~~of our patented inventions, either directly or indirectly, will depend in ~~certain~~part ~~circumstances~~on ~~for~~our ansuccess ~~unresolved~~in ~~clinical~~obtaining, ~~hold~~defending ~~with~~and ~~respect~~enforcing topatent ~~either~~claims that cover our technology, inventions, and improvements. Regardless of the ~~IBRANCE®~~coverage ~~(palbociclib)~~we seek under our existing patent applications, there is always a risk that an alteration to the product or ~~palazestrant~~process may provide sufficient basis for a competitor to avoid infringement claims. In addition, ~~either~~the ~~party~~coverage ~~may~~claimed ~~terminate~~in ~~the~~a ~~Pfizer~~patent ~~Agreement~~application ifcan ~~certain~~be ~~disputes~~significantly ~~between~~reduced ~~the~~before ~~parties~~a ~~are~~patent ~~not~~is ~~resolved~~issued and courts can reinterpret claim scope after ~~following~~issuance. ~~the~~Moreover, ~~applicable~~many ~~dispute~~jurisdictions, ~~resolution~~including ~~procedures~~the orUnited ifStates, ~~either~~permit ~~party~~third ~~determines~~parties to ~~discontinue~~challenge ~~clinical~~issued ~~development~~patents ~~for~~in ~~medical,~~administrative ~~scientific~~proceedings, ~~legal~~which may result in further narrowing or ~~other~~even ~~reasons~~cancellation of patent claims.

The Pfizer Agreement does not grant any right of first negotiation to participate in future clinical studies, and each of the parties retains all rights and ability to evaluate their respective compounds.28

~~License~~Table ~~Agreement~~of ~~with Aurigene~~ Contents

InAn ~~June~~issued ~~2022~~patent provides its owner (or possibly its licensee) with a right to exclude others from making, weusing ~~entered~~or ~~into~~selling anthat ~~exclusive~~which ~~global~~is ~~license~~claimed ~~agreement~~in ~~with~~the ~~Aurigene~~patent, tofor ~~research~~a specified period of time (the “term” of the patent), ~~develop~~in the jurisdiction in which the patent is issued. In the United States, and ~~commercialize~~in ~~novel~~many ~~small~~other ~~molecule~~countries, ~~inhibitors~~utility patents have a presumptive term of an20 ~~undisclosed~~years ~~oncology~~from ~~target~~their effective filing date (which is the ~~Aurigene~~earliest ~~Agreement~~non-provisional filing date to which the patent claims priority). However, many jurisdictions, including the United States, require the payment of periodic annuities or maintenance fees for patents to remain in force for the full 20‑year term. The United States also has provisions under which a patent’s term may be reduced if its claims are deemed insufficiently distinct from those of another patent owned by the same party with an earlier expiration date. The term of a patent, and the protection it affords, is therefore limited and once the patent term of our issued patents has expired, we may face competition. Because of the extensive time required for clinical development and regulatory review of the drugs we develop, it is possible that, before palazestrant, OP-3136, or any future product candidates we may develop can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of any such patent.

~~Under~~The ~~the~~United ~~terms~~States ofand ~~the~~certain ~~Aurigene~~other ~~Agreement,~~jurisdictions ~~Aurigene~~also ~~will~~have ~~provide~~provisions tothat uspermit anextension ~~exclusive license to its portfolio~~ of ~~novel~~patent ~~small molecule inhibitors of the target~~term. Patent ~~Financial~~term ~~terms~~extension ofmay ~~the~~be ~~Aurigene~~available ~~Agreement~~for ~~include~~an aunexpired ~~$8.0~~patent ~~million~~that ~~upfront~~claims ~~payment~~an ~~from~~approved usproduct, ~~for~~or ~~rights~~its toapproved ause ~~pre-existing~~or ~~Aurigene~~method ~~program and potential future milestone payments~~ of upmaking, towhere ~~$60.0~~the ~~million~~approval infollows ~~clinical~~a ~~development~~period ~~and~~of regulatory ~~milestones,~~review and upthe topatentee ~~$370.0~~files ~~million~~a intimely ~~commercial~~request ~~milestones.~~for ~~Aurigene~~an isextension ~~also eligible to receive mid-single-digit to low double-digit royalties as percentages~~ of ~~product~~patent ~~sales, if any~~term. ~~During~~In the ~~research~~United ~~term~~States, wesuch ~~will~~extension ~~contribute~~associated ~~funding~~with toregulatory ~~Aurigene~~approval tois ~~facilitate~~called ~~Aurigene’s~~a ~~ongoing~~Patent ~~discovery~~Term ~~efforts.~~Extension We(PTE) and ~~Aurigene~~it ~~will~~is ~~jointly~~limited ~~direct~~to ~~further~~a ~~pre-clinical~~maximum ~~work~~of ~~and,~~five ~~if successful~~years, weor ~~will~~less ~~lead~~if ~~clinical~~the ~~development~~extended aspatent ~~well~~term aswould ~~regulatory~~exceed ~~and~~14 ~~commercial~~years ~~activities.~~after Wethe ~~and~~date ~~Aurigene~~of ~~jointly~~regulatory ~~own~~approval. ~~collaboration~~Only ~~compounds~~one ~~and~~patent ~~rights~~can toreceive ~~any~~patent ~~inventions~~term ~~made~~extension ~~during~~(e.g., ~~the~~PTE) ~~research~~per ~~term~~product approval.

The ~~term~~United States also provides, in certain cases, a different form of ~~the~~added ~~Aurigene~~patent ~~Agreement~~term, ~~will~~known ~~continue~~as ~~until~~Patent Term Adjustment (PTA), whereby a particular patent’s term is automatically extended beyond the ~~expiration~~20‑year ofdate if the ~~last-to-expire~~United ofStates ~~all~~Patent ~~payment~~and ~~obligations~~Trademark ~~with~~Office ~~respect~~(USPTO) tocauses ~~all~~delay ~~licensed~~during ~~products~~its ~~thereunder~~examination; however, ~~unless~~potentially ~~terminated~~available ~~earlier~~PTA inis ~~accordance~~reduced ~~with~~by ~~the~~any ~~terms~~amount of any delay caused by the ~~Aurigene~~patent ~~Agreement~~applicant. ~~The~~Patent ~~Aurigene~~term ~~Agreement~~adjustment ~~may~~is begenerally ~~terminated~~calculated ~~(a)~~as bythe usnet ~~for~~number ~~convenience~~of days of USPTO-caused delay during prosecution, inminus ~~our~~any ~~sole~~periods ~~discretion~~of applicant-caused delay, ~~upon~~and ~~prior~~is ~~written~~added ~~notice~~to the patent’s expiration date. We may not receive an extension if we fail to ~~Aurigene,~~exercise ~~(b)~~due bydiligence ~~either~~during usthe testing phase or ~~Aurigene~~regulatory inreview ~~connection~~process, ~~with~~fail ~~the~~to ~~other~~apply ~~party’s~~within ~~uncured~~applicable ~~material~~deadlines, ~~breach~~fail orto ~~(c)~~apply byprior ~~either~~to usexpiration of relevant patents or ~~Aurigene~~otherwise infail ~~connection~~to ~~with~~satisfy applicable requirements. Moreover, the ~~insolvency~~length of the ~~other~~extension ~~party~~could be less than we request. There can be no assurance that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.

~~Other~~A ~~Licensing~~provisional ~~Agreements~~patent application can establish a priority date for a patent, but only if certain deadlines and procedures are met. Specifically, a non-provisional application must be filed within 12 months of the earliest-filed provisional filing date, and such non-provisional filing must be made by an applicant who has properly documented its right to claim priority. Furthermore, if any changes are made to the application between the provisional and the non- provisional filings, the changed material may not be entitled to an earlier priority date. In the biopharmaceutical industry, it is common for applicants to file an international patent application under the Patent Cooperation Treaty (PCT) as a non-provisional filing. Such an international application, referred to as a “PCT application,” like a provisional application, cannot itself issue as a patent but rather preserves the applicant’s right to pursue patent filings in individual countries, which patent filings are referred to as “national applications” or “national phase filings” and can claim the benefit of priority to the prior PCT application (which may in turn claim priority to the prior provisional filing(s)). For most jurisdictions, national phase applications claiming priority to a PCT application must be filed within 30 to 32 months of the PCT’s earliest priority date. If we fail to meet the deadline for filing non-provisional or national phase applications, or fail to complete all procedural requirements associated with such filings, we may lose our right to claim priority. Moreover, even if we comply with all deadlines and requirements, we may not be able to secure granted patents in relevant jurisdictions, and furthermore cannot predict whether any patents that might issue will provide us with any competitive advantage.

2629

Table of Contents

OnWe ~~October~~have 17granted patents and pending applications relating to palazestrant, ~~2024~~including granted claims that encompass the palazestrant compound, wepharmaceutical ~~signed~~compositions anthat ~~out-license~~include palazestrant, and certain methods of ~~our~~using ~~de-prioritized~~palazestrant, ~~TRPM4~~e.g., ~~targeted~~for ~~research~~treating ~~program~~particular todisorders ~~Black~~or ~~Shadow~~diseases, ~~Therapeutics~~where ~~LLC~~such intreatment ~~exchange~~may ~~for~~include ~~potential~~combination ~~single~~therapy. The 20-~~digit~~year ~~royalties~~term onfor ~~world-wide~~these ~~net~~patents ~~sales~~expires ~~should~~in a2036. ~~product~~In the United States, it is uncertain whether any PTE will be ~~approved~~available, byand ~~regulatory~~if ~~authorities~~so, how much. Additional patent applications are pending, including applications that relate to dosing regimens and treatment of particular cancers, formulations, and additional combination therapies, including combination therapy with ribociclib, among other patent applications, and, if granted, will have 20-year terms that expire between 2040 and 2046.

~~Intellectual~~We ~~Property~~co-own with Aurigene a patent-family related to OP-3136, which includes claims that encompass the OP-3136 compound, pharmaceutical compositions that include OP-3136, and certain methods of using OP-3136. Under the Aurigene Agreement, Aurigene has provided to us an exclusive license to Aurigene's rights to patents and applications related to OP-3136 and other KAT6 inhibitor compounds. The 20-year term for patents and applications in this patent family, including a granted U.S. patent, related to OP-3136 expires in 2044. In the United States, it is uncertain whether any PTE will be available, and if so, how much.

~~Our~~Certain ~~success~~patents ~~depends,~~related ~~in part, on our ability~~ to ~~obtain, maintain and protect our intellectual property and other proprietary rights for~~ palazestrant, or OP-3136 ~~and~~may ~~any~~be ~~future~~eligible ~~product~~for ~~candidates~~PTE ~~and other discoveries, inventions, trade secrets and know-how that are critical to our business operations. Our success also depends~~ in ~~part~~certain ~~on our ability to operate without infringing~~jurisdictions, ~~misappropriating~~including ~~or otherwise violating~~ the ~~intellectual~~United ~~property~~States and ~~proprietary rights of others~~Europe, ~~and~~upon inapproval ~~part,~~of ona ~~our~~commercial ~~ability~~use toof ~~prevent~~the ~~others~~corresponding ~~from~~product ~~infringing,~~by ~~misappropriating~~a orregulatory ~~otherwise~~agency ~~violating~~in ~~our~~the ~~intellectual~~jurisdiction ~~property~~where ~~and~~the ~~proprietary~~patent ~~rights~~was granted. AHowever, ~~comprehensive~~there ~~discussion~~can onbe ~~risks~~no ~~relating~~assurance tothat ~~intellectual~~we ~~property~~will isreceive ~~provided~~or ~~under~~benefit ~~the~~from ~~section~~any ~~titled~~PTE ~~“Risk~~with ~~Factors—Risks~~respect ~~Related~~ to ~~Our~~such ~~Intellectual Property~~patents.”

~~Intellectual~~With respect to our owned intellectual property, ~~rights~~we ~~relevant~~cannot tobe ~~pharmaceutical~~sure ~~companies~~that ~~typically~~patents ~~include~~will abe ~~combination~~granted with respect to any of our pending patent ~~rights,~~applications ~~regulatory~~or ~~exclusivities~~with respect to any patent applications filed by us in the future, ~~trademark~~nor ~~rights~~can we be sure that any current patents or any patents that may be granted to us in the future will be commercially useful in protecting palazestrant, OP-3136, or any future product candidates and ~~trade~~the ~~secret~~methods ~~protection~~used to manufacture them. ~~Our~~Moreover, ~~success~~any ~~depends~~issued patents and those that may be issued in the future may not guarantee us the right to prevent competitors from practicing our technology in relation to the commercialization of palazestrant, OP-3136, or any future product candidates. Any patents and those that may issue in ~~part~~the future may be challenged, onnarrowed, circumvented or invalidated, which could limit our ability to ~~secure~~stop ~~and~~competitors ~~enforce~~from ~~each~~marketing related product candidates or limit the length of ~~these~~the ~~types~~term of patent protection that we may have for palazestrant, OP-3136, or any future product candidates. In addition, the rights granted under any issued patents may not provide us with complete protection or competitive advantages against competitors with similar products to ours. For information regarding risks related to intellectual property, ~~rights~~see the section titled “Risk Factors—Risks related to our intellectual property.”

~~The~~We ~~patent~~do ~~positions~~not ofcurrently ~~companies~~own ~~like~~any ~~ours~~U.S. ~~are~~registered ~~generally~~trademarks ~~uncertain~~for ~~and~~our ~~involve~~brand ~~complex~~or ~~legal~~trade ~~and factual questions~~names. NoOur ~~consistent~~trademarks ~~policy~~or ~~regarding~~trade ~~the~~names ~~scope~~may ofbe ~~claims~~challenged, ~~allowable~~infringed, incircumvented, ~~patents~~or indeclared ~~the~~generic ~~field~~or ofdetermined ~~biotechnology~~to ~~has~~be ~~emerged~~infringing inon ~~the~~other ~~United~~marks. ~~States~~We ~~and~~may innot ~~Europe,~~be ~~among~~able ~~other~~to ~~countries.~~protect ~~Changes~~our inrights ~~the~~to ~~patent~~these ~~laws~~trademarks and ~~rules,~~trade ~~either by legislation~~names, ~~judicial~~which ~~decisions,~~we orneed ~~regulatory~~to ~~interpretation~~build inname ~~other~~recognition ~~countries~~among ~~may~~potential ~~diminish~~partners ~~our~~or ~~ability~~customers toin ~~protect~~ our ~~inventions~~markets ~~and~~of ~~enforce~~interest. ~~our~~At ~~intellectual property rights~~times, ~~and~~competitors ~~more~~may ~~generally~~adopt ~~could~~trade ~~affect~~names ~~the~~or ~~value~~trademarks ofsimilar ~~our~~to ~~intellectual~~ours, ~~property.~~thereby Inimpeding ~~particular,~~ our ability to ~~stop~~build ~~third~~brand ~~parties~~identity ~~from~~and ~~making,~~possibly ~~using,~~leading ~~selling, offering~~ to ~~sell,~~market ~~importing~~confusion. orIn ~~otherwise~~addition, ~~commercializing~~there ~~any~~could ofbe ~~our~~potential ~~patented~~trade ~~inventions,~~name ~~either~~or ~~directly~~trademark orinfringement ~~indirectly,~~claims ~~will~~brought ~~depend~~by inowners ~~part~~of onother ~~our~~registered ~~success~~trademarks inor ~~obtaining,~~trademarks ~~defending~~that ~~and~~incorporate ~~enforcing~~variations ~~patent~~of ~~claims~~our ~~that~~registered ~~cover~~or ~~our~~unregistered ~~technology,~~trademarks ~~inventions,~~or ~~and~~trade ~~improvements~~names. ~~Regardless~~Over of the ~~coverage~~long weterm, ~~seek~~if ~~under~~we ~~our~~are ~~existing~~unable ~~patent~~to ~~applications,~~establish ~~there~~name isrecognition ~~always~~based aon ~~risk~~our ~~that~~trademarks anand ~~alteration~~trade tonames, ~~the~~then ~~product~~we ~~or process~~ may ~~provide~~not ~~sufficient~~be ~~basis~~able ~~for a competitor~~ to ~~avoid~~compete ~~infringement claims. In addition~~effectively, ~~the~~and ~~coverage~~our ~~claimed~~business inmay ~~a patent application can~~ be ~~significantly~~adversely ~~reduced~~affected. ~~before~~Our aefforts ~~patent~~to isenforce ~~issued~~or ~~and~~protect ~~courts~~our ~~can~~proprietary ~~reinterpret~~rights ~~patent~~related ~~scope~~to ~~after~~trademarks, ~~issuance.~~trade ~~Moreover~~secrets, ~~many~~domain ~~jurisdictions~~names, ~~including~~copyrights ~~the~~or ~~United~~other ~~States,~~intellectual ~~permit~~property ~~third~~may ~~parties~~be toineffective ~~challenge~~and ~~issued~~could ~~patents~~result in ~~administrative~~substantial ~~proceedings,~~costs ~~which~~and ~~may~~diversion ~~result~~of inresources ~~further~~and ~~narrowing~~could oradversely ~~even~~impact ~~cancellation~~our offinancial ~~patent~~condition ~~claims~~or results of operations.

AnIn ~~issued~~addition ~~patent provides its owner (or possibly its licensee) with a right~~ to ~~exclude~~our ~~others from making~~patents, ~~using~~anticipated orregulatory ~~selling that which is claimed in the patent~~exclusivities, ~~for~~and ~~a specified period of time (the “term” of the patent)~~trademarks, inwe ~~the~~rely ~~jurisdiction~~on intrade ~~which~~secret ~~the patent is issued. In the United States,~~ and ~~in many other countries, utility patents have a presumptive term of 20 years from their effective filing date (which is the earliest non~~know-~~provisional~~how ~~filing~~protection ~~date~~ to ~~which~~further ~~the~~secure ~~patent~~our ~~claims~~proprietary ~~priority).~~position ~~However,~~around ~~many~~our ~~jurisdictions~~chemistry, ~~including~~technology the United States, require the payment of periodic annuities or maintenance fees for patents to remain in force for the full 20‑year term. The United States also has provisions that require a patent term to be shortened if its claims are too similar to another patent owned by the same party that has a shorter term. The term of a patent, and ~~the~~other ~~protection~~discoveries ~~it affords, is therefore limited~~ and ~~once~~inventions the patent term of our issued patents has expired, we may face competition. Because of the extensive time required for clinical development and regulatory review of the drugs we develop, it is possible that, ~~before palazestrant, OP-3136 or any future product candidates~~ we ~~may~~consider ~~develop~~important ~~can~~to beour ~~commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of any such patent~~business.

The United States and certain other jurisdictions also have provisions that permit extension of patent term for patents that claim a drug or drug product, or its approved use, if the patent was issued before clinical trials and were completed and regulatory approval secured, so long as certain specific requirements were satisfied. In the United States, such extension associated with regulatory approval is called a Patent Term Extension (PTE) and it is limited to a maximum of five years, or less if the extended patent term would exceed 14 years after the date of regulatory approval. Only one patent can receive regulatory extension (e.g., PTE) per product approval.30

27Table of Contents

~~Table~~We also seek to protect our intellectual property, including our trade secrets and know-how, in part by entering into confidentiality agreements with companies with whom we share proprietary and confidential information in the course of ~~Contents~~business discussions, and by having confidentiality terms in our agreements with our employees, consultants, scientific advisors, clinical investigators and other contractors and also by requiring our employees, commercial contractors, and certain consultants and investigators, to enter into invention assignment agreements that grant us ownership of any discoveries or inventions made by them while in our employ or carrying out work on behalf of Olema. However, trade secrets and know-how can be difficult to protect. We cannot guarantee that we have entered into such agreements with each party that may have or have had access to our trade secrets or proprietary technology and processes or that these agreements will afford us adequate protection of our intellectual property and proprietary rights. Despite these efforts, any of these parties may breach the agreements and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. For information regarding risks related to intellectual property, see the section titled “Risk Factors—Risks related to our intellectual property.”

TheSales United States also offers a different form of patent term extension, known as Patent Term Adjustment (PTA), whereby a particular patent’s term is automatically extended beyond the 20‑year date if the United States Patent and Trademark Office (USPTO) caused delay during its examination; however, potentially available PTA is reduced by any amount of any delay caused by the patent applicant. We may not receive an extension if we fail to exercise due diligence during the testing phase or regulatory review process, fail to apply within applicable deadlines, fail to apply prior to expiration of relevant patents or otherwise fail to satisfy applicable requirements. Moreover, the length of the extension could be less than we request. There can be no assurance that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.Marketing

AGiven ~~provisional~~our ~~patent~~stage ~~application can establish a priority date for a patent, but only if certain deadlines and procedures are met. Specifically, a non-provisional application must be filed within 12 months~~ of ~~the provisional filing date~~development, ~~and~~we ~~such~~have non-provisional filing must be made by an applicant who has properly documented its right to claim priority. Furthermore, if any changes are made to the application between the provisional and the non- provisional filings, the changed material may not beyet ~~entitled~~established ~~to the priority filing date. Still further, in the biopharmaceutical industry, it is common for applicants to file~~ a ~~so-called~~commercial ~~“international”~~organization ~~patent~~or ~~application~~distribution ~~under the Patent Cooperation Treaty (PCT) as a non-provisional filing~~capabilities. ~~Such~~We anintend ~~international application, often referred~~ to asbuild a ~~“PCT~~commercial ~~application,”~~infrastructure ~~like a provisional application, cannot itself issue as a patent but rather preserves the applicant’s right~~ to ~~pursue~~support ~~patent~~sales ~~filings~~of inany ~~individual~~approved ~~countries,~~products. ~~which~~We ~~patent~~intend ~~filings are referred~~ to ascontinue ~~“national~~evaluating ~~applications”~~opportunities ~~or “national phase filings” and can claim the benefit of priority~~ to ~~the~~work ~~prior~~with ~~PCT~~partners ~~application~~that ~~(which~~enhance ~~may~~our incapabilities ~~turn~~with ~~claim~~respect ~~priority~~ to the ~~prior~~development ~~provisional~~and ~~filing).~~commercialization ~~For most jurisdictions, national phase applications claiming priority to a PCT application must be filed within 30 to 32 months~~ of ~~the~~palazestrant ~~PCT’s~~and ~~earliest priority date~~OP-3136. IfIn ~~we fail to meet the deadline for filing non-provisional or national phase applications~~addition, orwe ~~fail~~intend to ~~complete~~commercialize ~~all procedural requirements associated with such filings, we may lose~~ our ~~right~~product ~~to claim priority. Moreover~~candidates, ~~even~~ if ~~we comply with all deadlines and requirements~~approved, wein ~~may~~key ~~not~~markets beeither ~~able~~alone toor ~~issue~~with ~~patents~~partners in ~~relevant~~order ~~jurisdictions,~~to ~~and~~maximize ~~furthermore~~the ~~cannot~~worldwide ~~predict~~commercial ~~whether~~potential ~~any~~of ~~patents~~our ~~that might issue will provide us with any competitive advantage~~programs.

We have granted patents and pending applications relating to palazestrant, including granted claims that encompass the palazestrant compound, pharmaceutical compositions that include palazestrant, and certain methods of using palazestrant, including in treatment which may involve combination therapy. The 20-year term for these patents expires in 2036. In the United States, it is uncertain whether any PTE will be available, and if so, how much. Additional applications are pending, including ones that relate to dosing regimens and treatment of particular cancers and patient populations, and, if granted, will have 20-year terms that expire between 2040 and 2043. Manufacturing

We ~~co-own~~currently ~~with~~do ~~Aurigene~~not aown ~~pending~~or ~~patent~~operate ~~application~~any ~~related~~manufacturing tofacilities. ~~OP-3136~~We rely, ~~which~~and ~~includes~~expect ~~claims~~to ~~that~~continue ~~encompass~~to rely for the ~~OP-3136~~foreseeable ~~compound~~future, ~~pharmaceutical~~on ~~compositions~~third-party ~~that~~contract ~~include~~manufacturing ~~OP-3136,~~organizations ~~and~~(CMOs) ~~certain~~to ~~methods~~produce ofpalazestrant ~~using~~and OP-3136. ~~Under~~for ~~the~~non-clinical ~~Aurigene~~and ~~Agreement~~clinical testing, ~~Aurigene~~as ~~has~~well ~~provided~~as tofor uscommercial anmanufacture ~~exclusive~~if ~~license~~palazestrant toor ~~Aurigene's~~OP-3136 ~~rights~~receives inmarketing ~~patents~~approval. ~~and~~We ~~applications~~require ~~related~~that toour ~~OP-3136~~CMOs produce bulk drug substances and ~~other~~finished ~~KAT6~~drug ~~inhibitor~~products ~~compounds.~~in ~~The~~accordance ~~20-year~~with ~~term~~current ~~for~~Good ~~the~~Manufacturing ~~pending~~Practices ~~patent~~(cGMPs) ~~application~~and ~~related~~all toother ~~OP-3136~~applicable ~~expires~~laws inand ~~2044~~regulations. In ~~the~~We ~~United~~maintain ~~States,~~agreements itwith isour ~~uncertain~~manufacturers ~~whether~~that ~~any~~include ~~PTE~~confidentiality ~~will~~and beintellectual ~~available,~~property ~~and~~provisions ifto ~~so,~~protect ~~how~~our ~~much~~proprietary rights related to palazestrant and OP-3136.

~~Certain~~We ~~patents~~have ~~related~~engaged CMOs to manufacture and package palazestrant orand OP-3136 ~~(once~~for ~~granted)~~non-clinical ~~may~~and beclinical ~~eligible~~use. ~~for~~Additional ~~PTE~~CMOs inare ~~certain~~used ~~jurisdictions,~~to ~~including~~label ~~the~~and ~~United~~distribute ~~States~~palazestrant and ~~Europe,~~OP-3136 ~~upon~~for ~~approval~~clinical ofuse. We obtain our supplies from these CMOs on a purchase order basis and do not have long-term supply arrangements in place. We expect to put commercial ~~use~~manufacturing agreements into place as we prepare for potential commercialization of ~~the~~palazestrant. We ~~corresponding~~have ~~product~~identified byand have under contract a ~~regulatory~~second ~~agency~~manufacturer infor ~~the~~palazestrant ~~jurisdiction~~active ~~where~~pharmaceutical ~~the~~ingredient ~~patent~~and ~~was~~also ~~granted~~anticipate two manufacturers for drug product. ~~However~~More broadly, ~~there~~for ~~can~~palazestrant, beOP-3136, noand ~~assurance~~any ~~that~~future product candidates we ~~will~~may ~~receive~~develop, orwe ~~benefit~~intend ~~from~~to ~~any~~identify ~~PTE~~and ~~with~~qualify ~~respect~~additional manufacturers to ~~such~~provide ~~patents~~the active pharmaceutical ingredient and fill-and-finish services prior to seeking regulatory approval.

In addition to patent term extension regulatory exclusivities, pharmaceutical marketing approval agencies, such as the FDA and the EMA, offer certain data exclusivities for first-approved products with a new chemical entity (NCE), exclusivity, and/or for approvals related to orphan indications (Orphan Drug designation), and/or pediatric approvals (Pediatric Exclusivity).Competition

~~Furthermore~~The biotechnology and pharmaceutical industries are characterized by rapid technological advancement, assignificant ~~neither~~competition ~~palazestrant~~and ~~nor~~an ~~OP-3136~~emphasis ~~has~~on ~~previously~~intellectual ~~been~~property. ~~approved~~We inface ~~the~~potential ~~United~~competition ~~States~~from ~~for~~many ~~any~~different ~~indication~~sources, ~~each~~including ofmajor ~~palazestrant~~and specialty pharmaceutical and ~~OP-3136~~biotechnology ~~may~~companies, beacademic ~~eligible~~research ~~for~~institutions, ~~five~~governmental ~~years~~agencies ofand ~~NCE~~public ~~exclusivity~~and ~~upon~~private ~~its~~research ~~first~~institutions. Any product candidates that we successfully develop and commercialize will compete with current therapies and new therapies that may become available in the future.

2831

Table of Contents

~~approval.~~Many ~~Should~~of ~~that~~the ~~approval~~companies beagainst ~~for~~which anwe ~~orphan~~may ~~indication~~compete ~~for~~have ~~which~~significantly wegreater ~~have~~financial ~~received~~resources ~~Orphan~~and ~~Drug~~expertise ~~designation~~in research and development, manufacturing, non-clinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. Mergers and acquisitions in the ~~NCE~~pharmaceutical, biotechnology and ~~Orphan~~oncology ~~Drug~~industries ~~exclusivity~~may ~~would~~result ~~run~~in ~~concurrently~~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 and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

~~With~~Our ~~respect~~commercial toopportunity ~~our~~could ~~owned intellectual property, we cannot~~ be ~~sure~~reduced ~~that~~or ~~patents~~eliminated ~~will~~if ~~be granted with respect to any of~~ our ~~pending~~competitors ~~patent~~develop ~~applications~~and orcommercialize ~~with~~products ~~respect~~that toare ~~any~~safer, ~~patent~~more ~~applications filed by us in the future~~effective, ~~nor~~have ~~can~~fewer ~~we be sure that any current patents~~ or ~~any~~less ~~patents~~severe ~~that~~side ~~may~~effects, beare ~~granted~~more toconvenient ~~us in the future will be commercially useful in protecting palazestrant, OP-3136~~ or ~~any~~less ~~future~~expensive ~~product~~than ~~candidates and the methods used to manufacture them. Moreover,~~ any ~~issued~~products ~~patents~~we ~~and those that~~ may bedevelop. ~~issued~~Our incompetitors ~~the~~also ~~future~~ may ~~not~~obtain ~~guarantee~~FDA usor ~~the~~other ~~right~~regulatory toapproval ~~practice~~for ~~our~~their ~~technology in relation to the commercialization of palazestrant, OP-3136 or any future~~ product candidates. ~~Any~~more ~~patents~~rapidly ~~and~~than ~~those~~we ~~that~~ may ~~issue~~obtain inapproval ~~the~~for ~~future may be challenged~~ours, ~~narrowed, circumvented or invalidated,~~ which could ~~limit~~result ~~our~~in ~~ability to stop~~ competitors ~~from~~establishing ~~marketing~~a ~~related~~strong ~~product~~market ~~candidates~~position orbefore ~~limit~~we ~~the~~are ~~length~~able ofto enter the ~~term~~market. ofWe ~~patent~~believe ~~protection~~ that wethe ~~may~~key ~~have~~competitive ~~for~~factors ~~palazestrant,~~affecting ~~OP-3136~~the orsuccess of any ~~future~~of our product candidates., Inif ~~addition~~approved, ~~the~~will ~~rights~~include ~~granted~~efficacy, ~~under~~combinability, ~~any~~safety ~~issued~~profile, ~~patents~~convenience, ~~may~~cost, ~~not~~level ~~provide~~of uspromotional ~~with~~activity ~~complete~~devoted ~~protection or competitive advantages against competitors with similar products~~ to ~~ours.~~them ~~For~~and ~~information regarding risks related to~~ intellectual property, ~~see the section titled “Risk Factors—Risks Related to Our Intellectual Property~~protection.”

WeIf ~~have also applied to register~~ the ~~“Olema,”~~product ~~“Olema~~candidates ~~Oncology,”~~for ~~“Olema~~our ~~Oncology~~priority ~~and~~programs ~~design,”~~are ~~and~~approved ~~“Olema~~for ~~Therapeutics” trademarks with~~ the ~~USPTO.~~indications Wewe doare ~~not~~ currently ~~own~~targeting, ~~any~~they ~~U.S.~~will ~~registered~~compete ~~trademarks~~with ~~for~~the ~~our~~products ~~brand~~discussed orbelow. ~~trade~~Furthermore, ~~names.~~it ~~Our~~is ~~trademarks~~possible orthat ~~trade~~other ~~names~~companies ~~may~~are bealso ~~challenged,~~engaged ~~infringed,~~in ~~circumvented,~~discovery or ~~declared~~non-clinical ~~generic~~development orof ~~determined~~product tocandidates befor ~~infringing~~the onsame ~~other marks~~indications. WeThese ~~may~~competitors, ~~not~~if besuccessful ~~able~~in toclinical ~~protect~~development, ~~our~~may ~~rights~~achieve toregulatory ~~these~~approval ~~trademarks~~ and ~~trade~~market ~~names,~~adoption ~~which we need to build name recognition among potential partners or customers~~ in ~~our~~advance ~~markets~~ of ~~interest.~~our Atproduct ~~times~~candidates, ~~competitors~~constraining ~~may adopt trade names or trademarks similar to ours, thereby impeding~~ our ability to ~~build~~gain ~~brand~~significant ~~identity~~market ~~and~~share ~~possibly~~for ~~leading~~such toproduct ~~market confusion~~candidates. In addition, ~~there could be potential trade name or trademark infringement claims brought by owners of other registered trademarks or trademarks that incorporate variations of~~ our ~~registered~~product ~~or unregistered trademarks or trade names. Over the long term~~candidates, if ~~we are unable to establish name recognition based on our trademarks and trade names~~approved, ~~then~~will wecomplete ~~may~~with ~~not~~multiple beapproved ~~able~~products ~~to compete effectively, and our business may be adversely affected. Our efforts to enforce~~ or ~~protect~~products ~~our~~that ~~proprietary rights related to trademarks, trade secrets, domain names, copyrights or other intellectual property~~ may be ~~ineffective~~approved ~~and~~for ~~could~~future ~~result~~indications infor ~~substantial~~which ~~costs~~we ~~and~~develop ~~diversion~~such ofproduct ~~resources and could adversely impact our financial condition or results of operations~~candidate.

InThere ~~addition~~are toseveral ~~patent,~~currently ~~regulatory~~marketed ~~exclusivity,~~drugs and ~~trademark~~product candidates currently in development for the treatment of ER+ breast cancer that target the estrogen receptor that may compete with palazestrant including: fulvestrant, wemarketed ~~rely~~as onFaslodex® ~~trade~~by ~~secret~~AstraZeneca PLC and ~~know~~or any generic equivalents of Faslodex that are marketed or in development; elacestrant, marketed as ORSERDUTM by Stemline Therapeutics Inc.; giredestrant (GDC-~~how~~9545), ~~protection~~being todeveloped ~~secure~~by ~~our~~Roche ~~proprietary~~Holding ~~position~~AG/Genentech, ~~around~~Inc.; ~~our~~camizestrant ~~chemistry~~(AZD9833), ~~technology~~being developed by AstraZeneca PLC; imlunestrant, marketed as InluriyoTM by Eli Lilly and ~~other~~Co.; ~~discoveries~~vepdegestrant (ARV‑471), being developed by Arvinas, Inc. in partnership with Pfizer, Inc.; and ~~inventions~~lasofoxifene, being developed by LeonaBio, Inc. There are a number of KAT6 inhibitor product candidates in development that wemay ~~consider~~compete ~~important~~with toOP-3136 ~~our~~including ~~business~~prifetrastat and PF-08032562, which are being developed by Pfizer, MEN2312 being developed by Stemline Therapeutics, and BG-75202 being developed by BeOne Medicines.

WeGovernment alsoRegulation seek to protect our intellectual property, including our trade secrets and know-how,Product in part by entering into confidentiality agreements with companies with whom we share proprietary and confidential information in the course of business discussions, and by having confidentiality terms in our agreements with our employees, consultants, scientific advisors, clinical investigators and other contractors and also by requiring our employees, commercial contractors, and certain consultants and investigators, to enter into invention assignment agreements that grant us ownership of any discoveries or inventions made by them while in our employ. However, trade secrets and know-how can be difficult to protect. We cannot guarantee that we have entered into such agreements with each party that may have or have had access to our trade secrets or proprietary technology and processes or that these agreements will afford us adequate protection of our intellectual property and proprietary rights. Despite these efforts, any of these parties may breach the agreements and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. For information regarding risks related to intellectual property, see the section titled “Risk Factors—Risks Related to Our Intellectual Property.”Approval

~~Sales~~As a biopharmaceutical company that operates in the United States, we are subject to extensive regulation. Government authorities in the United States (at the federal, state and ~~Marketing~~local level) and in other countries extensively regulate, among other things, the research, development, testing, manufacturing, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug products such as those we are developing. Any drug candidates that we develop must be approved by the FDA before they may be legally marketed in the United States and by the appropriate foreign regulatory agency before they may be legally marketed in foreign countries. Generally, our activities in other countries will be subject to regulation that is similar in nature and scope as that imposed in the United States, although there can be important differences. Additionally, some significant aspects of regulation in Europe are addressed in a centralized way, but country-specific regulation remains essential in many respects.

Given our stage of development, we have not yet established a commercial organization or distribution capabilities. We intend to build a commercial infrastructure to support sales of any approved products. We 32

29Table of Contents

~~Table~~U.S. ofdrug ~~Contents~~development process

~~intend~~In tothe ~~continue~~United ~~evaluating~~States, ~~opportunities~~the toFDA ~~work~~regulates ~~with~~drugs ~~partners~~under ~~that~~the ~~enhance~~Federal ~~our~~Food, ~~capabilities~~Drug ~~with~~and ~~respect~~Cosmetic Act (FDCA), and implementing regulations. Drugs are also subject to ~~the~~other ~~development~~federal, state and ~~commercialization~~local ofstatutes ~~palazestrant~~and regulations. InThe ~~addition~~process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, westate, ~~intend~~local and foreign statutes and regulations require the expenditure of substantial time and financial resources. Failure to ~~commercialize~~comply ~~our~~with the applicable U.S. requirements at any time during the product ~~candidates~~development process, ifapproval ~~approved~~process or after approval, inmay ~~key~~subject ~~markets~~an ~~either~~applicant ~~alone~~to administrative or ~~with~~judicial ~~partners~~sanctions. inFDA ~~order~~sanctions could include, among other actions, refusal to ~~maximize~~approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls or withdrawals from the ~~worldwide~~market, ~~commercial~~product ~~potential~~seizures, total or partial suspension of ~~our~~production ~~programs~~or distribution injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us. The process required by the FDA before a drug may be marketed in the United States generally involves the following:

•

~~Manufacturing~~completion of extensive non-clinical laboratory tests, non-clinical animal studies and formulation studies in accordance with applicable regulations, including the FDA’s Good Laboratory Practices, or GLP, regulations and other applicable regulations;

•

Wesubmission ~~currently do not own or operate any manufacturing facilities. We rely, and expect~~ to ~~continue to rely for~~ the ~~foreseeable~~FDA ~~future,~~of onan ~~third-party~~investigational ~~contract~~new ~~manufacturing~~drug ~~organizations~~application (~~CMOs~~IND), towhich ~~produce~~must ~~palazestrant~~become ~~for~~effective ~~non-clinical~~before ~~and~~human clinical ~~testing,~~trials asmay well as for commercial manufacture if palazestrant receives marketing approval. We require that our CMOs produce bulk drug substances and finished drug products in accordance with current Good Manufacturing Practices (cGMPs) and all other applicable laws and regulations. We maintain agreements with our manufacturers that include confidentiality and intellectual property provisions to protect our proprietary rights related to palazestrant.begin;

•

Weapproval ~~have~~by ~~engaged~~an ~~CMOs~~independent toinstitutional ~~manufacture~~review ~~and~~board ~~package~~(IRB) ~~palazestrant~~at ~~for~~each ~~non-~~clinical ~~and~~site ~~clinical~~before ~~use.~~each ~~Additional~~trial CMOs are used to label and distribute palazestrant for clinical use. We obtain our supplies from these CMOs on a purchase order basis and do not have long-term supply arrangements in place. Although we do not currently have contractual arrangements in place for redundant supply for palazestrant, it is our goal to identify and contract with at least two manufacturers for active pharmaceutical ingredient and two manufacturers for drug product. More broadly, for palazestrant and any other product candidates we may ~~develop,~~be ~~we intend to identify and qualify additional manufacturers to provide the active pharmaceutical ingredient and fill-and-finish services prior to seeking regulatory approval.~~initiated;

•

~~Competition~~performance of adequate and well-controlled human clinical trials in accordance with applicable regulations, including the FDA’s current good clinical practice (GCP) regulations to establish the safety and efficacy of the proposed drug for its proposed indication;

•

~~The~~submission ~~biotechnology~~to ~~and~~the ~~pharmaceutical~~FDA ~~industries~~of ~~are~~a ~~characterized~~New byDrug ~~rapid~~Application ~~technological~~(NDA) ~~advancement,~~for ~~significant~~a competition and an emphasis on intellectual property. We face potential competition from many different sources, including major and specialty pharmaceutical and biotechnology companies, academic research institutions, governmental agencies and public and private research institutions. Any product candidates that we successfully develop and commercialize will compete with current therapies and new ~~therapies that may become available in the future.~~drug;

•

~~Many~~a ofdetermination ~~the~~by companies against which we may compete have significantly greater financial resources and expertise in research and development, manufacturing, non-clinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. Mergers and acquisitions in the ~~pharmaceutical,~~FDA ~~biotechnology~~within ~~and~~60 ~~oncology~~days ~~industries~~of ~~may~~its ~~result~~receipt ~~in even more resources being concentrated among a smaller number~~ of ~~our~~an ~~competitors.~~NDA ~~Smaller or early-stage companies may also prove~~ to befile ~~significant~~the ~~competitors,~~NDA particularly through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for ~~clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.~~review;

•

~~Our~~satisfactory ~~commercial~~completion ~~opportunity~~of ~~could~~an beFDA ~~reduced~~pre-approval orinspection ~~eliminated~~of ifthe ~~our~~manufacturing ~~competitors~~facility ~~develop and commercialize products that are safer, more effective, have fewer~~ or ~~less~~facilities ~~severe~~where ~~side~~the ~~effects,~~drug ~~are~~is ~~more~~produced ~~convenient~~to orassess ~~less~~compliance ~~expensive~~with ~~than~~the ~~any products we may develop. Our competitors also may obtain~~ FDA’s orcurrent ~~other~~good ~~regulatory~~manufacturing ~~approval~~practice ~~for~~(cGMP) ~~their~~requirements ~~product~~to ~~candidates~~assure ~~more~~that ~~rapidly~~the ~~than we may obtain approval for ours~~facilities, ~~which~~methods ~~could~~and ~~result~~controls ~~in competitors establishing a strong market position before we~~ are ~~able~~adequate to ~~enter~~preserve the ~~market.~~drug’s ~~We believe that the key competitive factors affecting the success of any of our product candidates~~identity, ~~if approved~~strength, ~~will~~quality ~~include efficacy, combinability, safety profile, convenience, cost, level of promotional activity devoted to them~~ and ~~intellectual property protection.~~purity;

•

Ifpotential ~~the~~FDA ~~product~~audit ~~candidates~~of ~~for our priority programs are approved for~~ the ~~indications~~non-clinical weand/or ~~are~~clinical ~~currently~~trial ~~targeting,~~sites ~~they~~that ~~will~~generated ~~compete with~~ the ~~products~~data ~~discussed below. Furthermore, it is possible that other companies are also engaged~~ in ~~discovery~~support ~~or non-clinical development~~ of ~~product candidates for~~ the ~~same indications. These~~ NDA;

•

30satisfactory completion of an FDA advisory committee review, if applicable; and

•

~~Table~~FDA review and approval of ~~Contents~~the NDA prior to any commercial marketing or sale of the drug in the United States.

competitors, if successful in clinical development, may achieve regulatory approval and market adoption in advance of our product candidates, constraining our ability to gain significant market share for such product candidates. In addition, our product candidates, if approved, will complete with multiple approved products or products that may be approved for future indications for which we develop such product candidate.33

~~There~~Table ~~are several currently marketed drugs and product candidates currently in development for the treatment~~ of ER+ breast cancer that target the estrogen receptor that may compete with palazestrant including: fulvestrant, marketed as Faslodex® by AstraZeneca PLC and or any generic equivalents of Faslodex that are marketed or in development; elacestrant, marketed as ORSERDUTM by Stemline Therapeutics Inc.; giredestrant (GDC-9545), being developed by Roche Holding AG/Genentech, Inc.; camizestrant (AZD9833), being developed by AstraZeneca PLC; imlunestrant (LY3484356), being developed by Eli Lilly and Co.; vepdegestrant (ARV‑471), being developed by Arvinas, Inc. in partnership with Pfizer, Inc.; and lasofoxifene, being developed by Sermonix Pharmaceuticals. There are a number of KAT6 inhibitor product candidates in development that may compete with OP-3136 including PF-07248144, which is being developed by Pfizer.Contents

~~Government~~Before ~~Regulation~~testing any compounds with potential therapeutic value in humans, the drug candidate enters the non-clinical testing stage. Non-clinical tests include laboratory evaluations of product chemistry, toxicity and ~~Product~~formulation, ~~Approval~~as well as animal studies, to assess the characteristics and potential safety and activity of the drug candidate. The conduct of the non-clinical tests must comply with federal regulations and requirements including GLPs. The sponsor must submit the results of the non-clinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. An IND is a request for authorization from the FDA to administer an investigational drug product to humans. The central focus of an IND submission is on the general investigational plan and the protocol(s) for human trials. Some non-clinical testing may continue even after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the proposed clinical trials and places the IND on clinical hold within that 30 day time period. 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. The FDA may also impose clinical holds on a drug candidate at any time before or during clinical trials due to safety concerns or non-compliance.

AsFor aeach ~~biopharmaceutical~~successive ~~company~~clinical ~~that~~trial ~~operates~~conducted inwith the ~~United~~investigational ~~States~~drug, wea ~~are~~separate, ~~subject~~new toprotocol ~~extensive~~submission ~~regulation.~~to ~~Government~~an ~~authorities~~existing inIND ~~the~~must ~~United~~be ~~States (at the federal~~made, ~~state~~along ~~and~~with ~~local~~any ~~level)~~subsequent ~~and~~changes into ~~other countries extensively regulate, among other things,~~ the ~~research,~~investigational ~~development,~~plan. ~~testing,~~Sponsors ~~manufacturing,~~are ~~quality~~also ~~control,~~subject ~~approval,~~to ~~labeling,~~ongoing ~~packaging,~~reporting ~~storage~~requirements, ~~record-keeping,~~including ~~promotion,~~submission ~~advertising, distribution, post-approval monitoring and reporting, marketing and export and import~~ of ~~drug~~IND ~~products~~safety ~~such~~reports asfor ~~those~~any weserious ~~are~~adverse ~~developing.~~experiences ~~Any~~associated ~~drug~~with ~~candidates~~use ~~that~~of ~~we develop must be approved by~~ the ~~FDA~~investigational ~~before~~drug ~~they~~or ~~may~~findings befrom ~~legally~~non-clinical ~~marketed~~studies insuggesting ~~the~~a ~~United~~significant ~~States~~risk ~~and~~for byhuman ~~the appropriate foreign regulatory agency before they may be legally marketed in foreign countries. Generally~~subjects, ~~our~~as ~~activities~~well ~~in other countries will be subject to regulation that is similar in nature and scope~~ as ~~that~~IND ~~imposed~~annual inreports on the ~~United~~progress ~~States, although there can be important differences. Additionally, some significant aspects~~ of ~~regulation~~the ininvestigations ~~Europe~~conducted ~~are~~under ~~addressed~~the ~~in a centralized way, but country-specific regulation remains essential in many respects~~IND.

UClinical trials involve the administration of the drug candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.S Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy. ~~drug~~Each ~~development~~protocol, ~~process~~and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND. Further, each clinical trial must be reviewed and approved by an IRB, at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. There are also requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.

InHuman ~~the~~clinical ~~United~~trials ~~States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (FDCA), and implementing regulations. Drugs~~ are ~~also~~typically ~~subject~~conducted toin ~~other~~three ~~federal,~~sequential ~~state~~phases ~~and~~that local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require 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 after approval, may ~~subject~~overlap ~~an applicant to administrative~~ or judicial sanctions. FDA sanctions could include, among other actions, refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls or withdrawals from the market, product seizures, total or partial suspension of production or distribution injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us. The process required by the FDA before a drug may be ~~marketed in the United States generally involves the following~~combined:

•

~~completion~~Phase of1. ~~extensive~~The ~~non-clinical~~drug ~~laboratory~~is ~~tests~~initially introduced into healthy human subjects and tested for safety, ~~non-clinical~~dosage ~~animal~~tolerance, ~~studies~~absorption, metabolism, distribution and ~~formulation~~excretion, ~~studies~~the inside ~~accordance~~effects associated with ~~applicable~~increasing ~~regulations~~doses and if possible, ~~including~~to gain early evidence of effectiveness. In the ~~FDA’s~~case ~~Good~~of ~~Laboratory~~some ~~Practices,~~products for severe or ~~GLP~~life-threatening diseases, ~~regulations~~especially ~~and~~when ~~other~~the ~~applicable~~product ~~regulations;~~may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.

•

~~submission~~Phase 2. The drug is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the ~~FDA~~efficacy of anthe ~~investigational~~product ~~new~~for ~~drug~~specific ~~application~~targeted ~~(IND),~~diseases ~~which~~or ~~must~~conditions ~~become~~and ~~effective~~to ~~before~~determine ~~human~~dosage ~~clinical~~tolerance, ~~trials~~optimal ~~may~~dosage ~~begin;~~and dosing schedule.

•

~~approval~~Phase by3. anClinical ~~independent~~trials ~~institutional~~are ~~review~~undertaken ~~board~~to ~~(IRB)~~further atevaluate ~~each~~dosage, clinical ~~site~~efficacy ~~before~~and ~~each~~safety in an expanded patient population at geographically dispersed clinical trial ~~may~~sites. beThese ~~initiated;~~clinical trials are intended to establish the overall benefit/risk ratio of the product and provide an adequate basis for product approval. Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA.

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Table of Contents

~~performance~~Post-approval ofstudies ~~adequate~~(Phase ~~and~~4 ~~well-controlled~~clinical ~~human~~trials) ~~clinical~~may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in ~~accordance~~the ~~with~~intended ~~applicable~~therapeutic ~~regulations,~~indication. ~~including~~In certain instances, the FDA’s ~~current~~may ~~good~~mandate ~~clinical~~the ~~practice~~performance ~~(GCP)~~of ~~regulations~~Phase to4 ~~establish~~trials. In certain instances, the ~~safety~~FDA ~~and~~may ~~efficacy~~mandate the performance of ~~the~~Phase ~~proposed~~4 ~~drug~~clinical ~~for~~trials ~~its~~as ~~proposed~~a ~~indication;~~condition of approval of an NDA.

~~submission~~Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA ofand awritten ~~New~~IND ~~Drug~~safety ~~Application~~reports ~~(NDA)~~must be submitted to the FDA and the investigators for serious and unexpected adverse events or any finding from tests in laboratory animals that suggests a ~~new~~significant ~~drug;~~risk for human subjects.

aPhase ~~determination~~1, byPhase ~~the~~2 ~~FDA~~and Phase 3 clinical trials may not be completed successfully within 60any ~~days~~specified ofperiod, ~~its~~if ~~receipt~~at ofall. anThe ~~NDA~~FDA, tothe ~~file~~IRB, or the ~~NDA~~sponsor ~~for~~may ~~review;~~suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.

~~satisfactory~~Similarly, ~~completion~~an ofIRB ancan ~~FDA~~suspend ~~pre-approval~~or ~~inspection~~terminate approval of ~~the~~a ~~manufacturing~~clinical ~~facility~~trial orat ~~facilities~~its ~~where~~institution if the ~~drug~~clinical trial is ~~produced~~not tobeing ~~assess~~conducted ~~compliance~~in accordance with the ~~FDA~~IRB’s ~~current~~requirements ~~good~~or ~~manufacturing~~if ~~practice~~the ~~(cGMP)~~drug ~~requirements~~has tobeen ~~assure~~associated ~~that~~with ~~the~~unexpected ~~facilities~~serious harm to patients. Additionally, ~~methods~~some ~~and~~clinical ~~controls~~trials are ~~adequate~~overseen toby ~~preserve~~an independent group of qualified experts organized by the ~~drug’s~~clinical ~~identity,~~trial ~~strength~~sponsor, ~~quality~~known ~~and~~as ~~purity;~~a data safety monitoring board or committee. This group assesses whether or not a trial may move forward at designated check points based on access to certain data from the ongoing trial.

~~potential~~Concurrent ~~FDA~~with ~~audit~~clinical oftrials, companies usually complete additional animal studies and must also develop additional information about the ~~non-clinical~~chemistry and~~/or~~ ~~clinical~~physical ~~trial~~characteristics ~~sites~~of ~~that~~the ~~generated~~drug as well as finalize a process for manufacturing the ~~data~~product in ~~support~~commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the ~~NDA;~~drug candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final drug. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

~~satisfactory~~U.S. ~~completion of an FDA advisory committee~~ review, ifand ~~applicable;~~approval ~~and~~processes

~~FDA~~Assuming ~~review~~successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, non-clinical studies and ~~approval~~clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA ~~prior~~requesting approval to ~~any~~market ~~commercial~~the ~~marketing~~product. Data may come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or ~~sale~~from a number of alternative sources, including studies initiated by investigators. To support marketing approval, the ~~drug~~data submitted must be sufficient in quality and quantity to establish the ~~United~~safety ~~States~~and effectiveness of the investigational drug product to the satisfaction of the FDA. The submission of an NDA is subject to the payment of substantial user fees; a waiver of such fees may be obtained under certain limited circumstances.

Before testing any compounds with potential therapeutic value in humans, the drug candidate enters the non-clinical testing stage. Non-clinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies, to assess the characteristics and potential safety and activity of the drug candidate. The conduct of the non-clinical tests must comply with federal regulations and requirements including GLPs. The sponsor must submit the results of the non-clinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. An IND is a request for authorization from the FDA to administer an investigational drug product to humans. The central focus of an IND submission is on the general investigational plan and the protocol(s) for human trials. Some non-clinical testing may continue even after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the proposed clinical trials and places the IND on clinical hold within that 30 day time period. 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. The FDA may also impose clinical holds on a drug candidate at any time before or during clinical trials due to safety concerns or non-compliance.35

~~For~~Table each successive clinical trial conducted with the investigational drug, a separate, new protocol submission to an existing IND must be made, along with any subsequent changes to the investigational plan. Sponsors are also subject to ongoing reporting requirements, including submission of IND safety reports for any serious adverse experiences associated with use of the investigational drug or findings from non-clinical studies suggesting a significant risk for human subjects, as well as IND annual reports on the progress of the investigations conducted under the IND.Contents

~~Clinical~~In ~~trials~~addition, ~~involve~~ the ~~administration~~Pediatric ofResearch ~~the~~Equity ~~drug~~Act ~~candidate~~(PREA) torequires ~~healthy~~a ~~volunteers~~sponsor orto ~~patients~~conduct ~~under~~pediatric ~~the~~clinical ~~supervision~~trials offor ~~qualified~~most ~~investigators~~drugs, ~~generally~~for ~~physicians~~a ~~not~~new ~~employed~~active byingredient, ornew ~~under~~indication, ~~the~~new ~~trial~~dosage ~~sponsor’s control~~form, innew ~~accordance~~dosing ~~with~~regimen ~~GCPs,~~or ~~which~~new ~~include~~route ~~the~~of ~~requirement~~administration. ~~that~~Under ~~all~~PREA, ~~research~~original ~~subjects~~NDAs ~~provide~~and ~~their~~supplements ~~informed~~must ~~consent~~contain ~~for~~a ~~their~~pediatric ~~participation~~assessment inunless ~~any~~the ~~clinical~~sponsor ~~trial.~~has ~~Clinical~~received ~~trials~~a ~~are~~deferral ~~conducted~~or ~~under~~waiver. ~~protocols~~The ~~detailing,~~required ~~among~~assessment ~~other~~must ~~things,~~evaluate the ~~objectives~~safety and effectiveness of the ~~clinical~~product ~~trial,~~in ~~dosing~~all ~~procedures,~~relevant ~~subject~~pediatric ~~selection~~subpopulations and ~~exclusion~~support ~~criteria~~dosing and ~~the~~administration ~~parameters~~for toeach bepediatric ~~used~~subpopulation tofor ~~monitor~~which ~~subject~~the ~~safety~~product ~~and~~is ~~assess~~safe ~~efficacy~~and effective. ~~Each~~The ~~protocol,~~sponsor ~~and~~or ~~any~~FDA ~~subsequent~~may ~~amendments~~request toa ~~the~~deferral ~~protocol,~~of ~~must~~pediatric beclinical ~~submitted~~trials tofor ~~the~~some ~~FDA~~or asall ~~part~~ of the ~~IND~~pediatric subpopulations. ~~Further~~A deferral may be granted for several reasons, ~~each~~including ~~clinical~~a ~~trial~~finding ~~must~~that bethe ~~reviewed~~drug ~~and~~is ~~approved~~ready byfor anapproval ~~IRB,~~for atuse in adults before pediatric clinical trials are complete or ~~servicing~~that ~~each~~additional ~~institution~~safety ator ~~which~~effectiveness data needs to be collected before the pediatric clinical ~~trial~~trials ~~will~~begin. beThe ~~conducted.~~FDA Anmust ~~IRB~~send isa ~~charged~~non-compliance ~~with~~letter ~~protecting~~to ~~the~~any ~~welfare~~sponsor ~~and~~that ~~rights~~fails ofto ~~trial~~submit ~~participants~~the ~~and~~required ~~considers~~assessment, ~~such~~keep ~~items~~a asdeferral ~~whether~~current ~~the~~or ~~risks~~fails to ~~individuals~~submit ~~participating~~a inrequest ~~the~~for ~~clinical~~approval ~~trials~~of ~~are~~a ~~minimized~~pediatric ~~and~~formulation. ~~are~~Unless ~~reasonable~~otherwise inrequired ~~relation~~by regulation, the PREA does not apply to ~~anticipated~~any ~~benefits.~~drug ~~The~~for ~~IRB~~an ~~also~~indication ~~approves~~for ~~the~~which ~~informed~~orphan ~~consent~~designation ~~form~~has ~~that~~been ~~must~~granted. beHowever, ~~provided~~if toonly ~~each~~one ~~clinical~~indication ~~trial~~for ~~subject~~a orproduct ~~his~~has ororphan ~~her~~designation, ~~legal~~a ~~representative~~pediatric ~~and~~assessment ~~must~~may ~~monitor~~still ~~the~~be ~~clinical~~required ~~trial~~for ~~until~~any ~~completed.~~applications ~~There~~to ~~are~~market ~~also~~that same product for the non-orphan indication(s).

32The FDA reviews all NDAs submitted before it accepts them for filing and may request additional information rather than accepting an NDA for filing. The FDA must make a decision on accepting an NDA for filing within 60 days of receipt. Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA. Under the Prescription Drug User Fee Act (PDUFA) guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission. This review typically takes twelve months from the date the NDA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision after it the application is submitted The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often significantly extended by FDA requests for additional information or clarification.

~~Table~~After the NDA submission is accepted for filing, the FDA reviews the NDA to determine, among other things, whether the proposed product is safe and effective for its intended use and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality and purity. The FDA may refer applications for novel drug products or drug products which present difficult questions of ~~Contents~~safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions and typically follows the advisory committee’s recommendations.

Before approving an NDA, the FDA will inspect the facilities at which the product is manufactured. The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements ~~governing~~and adequate to assure consistent production of the ~~reporting~~product within required specifications. Additionally, before approving an NDA, the FDA may inspect one or more clinical sites to assure compliance with GCP requirements. After the FDA evaluates the application, manufacturing process and manufacturing facilities, it may issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of ~~ongoing~~the drug with specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form. A Complete Response Letter usually describes all of the specific deficiencies in the NDA identified by the FDA. The Complete Response Letter may require additional clinical ~~trials~~data and/or ~~completed~~(an) additional pivotal Phase 3 clinical trial(s), ~~results~~and/or other significant and time-consuming requirements related to ~~public~~clinical ~~registries~~trials, non-clinical studies or manufacturing. If a Complete Response Letter is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information is submitted, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval.

~~Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:~~36

~~Phase~~Table 1. The drug is initially introduced into healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution and excretion, the side effects associated with increasing doses and if possible, to gain early evidence of effectiveness. In the case of some products for severe or life-threatening diseases, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.Contents

~~Phase~~If 2a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. ~~The~~Further, ~~drug~~the isFDA ~~evaluated~~may require that certain contraindications, warnings or precautions be included in the product labeling or may condition the approval of the NDA on other changes to the proposed labeling, development of adequate controls and specifications, or a ~~limited~~commitment ~~patient~~to ~~population~~conduct one or more post-market studies or clinical trials. For example, the FDA may require Phase 4 testing, which involves clinical trials designed to ~~identify~~further ~~possible~~assess ~~adverse~~a ~~effects~~drug safety and effectiveness and may require testing and surveillance programs to monitor the safety ~~risks,~~of approved products that have been commercialized. The FDA may also determine that a risk evaluation and mitigation strategy (REMS) is necessary to ~~preliminarily~~assure ~~evaluate~~the safe use of the ~~efficacy~~drug. If the FDA concludes a REMS is needed, the sponsor of the ~~product~~NDA ~~for~~must ~~specific~~submit ~~targeted~~a ~~diseases~~proposed orREMS; ~~conditions~~the ~~and~~FDA will not approve the NDA without an approved REMS, if required. A REMS could include medication guides, physician communication plans, or elements to ~~determine~~assure ~~dosage~~safe ~~tolerance~~use, ~~optimal~~such ~~dosage~~as restricted distribution methods, patient registries and ~~dosing~~other ~~schedule~~risk minimization tools.

~~Phase~~Expedited 3.development ~~Clinical trials are undertaken to further evaluate dosage, clinical efficacy~~ and ~~safety~~review in an expanded patient population at geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall benefit/risk ratio of the product and provide an adequate basis for product approval. Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA.programs

~~Post-approval~~The ~~studies~~FDA ~~(Phase~~has 4a ~~clinical~~Fast ~~trials)~~Track ~~may~~designation beprogram ~~conducted~~that ~~after~~is ~~initial~~intended ~~marketing~~to ~~approval~~expedite or facilitate the process for reviewing new drug products that meet certain criteria. ~~These~~Specifically, ~~trials~~new drugs are ~~used~~eligible for Fast Track designation if they are intended to ~~gain~~treat ~~additional~~a ~~experience~~serious ~~from~~or life-threatening disease or condition and demonstrate the ~~treatment~~potential ofto ~~patients~~address inunmet medical needs for the ~~intended~~disease ~~therapeutic~~or ~~indication~~condition. InUnique ~~certain~~to ~~instances~~a Fast Track product, the FDA may ~~mandate~~consider ~~the~~for ~~performance~~review sections of ~~Phase~~the 4NDA ~~trials.~~on Ina ~~certain~~rolling ~~instances~~basis before the complete application is submitted, if the ~~FDA~~sponsor ~~may~~provides ~~mandate~~a schedule for the ~~performance~~submission of ~~Phase~~the 4sections ~~clinical~~of ~~trials~~the asNDA, athe ~~condition~~FDA agrees to accept sections of ~~approval~~the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of anthe first section of the NDA.

~~Progress~~Any ~~reports~~product ~~detailing~~submitted to the ~~results~~FDA offor ~~the~~approval, ~~clinical~~including ~~trials~~a ~~must~~product with a Fast Track designation, may also be ~~submitted~~eligible atfor ~~least~~other ~~annually~~types of FDA programs intended to ~~the~~expedite ~~FDA~~development and ~~written~~review, ~~IND~~such ~~safety~~as ~~reports~~priority ~~must~~review beand ~~submitted~~accelerated toapproval. A product is eligible for priority review if it has the ~~FDA~~potential to provide safe and ~~the~~effective ~~investigators~~therapy for a serious ~~and~~condition ~~unexpected~~where ~~adverse~~no ~~events~~satisfactory oralternative ~~any~~therapy ~~finding~~exists ~~from~~or ~~tests~~a significant improvement in ~~laboratory~~the ~~animals~~treatment, ~~that~~diagnosis ~~suggests~~or prevention of a ~~significant~~serious ~~risk~~condition compared to marketed products. The FDA will attempt to direct additional resources to the evaluation of an application for ~~human~~a ~~subjects~~new drug designated for priority review in an effort to facilitate the review.

~~Phase~~In 1addition, ~~Phase~~a 2product ~~and~~may ~~Phase~~be 3eligible ~~clinical~~for ~~trials~~accelerated approval. Drug products intended to treat serious or life- threatening diseases or conditions may ~~not~~be eligible for 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 ~~completed~~measured ~~successfully~~earlier ~~within~~than ~~any~~irreversible ~~specified~~morbidity ~~period~~or mortality, ifthat atis ~~all.~~reasonably ~~The~~likely ~~FDA~~to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the ~~IRB~~severity, rarity, or prevalence of the ~~sponsor~~condition ~~may~~and ~~suspend~~the availability or ~~terminate~~lack of alternative treatments. As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post- marketing clinical ~~trial~~trials. atIn ~~any~~addition, ~~time~~the onFDA ~~various~~currently ~~grounds~~requires, ~~including~~as a ~~finding~~condition ~~that~~for accelerated approval, pre-approval of promotional materials, which could adversely impact the ~~research~~timing ~~subjects~~of orthe ~~patients~~commercial ~~are~~launch ~~being~~of ~~exposed~~the toproduct. anFast ~~unacceptable~~Track ~~health~~designation, ~~risk~~priority review and accelerated approval do not change the standards for approval but may expedite the development or approval process.

~~Similarly,~~Even anif ~~IRB~~a ~~can~~product ~~suspend~~qualifies orfor ~~terminate~~one ~~approval~~or more of athese ~~clinical~~programs, ~~trial at its institution if~~ the ~~clinical~~FDA ~~trial~~may islater ~~not~~decide ~~being~~that ~~conducted in accordance with~~ the ~~IRB’s~~product ~~requirements~~no orlonger ifmeets the ~~drug~~conditions ~~has~~for ~~been~~qualification ~~associated~~or ~~with~~decide ~~unexpected~~that ~~serious harm to patients. Additionally, some clinical trials are overseen by an independent group of qualified experts organized by~~ the ~~clinical~~time ~~trial~~period ~~sponsor,~~for ~~known~~FDA asreview aor ~~data~~approval ~~safety~~will ~~monitoring~~not ~~board~~be ~~or committee~~shortened. ~~This~~In ~~group~~addition, ~~assesses~~this ~~whether~~designation ormay not provide a ~~trial~~material ~~may~~commercial ~~move forward at designated check points based on access to certain data from the ongoing trial~~advantage.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as 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 drug candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final drug. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.37

~~U.S.~~Table ~~review~~of ~~and approval processes~~Contents

~~Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, non~~Post-~~clinical~~approval ~~studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and~~ requirements

33Any drug products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, and complying with FDA promotion and advertising requirements, which include, among others, standards for direct- to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet. Although physicians may prescribe legally available drugs for off-label uses, manufacturers may not market or promote such off-label uses.

~~Table~~In addition, quality control and manufacturing procedures must continue to conform to applicable manufacturing requirements after approval to ensure the long-term stability of ~~Contents~~the drug product. We rely, and expect to continue to rely, on third parties for the production of clinical and commercial quantities of our products in accordance with cGMP regulations. cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP. Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs 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 cGMP and other laws. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance. Discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved NDA, including, among other things, recall or withdrawal of the product from the market. In addition, changes to the manufacturing process are strictly regulated, and depending on the significance of the change, may require prior FDA approval before being implemented. Other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval.

~~other~~The ~~relevant~~FDA ~~information~~also ~~are~~may ~~submitted~~require topost-marketing ~~the~~testing, ~~FDA~~known as ~~part~~Phase of4 antesting, ~~NDA~~and ~~requesting~~surveillance ~~approval~~ to ~~market~~monitor the effects of an approved product. ~~Data~~Discovery ~~may~~of ~~come~~previously ~~from~~unknown ~~company-sponsored~~problems ~~clinical~~with ~~trials~~a ~~intended~~product or the failure to ~~test~~comply ~~the~~with ~~safety~~applicable ~~and~~FDA ~~effectiveness~~requirements ofcan ahave ~~use~~negative ofconsequences, aincluding ~~product~~adverse publicity, judicial or ~~from~~administrative aenforcement, ~~number~~warning ofletters ~~alternative~~from ~~sources~~the FDA, ~~including~~mandated ~~studies~~corrective ~~initiated~~advertising byor ~~investigators.~~communications Towith ~~support~~doctors, ~~marketing~~and ~~approval~~civil or criminal penalties, ~~the~~among ~~data~~others. ~~submitted~~Newly ~~must~~discovered beor ~~sufficient~~developed insafety ~~quality~~or ~~and~~effectiveness ~~quantity~~data may require changes to ~~establish~~a ~~the~~product’s ~~safety~~approved ~~and~~labeling, ~~effectiveness~~including the addition of ~~the~~new ~~investigational~~warnings ~~drug~~and ~~product~~contraindications, toand also may require the ~~satisfaction~~implementation of ~~the~~other ~~FDA.~~risk ~~The~~management ~~submission~~measures. ofAlso, annew ~~NDA~~government isrequirements, ~~subject~~including tothose ~~the~~resulting ~~payment~~from ofnew ~~substantial~~legislation, ~~user~~may ~~fees;~~be aestablished, ~~waiver~~or ofthe ~~such~~FDA’s ~~fees~~policies may bechange, ~~obtained~~which ~~under~~could ~~certain~~delay ~~limited~~or ~~circumstances~~prevent regulatory approval of our products under development.

In addition, the Pediatric Research Equity Act (PREA) requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration. Under PREA, original NDAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver. The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The sponsor or FDA may request a deferral of pediatric clinical trials for some or all of the pediatric subpopulations. A deferral may be granted for several reasons, including a finding that the drug is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric clinical trials begin. The FDA must send a non-compliance letter to any sponsor that fails to submit the required assessment, keep a deferral current or fails to submit a request for approval of a pediatric formulation. Unless otherwise required by regulation, the Pediatric Research Equity Act does not apply to any drug for an indication for which orphan designation has been granted. However, if only one indication for a product has orphan designation, a pediatric assessment may still be required for any applications to market that same product for the non-orphan indication(s).38

~~The~~Table FDA reviews all NDAs submitted before it accepts them for filing and may request additional information rather than accepting an NDA for filing. The FDA must make a decision on accepting an NDA for filing within 60 days of receipt. Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA. Under the Prescription Drug User Fee Act (PDUFA) guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission. This review typically takes twelve months from the date the NDA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision after it the application is submitted The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often significantly extended by FDA requests for additional information or clarification.Contents

After the NDA submission is accepted for filing, the FDA reviews the NDA to determine, among other things, whether the proposed product is safe and effective for its intended use and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality and purityU. The FDA may refer applications for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditionsS. ~~The~~patent ~~FDA~~term isrestoration ~~not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions~~ and ~~typically~~marketing ~~follows the advisory committee’s recommendations.~~exclusivity

~~Before~~Depending ~~approving~~upon anthe ~~NDA~~timing, ~~the~~duration ~~FDA~~and ~~will~~specifics ~~inspect~~of the ~~facilities~~FDA atapproval ~~which~~of the use of our product iscandidates, ~~manufactured~~some of our U.S. ~~The~~patents, ~~FDA~~if ~~will~~granted, ~~not~~may ~~approve~~be eligible for limited PTE under the ~~product~~Drug ~~unless~~Price itCompetition ~~determines~~and ~~that~~Patent Term Restoration Act of 1984, commonly referred to as the ~~manufacturing~~Hatch-Waxman ~~processes~~Amendments. ~~and~~As ~~facilities~~compensation ~~are~~for inpatent ~~compliance~~term ~~with~~lost ~~cGMP~~during ~~requirements~~product development and ~~adequate~~the toFDA ~~assure~~regulatory ~~consistent~~review ~~production~~process, of the ~~product~~Hatch-Waxman ~~within~~Amendments ~~required~~permit ~~specifications.~~a ~~Additionally~~patent restoration term (PTE), ~~before~~which ~~approving~~is anlimited ~~NDA~~to a maximum of five years, or less if the ~~FDA~~extended ~~may~~patent ~~inspect~~term ~~one~~would orexceed ~~more~~14 ~~clinical~~years ~~sites~~after tothe ~~assure~~date ~~compliance~~of ~~with~~the ~~GCP~~regulatory ~~requirements~~approval of the product. ~~After~~The patent term restoration period is generally one-half the ~~FDA~~time ~~evaluates~~between the ~~application,~~effective ~~manufacturing~~date ~~process~~of an IND and ~~manufacturing~~the ~~facilities,~~submission itdate ~~may~~of ~~issue~~an NDA plus the time between the submission date of an ~~approval~~NDA ~~letter~~and orthe aapproval ~~Complete~~of ~~Response~~that ~~Letter~~application. AnOnly ~~approval~~one ~~letter~~patent ~~authorizes~~applicable ~~commercial~~to ~~marketing~~an ofapproved ~~the~~drug or drug ~~with~~product, ~~specific~~or ~~prescribing~~its ~~information~~approved ~~for~~use, ~~specific~~is ~~indications.~~eligible Afor ~~Complete~~the ~~Response~~extension ~~Letter~~and ~~indicates~~the ~~that~~application for the ~~review~~extension ~~cycle~~must be submitted prior to the expiration of the ~~application~~patent. isThe ~~complete~~U.S. Patent and Trademark Office, in consultation with the ~~application~~FDA, ~~will~~reviews ~~not~~and beapproves ~~approved~~the inapplication ~~its~~for ~~present~~any ~~form~~patent term extension or restoration. AIn ~~Complete~~the ~~Response~~future, ~~Letter~~we ~~usually~~may ~~describes~~intend ~~all~~to apply for restoration of a patent term for one of our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the ~~specific~~expected ~~deficiencies~~length of the clinical trials and other factors involved in the filing of the relevant NDA. ~~identified~~However, bywe may not receive an extension if we fail to exercise due diligence during the ~~FDA.~~testing ~~The~~phase ~~Complete~~or ~~Response~~regulatory ~~Letter~~review ~~may~~process, ~~require~~fail ~~additional~~to ~~clinical~~apply ~~data~~within ~~and/~~applicable deadlines, fail to apply prior to expiration of relevant patents or ~~(an)~~otherwise ~~additional~~fail ~~pivotal~~to ~~Phase~~satisfy 3applicable ~~clinical~~requirements. ~~trial(s)~~Moreover, ~~and/~~the length of the extension could be less than we request. There can be no assurance that we will benefit from any PTE or ~~other~~favorable ~~significant~~adjustment ~~and~~to ~~time-consuming~~the term of any of our patents.

34Market exclusivity provisions under the FDCA can also delay the submission or the approval of certain marketing applications. The FDCA provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not approve or even accept for review an abbreviated new drug application (ANDA), or a 505(b)(2) NDA submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder. The FDCA alternatively provides three years of marketing exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the active agent for the original indication or condition of use. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the non-clinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

~~Table~~Orphan drug exclusivity, as described above, may offer a seven-year period of ~~Contents~~marketing exclusivity, except in certain circumstances. Pediatric exclusivity is another type of non-patent 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 trial in accordance with an FDA-issued “Written Request” for such a trial.

requirements related to clinical trials, non-clinical studies or manufacturing. If a Complete Response Letter is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information is submitted, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval.39

IfTable a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling or may condition the approval of the NDA on other changes to the proposed labeling, development of adequate controls and specifications, or a commitment to conduct one or more post-market studies or clinical trials. For example, the FDA may require Phase 4 testing, which involves clinical trials designed to further assess a drug safety and effectiveness and may require testing and surveillance programs to monitor the safety of approved products that have been commercialized. The FDA may also determine that a risk evaluation and mitigation strategy (REMS) is necessary to assure the safe use of the drug. If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS; the FDA will not approve the NDA without an approved REMS, if required. A REMS could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.Contents

~~Expedited~~Other ~~development~~U.S. healthcare laws and ~~review~~compliance ~~programs~~requirements

~~The~~Although ~~FDA~~we ~~has~~currently ado ~~fast~~not ~~track~~have ~~designation~~any ~~program~~products ~~that~~on ~~is intended to expedite or facilitate~~ the ~~process for reviewing new drug products that meet certain criteria. Specifically~~market, ~~new~~we ~~drugs~~ are ~~eligible~~and, ~~for~~upon ~~Fast~~approval ~~Track~~and ~~designation~~commercialization, ifwill ~~they~~be ~~are~~subject ~~intended~~ to ~~treat~~additional ahealthcare ~~serious~~regulation ~~or life-threatening disease or condition~~ and ~~demonstrate~~enforcement ~~the~~by ~~potential to address unmet medical needs for~~ the ~~disease~~federal orgovernment ~~condition.~~and ~~Unique~~by toauthorities ain ~~fast track product,~~ the ~~FDA~~states ~~may~~and ~~consider~~foreign ~~for~~jurisdictions ~~review~~in ~~sections~~which ofwe ~~the~~conduct ~~NDA~~our onbusiness. aIn ~~rolling basis before~~ the ~~complete~~United ~~application is submitted~~States, ifsuch ~~the~~laws ~~sponsor~~include, ~~provides~~without ~~a schedule for the submission of the sections of the NDA~~limitation, ~~the~~state ~~FDA~~and ~~agrees~~federal tofraud ~~accept~~and ~~sections~~abuse of(such ~~the~~as ~~NDA~~anti-kickback and ~~determines~~false ~~that~~claims), ~~the~~privacy ~~schedule~~and issecurity, ~~acceptable~~price reporting, and ~~the~~provider ~~sponsor~~transparency ~~pays~~laws ~~any~~and ~~required user fees upon submission of the first section of the NDA~~regulations.

~~Any~~The ~~product~~federal ~~submitted~~Anti-Kickback toStatute ~~the~~prohibits, ~~FDA~~among ~~for~~other ~~approval~~things, ~~including~~any aperson ~~product~~or ~~with~~entity, afrom ~~fast~~knowingly ~~track~~and ~~designation~~willfully offering, ~~may~~paying, ~~also~~soliciting beor ~~eligible~~receiving ~~for~~any ~~other~~remuneration, ~~types~~directly ofor ~~FDA~~indirectly, ~~programs~~overtly ~~intended~~or tocovertly, ~~expedite~~in ~~development~~cash ~~and~~or ~~review~~in kind, ~~such~~to asinduce ~~priority~~or ~~review~~in ~~and~~return ~~accelerated~~for ~~approval.~~purchasing, Aleasing, ~~product~~ordering isor ~~eligible~~arranging for ~~priority~~the ~~review~~purchase, iflease itor order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs. The term remuneration has ~~the~~been ~~potential~~interpreted broadly to ~~provide~~include ~~safe~~anything ~~and~~of ~~effective~~value. ~~therapy~~The ~~for~~Anti-Kickback aStatute ~~serious~~has ~~condition~~been ~~where~~interpreted noto ~~satisfactory~~apply ~~alternative~~to ~~therapy~~arrangements ~~exists~~between orpharmaceutical amanufacturers ~~significant~~on ~~improvement~~the inone ~~the~~hand ~~treatment~~and prescribers, ~~diagnosis~~purchasers, orand ~~prevention~~formulary ofmanagers on the other. There are a ~~serious~~number ~~condition~~of ~~compared~~statutory toexceptions ~~marketed~~and ~~products~~regulatory safe harbors protecting some common activities from prosecution. The ~~FDA~~exceptions ~~will~~and ~~attempt~~safe toharbors ~~direct~~are ~~additional~~drawn ~~resources~~narrowly and practices that involve remuneration that may be alleged to ~~the~~be ~~evaluation~~intended ofto aninduce ~~application~~prescribing, ~~for~~purchasing aor ~~new~~recommending ~~drug~~may ~~designated~~be ~~for~~subject ~~priority~~to ~~review~~scrutiny inif they do not qualify for an ~~effort~~exception toor ~~facilitate~~safe harbor but the ~~review~~exceptions and safe harbors are drawn narrowly and require strict compliance in order to offer protection.

InFailure ~~addition, a product may be eligible for accelerated approval. Drug products intended~~ to ~~treat~~meet ~~serious~~all orof ~~life- threatening diseases or conditions may be eligible for accelerated approval upon a determination that~~ the ~~product~~requirements ~~has~~of ~~an effect on~~ a ~~surrogate~~particular ~~endpoint~~applicable ~~that~~statutory isexception ~~reasonably likely to predict clinical benefit,~~ or onregulatory asafe ~~clinical~~harbor ~~endpoint~~does ~~that~~not ~~can~~make ~~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,~~conduct ~~rarity,~~per orse ~~prevalence~~illegal ofunder the ~~condition~~Anti-Kickback ~~and the availability or lack of alternative treatments~~Statute. AsInstead, athe ~~condition~~legality of ~~approval,~~ the ~~FDA~~arrangement ~~may~~will ~~require~~be ~~that~~evaluated aon ~~sponsor of~~ a ~~drug receiving accelerated approval perform adequate and well~~case-~~controlled post~~by-case ~~marketing~~basis ~~clinical~~based ~~trials.~~on ~~In addition, the FDA currently requires, as~~ a ~~condition~~cumulative ~~for~~review ~~accelerated approval, pre-approval~~ of ~~promotional~~all ~~materials, which could adversely impact the timing~~ of ~~the~~its ~~commercial~~facts ~~launch~~and ~~of the product~~circumstances. ~~Fast~~Our ~~track~~practices ~~designation,~~may ~~priority~~not ~~review~~in ~~and~~all ~~accelerated~~cases ~~approval~~meet doall ~~not~~of ~~change~~ the ~~standards~~criteria for ~~approval~~protection ~~but~~under ~~may~~a ~~expedite~~statutory ~~the~~exception ~~development~~ or ~~approval~~regulatory ~~process~~safe harbor.

~~Even~~Additionally, ifthe aintent ~~product~~standard ~~qualifies~~under ~~for~~the ~~one~~Anti-Kickback orStatute ~~more~~and certain criminal healthcare fraud statutes (discussed below) was amended by the Patient Protection and Affordable Care Act of ~~these~~2010, ~~programs~~as amended by the Health Care and Education Reconciliation Act of 2010, together with subsequent amendments and regulations, collectively, the ~~FDA~~ACA, ~~may~~to ~~later~~a ~~decide~~stricter standard such that ~~the~~a ~~product~~person or entity no longer ~~meets~~needs ~~the~~to ~~conditions~~have ~~for~~actual ~~qualification~~knowledge orof ~~decide~~the ~~that~~statute ~~the~~or ~~time~~specific ~~period~~intent ~~for~~to ~~FDA~~violate ~~review~~it orin ~~approval~~order ~~will~~to ~~not~~have becommitted ~~shortened~~a violation. In addition, ~~this~~the ~~designation~~ACA ~~may~~codified ~~not~~case ~~provide~~law that a ~~material~~claim ~~commercial~~including ~~advantage~~items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act (discussed below).

35The federal False Claims Act prohibits, among other things, any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to, or approval by, the federal government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government. As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S. government. Pharmaceutical and other healthcare companies have been prosecuted under these laws for, among other things, allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product and for causing false claims to be submitted because of the companies’ marketing of the product for unapproved, and thus non- covered, uses.

~~Table~~The federal Health Insurance Portability and Accountability Act of ~~Contents~~1996 (HIPAA) also created new federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services. Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

~~Post-approval requirements~~40

~~Any~~Table ~~drug products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting~~ of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, and complying with FDA promotion and advertising requirements, which include, among others, standards for direct- to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet. Although physicians may prescribe legally available drugs for off-label uses, manufacturers may not market or promote such off-label uses.Contents

~~In addition~~Additionally, ~~quality~~the ~~control~~federal ~~and~~Physician ~~manufacturing~~Payments ~~procedures~~Sunshine ~~must~~Act ~~continue~~within ~~to conform to applicable manufacturing requirements after approval to ensure~~ the ~~long-term stability of the drug product. We rely~~ACA, and ~~expect~~its toimplementing ~~continue to rely~~regulations, onrequire ~~third~~that ~~parties~~certain ~~for~~manufacturers ~~the production~~ of ~~clinical~~drugs, ~~and commercial quantities of our products in accordance with cGMP regulations. cGMP regulations require among other things~~devices, ~~quality~~biological ~~control~~ and ~~quality~~medical ~~assurance~~supplies asfor ~~well~~which aspayment ~~the~~is ~~corresponding~~available ~~maintenance~~under ofMedicare, ~~records~~Medicaid ~~and~~or ~~documentation and~~ the ~~obligation~~Children’s toHealth ~~investigate~~Insurance ~~and~~Program ~~correct any deviations from cGMP. Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments~~ (with ~~the FDA and~~ certain ~~state~~exceptions) ~~agencies~~annually ~~and~~report ~~are~~information ~~subject~~related to ~~periodic unannounced inspections by the FDA and~~ certain ~~state~~payments ~~agencies~~or ~~for compliance with cGMP and~~ other ~~laws.~~transfers ~~Accordingly, manufacturers must continue to expend time, money, and effort in the area~~ of ~~production~~value ~~and~~made ~~quality~~or ~~control~~distributed to ~~maintain~~physicians ~~cGMP~~(defined ~~compliance.~~to ~~Discovery~~include ofdoctors, ~~problems with a product after approval may result in restrictions on a product~~dentists, ~~manufacturer~~optometrists, orpodiatrists ~~holder~~and ~~of an approved NDA~~chiropractors), ~~including, among~~ other ~~things,~~healthcare ~~recall~~professionals or(such ~~withdrawal~~as ofphysician ~~the~~assistants ~~product~~and ~~from~~nurse ~~the market. In addition~~practitioners), ~~changes~~and toteaching ~~the manufacturing process are strictly regulated~~hospitals, and ~~depending~~certain onownership ~~the~~and ~~significance~~investment ofinterests ~~the~~held ~~change,~~by ~~may~~these ~~require~~physicians ~~prior FDA approval before being implemented. Other types of changes to the approved product, such as adding new indications~~ and ~~additional~~their ~~labeling~~immediate ~~claims,~~family ~~are also subject to further FDA review and approval~~members.

~~The~~We ~~FDA~~may also ~~may~~be ~~require~~subject ~~post-marketing~~to ~~testing,~~data ~~known~~privacy asand ~~Phase~~security 4regulations ~~testing,~~promulgated ~~and~~by ~~surveillance~~both tothe ~~monitor~~federal government and the ~~effects~~states ofin anwhich ~~approved~~we ~~product.~~conduct ~~Discovery~~our ofbusiness. ~~previously~~HIPAA, ~~unknown~~as ~~problems~~amended ~~with~~by athe ~~product~~Health orInformation ~~the~~Technology ~~failure~~for toEconomic ~~comply~~and ~~with~~Clinical ~~applicable~~Health ~~FDA~~Act ~~requirements~~(HITECH) ~~can~~and ~~have~~its ~~negative~~implementing ~~consequences~~regulations, ~~including~~impose ~~adverse~~requirements ~~publicity~~on covered entities, ~~judicial~~including orcertain ~~administrative~~healthcare ~~enforcement~~providers, ~~warning~~health ~~letters~~plans, ~~from~~and ~~the~~healthcare ~~FDA~~clearinghouses, ~~mandated~~and ~~corrective~~their ~~advertising~~respective orbusiness ~~communications~~associates ~~with~~that ~~doctors~~create, ~~and~~receive, ~~civil~~maintain or ~~criminal~~transmit ~~penalties,~~individually ~~among~~identifiable ~~others.~~health ~~Newly~~information ~~discovered~~for or ~~developed~~on ~~safety~~behalf orof ~~effectiveness~~a ~~data~~covered ~~may~~entity ~~require~~as ~~changes~~well toas atheir ~~product’s~~covered ~~approved~~subcontractors ~~labeling,~~relating ~~including~~to the ~~addition~~privacy, security and transmission of ~~new~~individually ~~warnings~~identifiable ~~and~~health ~~contraindications~~information. Among other things, HITECH makes HIPAA’s privacy and ~~also~~security ~~may~~standards ~~require~~directly ~~the~~applicable ~~implementation~~to business associates, independent contractors or agents of ~~other~~covered ~~risk~~entities ~~management~~that ~~measures~~receive or obtain protected health information in connection with providing a service on behalf of a covered entity. ~~Also,~~HITECH also created four new ~~government~~tiers ~~requirements~~of civil monetary penalties, ~~including~~amended ~~those~~HIPAA ~~resulting~~to ~~from~~make ~~new~~civil ~~legislation,~~and ~~may~~criminal bepenalties ~~established~~directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the ~~FDA~~federal HIPAA laws and seek attorneys’s ~~policies~~fees ~~may~~and ~~change~~costs associated with pursuing federal civil actions. In addition, ~~which~~state ~~could~~laws ~~delay~~govern orthe ~~prevent~~privacy ~~regulatory~~and ~~approval~~security of ~~our~~health ~~products~~information ~~under~~in ~~development~~specified circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

The U.S. ~~Patent~~Department ~~term~~of ~~restoration~~Justice issued a rule entitled the Preventing Access to U.S. Sensitive Personal Data and ~~marketing~~Government-Related ~~exclusivity~~Data by Countries of Concern or Covered Persons, which places additional restriction on certain data transactions involving countries of concern (e.g., China, Russia, Iran) and covered persons. Violations of the rule could lead to significant civil and criminal fines and penalties. The rule applies regardless of whether data is anonymized, key-coded, pseudonymized, de-identified or encrypted. In Europe, the Network and Information Security Directive (NIS2) regulates resilience and incident response capabilities of entities operating in a number of sectors, including the health sector. Non-compliance with NIS2 may lead up to administrative fines of a maximum of 10 million Euros or up to 2% of the total worldwide revenue of the preceding fiscal year. Also in Europe, some of our customers may be subject to the EU’s Digital Operational Resilience Act (DORA) and similar UK regulatory requirements on operational resilience. These laws may obligate our customers to impose contractual provisions on us, including certain mandatory third-party risk management provisions.

~~Depending~~In ~~upon~~order ~~the~~to ~~timing~~distribute products commercially, ~~duration~~we ~~and~~must ~~specifics~~comply ofwith ~~the~~state ~~FDA~~laws ~~approval~~that ofrequire the ~~use~~registration of ~~our~~manufacturers ~~product~~and ~~candidates,~~wholesale ~~some~~distributors of ~~our~~pharmaceutical ~~U.S.~~products ~~patents,~~in ifa ~~granted~~state, ~~may~~including, bein ~~eligible~~certain ~~for~~states, ~~limited~~manufacturers ~~PTE under the Drug Price Competition~~ and ~~Patent~~distributors ~~Term~~who ~~Restoration~~ship ~~Act~~products ofinto ~~1984, commonly referred to as~~ the ~~Hatch-Waxman~~state ~~Amendments.~~even Asif ~~compensation~~such ~~for~~manufacturers ~~patent~~or ~~term~~distributors ~~lost~~have ~~during~~no ~~product~~place ~~development~~of ~~and~~business ~~the~~within ~~FDA regulatory review process,~~ the ~~Hatch-Waxman~~state. ~~Amendments~~Some ~~permit~~states aalso ~~patent~~impose ~~restoration~~requirements ~~term~~on ~~(PTE),~~manufacturers ~~which~~and isdistributors ~~limited~~ to aestablish ~~maximum of five years, or less if~~ the ~~extended~~pedigree ~~patent~~of ~~term~~product ~~would~~in ~~exceed 14 years after~~ the ~~date~~chain of ~~the~~distribution, ~~regulatory~~including ~~approval~~some ofstates ~~the~~that ~~product.~~require ~~The~~manufacturers ~~patent~~and ~~term~~others ~~restoration~~to ~~period~~adopt isnew ~~generally~~technology ~~one-half~~capable ~~the time between the effective date~~ of antracking ~~IND~~ and ~~the~~tracing ~~submission~~product ~~date~~as ofit anmoves ~~NDA~~through ~~plus~~ the ~~time~~distribution ~~between~~chain. ~~the~~Several ~~submission~~states ~~date~~have ofenacted anlegislation ~~NDA~~requiring ~~and~~pharmaceutical ~~the~~companies ~~approval~~to ofestablish ~~that~~marketing ~~application.~~compliance ~~Only~~programs, ~~one~~file ~~patent~~periodic ~~applicable~~reports towith anthe ~~approved~~state, ~~drug~~make orperiodic ~~drug~~public ~~product,~~disclosures oron ~~its~~sales, ~~approved~~marketing, ~~use~~pricing, istrack ~~eligible~~and ~~for~~report ~~the~~gifts, ~~extension~~compensation and ~~the~~other ~~application~~remuneration ~~for~~made ~~the extension must be submitted prior~~ to ~~the~~physicians ~~expiration~~and ofother ~~the~~healthcare ~~patent.~~providers, ~~The~~clinical ~~U.S.~~trials ~~Patent~~ and ~~Trademark~~other ~~Office~~activities, inand/or ~~consultation~~register ~~with~~their ~~the~~sales ~~FDA~~representatives, ~~reviews~~as ~~and~~well ~~approves~~as ~~the~~to ~~application~~prohibit ~~for~~pharmacies ~~any~~and ~~patent~~other ~~term~~healthcare ~~extension~~entities orfrom ~~restoration.~~providing Incertain ~~the~~physician ~~future,~~prescribing wedata ~~may intend~~ to ~~apply~~pharmaceutical ~~for~~companies ~~restoration of a patent term~~ for ~~one~~use ofin ~~our~~sales ~~currently~~and ~~owned~~marketing, orand ~~licensed patents~~ to ~~add~~prohibit ~~patent~~certain ~~life~~other ~~beyond~~sales ~~its~~and ~~current~~marketing ~~expiration~~practices. ~~date,~~All ~~depending~~of onour ~~the~~activities ~~expected~~are ~~length~~potentially ofsubject ~~the~~to ~~clinical~~federal ~~trials~~ and ~~other~~state ~~factors~~consumer ~~involved~~protection inand ~~the~~unfair ~~filing~~competition ~~of the relevant~~ laws.

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~~NDA.~~If ~~However,~~our weoperations ~~may~~are ~~not~~found ~~receive~~to anbe ~~extension~~in ifviolation weof ~~fail~~any toof ~~exercise~~the ~~due~~federal ~~diligence~~and ~~during~~state ~~the~~healthcare ~~testing~~laws ~~phase~~described above or ~~regulatory~~any ~~review~~other ~~process,~~governmental ~~fail~~regulations tothat apply ~~within~~to ~~applicable deadlines~~us, ~~fail~~we tomay ~~apply~~be ~~prior~~subject to ~~expiration~~significant ofpenalties, ~~relevant~~including ~~patents~~without limitation, civil, criminal and/or ~~otherwise~~administrative ~~fail~~penalties, todamages, ~~satisfy~~fines, ~~applicable~~disgorgement, ~~requirements.~~imprisonment, ~~Moreover~~exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the ~~length~~name of the ~~extension~~government, ~~could~~or berefusal ~~less~~to ~~than~~allow weus ~~request.~~to ~~There~~enter ~~can~~into begovernment nocontracts, ~~assurance~~contractual ~~that~~damages, wereputational ~~will~~harm, ~~benefit~~administrative ~~from~~burdens, ~~any~~diminished ~~PTE~~profits orand ~~favorable~~future ~~adjustment~~earnings, toand the ~~term~~curtailment or restructuring of our operations, any of which could adversely affect our ~~patents~~ability to operate our business and our results of operations.

~~Market exclusivity provisions under the FDCA can also delay the submission or the approval of certain marketing applications~~U. ~~The FDCA provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity~~S. Aand ~~drug~~foreign ~~is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety~~laws, ~~which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period~~regulations, ~~the FDA may not approve or even accept for review an abbreviated new drug application (ANDA)~~rules, orcontractual ~~a 505(b)(2) NDA submitted by another company for another drug based on the same active moiety~~obligations, ~~regardless~~policies ofand ~~whether~~other ~~the~~obligations ~~drug~~related ~~is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference~~ to ~~all the~~ data ~~required~~privacy for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder. The FDCA alternatively provides three years of marketing exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the active agent for the original indication or condition of use. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the non-clinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.security

~~Orphan~~We ~~drug~~are ~~exclusivity,~~or aswill ~~described~~become ~~above,~~subject ~~may~~to ~~offer~~privacy alaws ~~seven-year~~in ~~period~~the ofjurisdictions ~~marketing~~in ~~exclusivity,~~which ~~except~~we are established or in ~~certain~~which ~~circumstances.~~we ~~Pediatric~~sell ~~exclusivity~~or ismarket ~~another~~our ~~type~~products ofor ~~non-patent~~run ~~market~~clinical ~~exclusivity~~trials. For example, in Europe we are subject to the ~~United~~General ~~States.~~Data ~~Pediatric~~Protection ~~exclusivity~~Regulation (GDPR) in relation to our collection, ifcontrol, ~~granted~~processing and other use of personal data (i.e., ~~adds~~data ~~six~~relating ~~months~~to an identified or identifiable living individual). We process personal data in relation to ~~existing~~participants ~~exclusivity~~in ~~periods~~our clinical trials in the European Economic Area (EEA), including the health and ~~patent~~medical ~~terms~~information of these participants. ~~This~~The ~~six-month~~GDPR ~~exclusivity,~~is ~~which~~directly ~~runs~~applicable ~~from~~in each of the ~~end~~twenty-seven member states of ~~other~~the ~~exclusivity~~European ~~protection~~Union or(EU ~~patent~~Member ~~term~~States), ~~may~~however, beit ~~granted~~provides ~~based~~that onEU ~~the~~Member ~~voluntary~~States ~~completion~~may ofintroduce afurther ~~pediatric~~conditions ~~trial~~that incould ~~accordance~~cause ~~with~~our ancompliance ~~FDA-issued~~costs ~~“Written~~to ~~Request”~~increase, ~~for~~ultimately ~~such~~having aan ~~trial~~adverse impact on our business.

~~Other~~We Uare subject to the supervision of local data protection authorities in those European Union jurisdictions where we are established or otherwise subject to the GDPR.S Fines for certain breaches of the GDPR are significant: up to the greater of €20 million or 4% of total global annual turnover. ~~healthcare~~Further, we must comply with both the GDPR and separately the GDPR as implemented in the United Kingdom (UK), each regime having the ability to fine up to the greater of €20 million / £17 million or 4% of global turnover. A breach of the GDPR or other applicable privacy and data protection laws and ~~compliance~~regulations ~~requirements~~could result in regulatory investigations, reputational damage, orders to cease/change our use of data, enforcement notices, or potential civil claims including class action type litigation. In general, if our efforts to comply with the GDPR or other applicable European Union laws and regulations are not successful, it could adversely affect our business in the European Union.

~~Although~~In the ordinary course of business, we ~~currently~~may dotransfer ~~not~~personal ~~have~~data ~~any~~from ~~products~~Europe onand other jurisdictions to the ~~market,~~United weStates ~~are~~or ~~and,~~other ~~upon~~countries. ~~approval~~In ~~and~~the ~~commercialization~~United States, ~~will~~the beU.S. ~~subject~~Department toof ~~additional~~Justice ~~healthcare~~issued ~~regulation~~a ~~and~~rule ~~enforcement~~entitled by the ~~federal~~Preventing ~~government~~Access to U.S. Sensitive Personal Data and byGovernment-Related ~~authorities~~Data inby ~~the~~Countries ~~states~~of ~~and~~Concern ~~foreign~~or ~~jurisdictions~~Covered inPersons, which weplaces ~~conduct~~additional ~~our~~restriction ~~business.~~on Incertain ~~the~~data ~~United~~transactions ~~States,~~involving ~~such~~countries ~~laws~~of ~~include~~concern (e.g., ~~without~~China, ~~limitation~~Russia, ~~state~~Iran) and ~~federal~~covered ~~fraud~~persons ~~and~~that ~~abuse~~may (impact certain business activities such as ~~anti-kickback~~vendor ~~and~~engagements, ~~false~~sale ~~claims)~~or sharing of data, ~~privacy~~employment of certain individuals, and ~~security~~investor agreements. Violations of the rule could lead to significant civil and criminal fines and penalties. The rule applies regardless of whether data is anonymized, ~~price~~key-coded, ~~reporting~~pseudonymized, ~~and~~de-identified ~~provider~~or ~~transparency~~encrypted, ~~laws~~which presents particular challenges for companies like ours and ~~regulations~~may impact our ability to transfer data in connection with certain transactions or agreements.

~~The~~Europe ~~federal~~and ~~Anti-Kickback Statute prohibits, among~~ other ~~things,~~jurisdictions ~~any~~have ~~person~~enacted orlaws ~~entity,~~requiring ~~from~~data ~~knowingly~~to ~~and~~be ~~willfully~~localized ~~offering, paying, soliciting~~ or ~~receiving~~limiting ~~any~~the ~~remuneration,~~transfer ~~directly~~of orpersonal ~~indirectly,~~data ~~overtly~~to orother ~~covertly,~~countries. inIn ~~cash or in kind~~particular, tothe ~~induce~~EEA orand inthe ~~return~~UK ~~for~~have ~~purchasing,~~significantly ~~leasing,~~restricted ~~ordering or arranging for~~ the ~~purchase,~~transfer ~~lease or order~~ of ~~any~~personal ~~item~~data orto ~~service~~the ~~reimbursable~~United ~~under~~States ~~Medicare,~~and ~~Medicaid or~~ other ~~federal~~countries ~~healthcare~~whose ~~programs.~~privacy ~~The~~laws ~~term~~it ~~remuneration~~believes ~~has~~are ~~been interpreted broadly to include anything of value~~inadequate. ~~The~~Other ~~Anti-Kickback~~jurisdictions ~~Statute~~may ~~has~~adopt ~~been~~similarly ~~interpreted~~stringent tointerpretations ~~apply~~of totheir ~~arrangements~~data ~~between~~localization ~~pharmaceutical manufacturers on the one hand~~ and ~~prescribers,~~cross-border ~~purchasers,~~data ~~and~~transfer ~~formulary managers on the other~~laws. ~~There~~Although there are acurrently ~~number~~various ofmechanisms ~~statutory~~that ~~exceptions~~may ~~and~~be ~~regulatory~~used ~~safe~~to ~~harbors~~transfer ~~protecting~~personal ~~some~~data ~~common activities~~ from ~~prosecution.~~the ~~The~~EEA ~~exceptions~~ and ~~safe~~UK ~~harbors~~to ~~are~~the ~~drawn~~United ~~narrowly~~States ~~and~~in ~~practices~~compliance ~~that~~with ~~involve~~law, ~~remuneration~~such ~~that~~as ~~may~~the beEEA ~~alleged~~and toUK’s bestandard ~~intended~~contractual ~~to induce prescribing~~clauses, ~~purchasing~~these ormechanisms ~~recommending~~are ~~may be~~ subject to ~~scrutiny~~legal ifchallenges, ~~they~~and dothere ~~not~~is ~~qualify~~no ~~for~~assurance anthat ~~exception~~we orcan ~~safe~~satisfy ~~harbor~~or ~~but~~rely ~~the~~on ~~exceptions~~these ~~and~~measures ~~safe~~to ~~harbors~~lawfully ~~are~~transfer ~~drawn~~personal ~~narrowly~~data ~~and require strict compliance in order~~ to ~~offer~~the ~~protection~~United States.

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~~Failure~~If there is no lawful manner for us to ~~meet~~transfer ~~all~~personal ofdata from the EEA, the UK or other jurisdictions to the United States, or if the requirements offor a ~~particular~~legally-compliant ~~applicable~~transfer ~~statutory~~are ~~exception~~too onerous, we could face significant adverse consequences, including the interruption or degradation of our operations, the need to relocate part of or all of our business or data processing activities to other jurisdictions at significant expense, increased exposure to regulatory ~~safe~~actions, ~~harbor~~substantial ~~does~~fines ~~not~~and ~~make~~penalties, the ~~conduct~~inability ~~per~~to setransfer ~~illegal~~data ~~under~~and ~~the~~work ~~Anti-Kickback~~with ~~Statute~~partners, vendors and other third parties, and injunctions against our processing or transferring of personal data necessary to operate our business. ~~Instead~~Additionally, ~~the~~companies ~~legality~~that transfer personal data out of the ~~arrangement~~EEA ~~will~~and beUK ~~evaluated~~to onother ajurisdictions, ~~case-by-case~~particularly ~~basis~~to ~~based~~the onUnited aStates, ~~cumulative~~are ~~review~~subject ofto ~~all~~increased ofscrutiny ~~its~~from ~~facts~~regulators, individual litigants, and ~~circumstances~~activist groups. ~~Our~~Some ~~practices~~European ~~may~~regulators ~~not~~have inordered ~~all~~certain ~~cases~~companies ~~meet~~to ~~all~~suspend ofor ~~the~~permanently ~~criteria~~cease ~~for~~certain ~~protection~~transfers ~~under~~out aof ~~statutory~~Europe ~~exception~~for orallegedly ~~regulatory~~violating ~~safe~~the ~~harbor~~GDPR’s cross-border data transfer limitations.

~~Additionally~~In the United States, the ~~intent~~California ~~standard~~Consumer ~~under~~Privacy ~~the~~Act ~~Anti-Kickback~~(CCPA) ~~Statute~~creates ~~and~~individual ~~certain~~privacy ~~criminal~~rights ~~healthcare~~for ~~fraud~~California ~~statutes~~consumers (~~discussed~~as ~~below)~~defined ~~was~~in ~~amended~~the bylaw) ~~the~~and ~~Patient~~places ~~Protection~~increased privacy and ~~Affordable~~security ~~Care~~obligations ~~Act~~on entities handling certain personal data of ~~2010,~~consumers asor ~~amended~~households. byThe ~~the~~CCPA ~~Health~~requires ~~Care~~covered ~~and~~companies ~~Education~~to ~~Reconciliation~~provide ~~Act~~new ofdisclosure ~~2010,~~to ~~together~~consumers ~~with~~about ~~subsequent~~such ~~amendments~~companies’ ~~and~~data ~~regulations~~collection, ~~collectively,~~use ~~the~~and ~~ACA~~sharing practices, toprovide asuch ~~stricter~~consumers ~~standard~~new ~~such~~ways ~~that~~to aopt-out ~~person~~of certain sales or ~~entity~~transfers noof ~~longer~~personal ~~needs~~information, toand ~~have~~provide ~~actual~~consumers ~~knowledge~~with ofadditional ~~the~~causes ~~statute~~of oraction. ~~specific~~The ~~intent~~CCPA toprovides ~~violate~~for itcivil inpenalties ~~order~~for toviolations, ~~have~~as ~~committed~~well as a ~~violation.~~private Inright ~~addition,~~of ~~the~~action ~~ACA~~for ~~codified~~certain ~~case~~data ~~law~~breaches that aresult ~~claim~~in ~~including~~the ~~items~~loss orof ~~services~~personal ~~resulting~~information. ~~from~~This aprivate ~~violation~~right of action may increase the ~~federal~~likelihood ~~Anti-Kickback~~of, ~~Statute~~and ~~constitutes~~risks aassociated ~~false~~with, ordata ~~fraudulent~~breach ~~claim~~litigation. ~~for~~The ~~purposes~~CCPA of(a) allows enforcement by the ~~federal~~California ~~False~~Attorney ~~Claims~~General ~~Act~~with ~~(discussed~~fines ~~below~~and (b) authorizes private lawsuits to recover statutory damages for certain data breaches.

~~The~~In ~~federal~~addition, ~~False~~laws ~~Claims~~in ~~Act~~all ~~prohibits,~~50 ~~among~~U.S. ~~other~~states ~~things,~~require ~~any~~businesses ~~person~~to orprovide ~~entity~~notice ~~from~~to ~~knowingly~~consumers ~~presenting,~~whose orpersonal ~~causing~~information tohas bebeen ~~presented,~~disclosed as a ~~false~~result ~~claim~~of ~~for~~a ~~payment~~data ~~to,~~breach. orState ~~approval~~laws ~~by,~~are changing rapidly and there is discussion in the ~~federal~~U.S. ~~government~~Congress orof ~~knowingly~~a ~~making,~~new ~~using,~~comprehensive orfederal ~~causing~~data privacy law to bewhich ~~made~~we orwould ~~used~~become asubject ~~false~~if ~~record~~it oris ~~statement~~enacted. ~~material~~The CCPA may impact our business activities and exemplifies the vulnerability of our business to athe ~~false~~evolving orregulatory ~~fraudulent~~environment ~~claim~~related to personal data and protected health information. Additionally, the ~~federal~~California ~~government~~Privacy Rights Act (CPRA) significantly modifies the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information. AsThe aCPRA ~~result~~also ofcreates a ~~modification~~new ~~made~~state byagency ~~the~~that ~~Fraud~~will ~~Enforcement~~be vested with authority to implement and ~~Recovery~~enforce ~~Act~~the ofCCPA ~~2009,~~and athe ~~claim~~CPRA. ~~includes~~New ~~“any~~legislation ~~request~~proposed or ~~demand”~~enacted ~~for~~in ~~money~~various orother ~~property~~states ~~presented~~will continue to shape the ~~U.S.~~data ~~government~~privacy environment nationally. ~~Pharmaceutical~~For ~~and~~example, ~~other~~Virginia, ~~healthcare~~Colorado, ~~companies~~Utah, and Connecticut have ~~been~~all ~~prosecuted~~enacted ~~under~~broad ~~these~~privacy legislation. Certain state laws ~~for,~~may ~~among~~be ~~other~~more ~~things,~~stringent ~~allegedly~~or ~~providing~~broader ~~free~~in ~~product~~scope, toor ~~customers~~offer greater individual rights, with ~~the~~respect ~~expectation~~to ~~that~~confidential, ~~the~~sensitive ~~customers~~and ~~would~~personal ~~bill~~information than federal, ~~programs~~international ~~for~~or ~~the~~other ~~product~~state laws, and ~~for~~such ~~causing~~laws ~~false~~may ~~claims~~differ from each other, which may complicate compliance efforts. In addition to bethe ~~submitted~~foregoing, ~~because~~any breach of privacy laws or data security laws, particularly resulting in a significant security incident or breach involving the ~~companies’~~misappropriation, ~~marketing~~loss or other unauthorized use or disclosure of ~~the~~sensitive ~~product~~or confidential patient or consumer information, could have a material adverse effect on our business, reputation and financial condition. As a data controller, we will be accountable for ~~unapproved~~any third-party service providers we engage to process personal data on our behalf, including our contract research organizations (CROs). We attempt to mitigate the associated risks but there is no assurance that privacy and ~~thus~~security-related ~~non~~safeguards will protect us from all risks associated with the third-party ~~covered~~processing, ~~uses~~storage and transmission of such information.

~~The~~Pharmaceutical ~~federal Health Insurance Portability and Accountability Act of 1996 (HIPAA) also created new federal criminal statutes that prohibit~~coverage, ~~among~~pricing ~~other things, knowingly~~ and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services. Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.reimbursement

~~Additionally,~~Significant ~~the~~uncertainty ~~federal~~exists ~~Physician~~as ~~Payments~~to ~~Sunshine Act within~~ the ~~ACA,~~coverage and ~~its~~reimbursement ~~implementing~~status ~~regulations,~~of ~~require~~any ~~that~~product ~~certain~~candidates ~~manufacturers~~for ofwhich ~~drugs,~~we ~~devices,~~or ~~biological~~our ~~and~~collaborators ~~medical~~obtain ~~supplies~~regulatory ~~for~~approval. ~~which~~In ~~payment~~the isUnited ~~available~~States ~~under~~and ~~Medicare,~~markets ~~Medicaid~~in orother ~~the~~countries, ~~Children’s~~sales ~~Health~~of ~~Insurance~~any ~~Program~~products ~~(with~~for ~~certain~~which ~~exceptions)~~we ~~annually~~or ~~report~~our ~~information~~collaborators ~~related~~receive toregulatory ~~certain~~approval ~~payments~~for orcommercial ~~other~~sale ~~transfers~~will ofdepend, ~~value~~in ~~made~~part, oron ~~distributed~~the extent to ~~physicians~~which ~~(defined~~third-party topayors ~~include~~provide ~~doctors~~coverage, ~~dentists, optometrists, podiatrists~~ and ~~chiropractors),~~establish ~~other~~adequate ~~healthcare~~reimbursement ~~professionals~~levels (for such asdrug ~~physician~~products. ~~assistants~~In ~~and~~the ~~nurse~~United ~~practitioners)~~States, ~~and~~third-party ~~teaching~~payors ~~hospitals,~~include federal and ~~certain~~state ~~ownership~~healthcare ~~and~~programs, ~~investment~~government ~~interests~~authorities, ~~held~~private bymanaged ~~these~~care ~~physicians~~providers, ~~and~~private ~~their~~health ~~immediate~~insurers ~~family~~and ~~members.~~other organizations.

We may also be subject to data privacy and security regulations promulgated by both the federal government and the states in which we conduct our business. HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH) and its implementing regulations, impose requirements on covered entities, including certain healthcare providers, health plans, and healthcare clearinghouses, and their respective business associates that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity as well as their covered subcontractors relating to the privacy, security and transmission of individually identifiable health information. Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to business associates, independent contractors or agents of covered entities that receive or obtain protected health information in connection with providing a service on behalf of a covered entity. HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal 43

38Table of Contents

~~Table~~Third-party payors are increasingly challenging the price, examining the medical necessity and reviewing the cost-effectiveness of ~~Contents~~medical drug products and medical services, in addition to questioning their safety and efficacy. Such payors may limit coverage to specific drug products on an approved list, also known as a formulary, which might not include all of the FDA-approved drugs for a particular indication. We or our collaborators may need to conduct expensive pharmaco-economic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain the FDA approvals. Nonetheless, our product candidates may not be considered medically necessary or cost-effective. Moreover, the process for determining whether a third-party payor will provide coverage for a drug product may be separate from the process for setting the price of a drug product or for establishing the reimbursement rate that such a payor will pay for the drug product. A payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Further, one payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage for the drug product. Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.

~~HIPAA~~If ~~laws~~we ~~and~~elect ~~seek~~to ~~attorneys’~~participate ~~fees~~in certain governmental programs, we may be required to participate in discount and ~~costs~~rebate ~~associated~~programs, ~~with~~which ~~pursuing~~may ~~federal~~result ~~civil~~in ~~actions~~prices for our future products that will likely be lower than the prices we might otherwise obtain. InFor ~~addition~~example, drug manufacturers participating under the Medicaid Drug Rebate Program must pay rebates on prescription drugs to state ~~laws~~Medicaid ~~govern~~programs. Under the ~~privacy~~Veterans Health Care Act (VHCA) drug companies are required to offer certain drugs at a reduced price to a number of federal agencies, including the U.S. Department of Veterans Affairs and ~~security~~Department of ~~health~~Defense, ~~information~~the Public Health Service and certain private Public Health Service designated entities in ~~specified~~order ~~circumstances~~to participate in other federal funding programs, ~~many~~including Medicare and Medicaid. Recent legislative changes require that discounted prices be offered for certain U.S. Department of ~~which~~Defense ~~differ~~purchases ~~from~~for ~~each~~its ~~other~~TRICARE inprogram ~~significant~~via ~~ways~~a rebate system. Participation under the VHCA also requires submission of pricing data and ~~may~~calculation ~~not~~of ~~have~~discounts and rebates pursuant to complex statutory formulas, as well as the ~~same~~entry ~~effect~~into government procurement contracts governed by the Federal Acquisition Regulations. If our products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, ~~thus~~additional ~~complicating~~laws ~~compliance~~and ~~efforts~~requirements apply.

InThere ~~order~~has tobeen ~~distribute~~heightened ~~products~~governmental ~~commercially,~~scrutiny werecently ~~must~~over ~~comply~~the ~~with~~manner ~~state~~in ~~laws~~which ~~that~~pharmaceutical ~~require~~companies ~~the~~set ~~registration~~prices offor ~~manufacturers~~their ~~and~~marketed ~~wholesale~~products, ~~distributors~~which ofhas ~~pharmaceutical~~resulted ~~products~~ in aseveral ~~state,~~Presidential ~~including,~~executive ~~in certain states~~orders, ~~manufacturers~~Congressional inquiries and ~~distributors~~proposed ~~who~~federal ~~ship~~legislation, ~~products~~as ~~into~~well ~~the~~as state ~~even~~efforts, ifdesigned ~~such~~to, ~~manufacturers~~among orother ~~distributors~~things, ~~have~~bring nomore ~~place~~transparency ofto ~~business~~product ~~within~~pricing, reduce the ~~state.~~cost ~~Some~~of ~~states~~prescription ~~also~~drugs ~~impose~~under ~~requirements~~Medicare, onreview ~~manufacturers and distributors to establish~~ the ~~pedigree~~relationship ofbetween ~~product~~pricing inand ~~the~~manufacturer ~~chain~~patient ~~of distribution~~programs, ~~including~~and ~~some~~reform ~~states~~government ~~that~~program ~~require~~reimbursement ~~manufacturers~~methodologies ~~and~~for ~~others~~drug toproducts. ~~adopt~~For ~~new~~example, ~~technology~~The ~~capable~~U.S. Department of ~~tracking~~Health and ~~tracing~~Human ~~product~~Services as(HHS) itimposes ~~moves~~rebates ~~through~~on ~~the~~many ~~distribution~~Medicare ~~chain.~~Part ~~Several~~B ~~states~~and ~~have~~Medicare ~~enacted~~Part ~~legislation~~D ~~requiring~~products ~~pharmaceutical~~to ~~companies~~penalize toprice ~~establish~~increases ~~marketing~~that ~~compliance~~outpace ~~programs,~~inflation ~~file~~on ~~periodic~~an ~~reports~~annual ~~with~~basis. ~~the~~In ~~state~~addition, ~~make~~HHS ~~periodic~~has ~~public~~been ~~disclosures~~empowered onto ~~sales,~~negotiate ~~marketing,~~the ~~pricing,~~price ~~track~~of ~~and~~certain ~~report~~single-source ~~gifts,~~drugs ~~compensation~~that ~~and~~have ~~other~~been ~~remuneration~~on ~~made~~the tomarket ~~physicians~~for ~~and~~at ~~other~~least ~~healthcare~~seven ~~providers,~~(7) ~~clinical~~years ~~trials~~covered ~~and~~under ~~other~~Medicare ~~activities,~~as ~~and/or~~part ~~register~~of ~~their~~the ~~sales~~Medicare ~~representatives,~~Drug asPrice ~~well~~Negotiation asProgram. toEach ~~prohibit~~year ~~pharmacies~~up ~~and~~to ~~other~~twenty ~~healthcare~~(20) ~~entities~~products ~~from~~will ~~providing~~be ~~certain~~selected ~~physician~~by ~~prescribing~~HHS ~~data~~for tothe ~~pharmaceutical~~Medicare ~~companies~~Drug ~~for~~Price ~~use~~Negotiation inProgram. ~~sales~~Products ~~and~~subject ~~marketing, and~~ to ~~prohibit~~the ~~certain~~Medicare ~~other~~Drug ~~sales~~Price ~~and~~Negotiation ~~marketing~~Program ~~practices.~~are ~~All~~expected ofto ~~our~~experience ~~activities~~a ~~are~~significant ~~potentially~~reduction ~~subject~~in toreimbursement ~~federal~~from ~~and~~the ~~state~~Medicare ~~consumer~~program ~~protection~~on ~~and~~a ~~unfair~~per ~~competition~~unit ~~laws~~basis.

If our operations are found to be in violation of any of the federal and state healthcare laws described above or any other governmental regulations that apply to us, we may be subject to significant penalties, including without limitation, civil, criminal and/or administrative penalties, damages, fines, disgorgement, imprisonment, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.44

~~U.S.~~Table ~~and~~of ~~foreign laws, regulations, rules, contractual obligations, policies and other obligations related to data privacy and security.~~Contents

WeDifferent ~~are~~pricing orand ~~will~~reimbursement ~~become~~schemes ~~subject~~exist toin ~~privacy~~other ~~laws~~countries. inIn the European Union, governments influence the price of pharmaceutical products through their pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those products to consumers. Some jurisdictions inoperate ~~which~~positive weand ~~are~~negative ~~established~~list orsystems inunder which weproducts ~~sell~~may oronly ~~market~~be ~~our~~marketed ~~products~~once a reimbursement price has been agreed. To obtain reimbursement or ~~run~~pricing approval, some of these countries may require the completion of clinical trials. ~~For~~that ~~example,~~compare inthe ~~Europe~~cost-effectiveness weof ~~are~~a ~~subject~~particular drug candidate to ~~the~~currently ~~General~~available ~~Data~~therapies. ~~Protection~~This ~~Regulation~~Health Technology Assessment (~~GDPR~~HTA) inprocess ~~relation~~is the procedure according to ~~our~~which ~~collection,~~the ~~control~~assessment of the public health impact, ~~processing~~therapeutic impact and ~~other~~the economic and societal impact of use of ~~personal~~a ~~data~~given ~~(i.e.,~~medicinal ~~data~~product ~~relating~~in tothe annational ~~identified~~healthcare orsystems ~~identifiable~~of ~~living~~the individual) country is conducted. WeThe ~~process~~outcome ~~personal~~of ~~data~~HTA inregarding ~~relation~~specific medicinal products will often influence the pricing and reimbursement status granted to ~~participants~~these inmedicinal ~~our~~products ~~clinical~~by ~~trials~~the incompetent authorities of individual EU Member States. At the ~~European~~EU ~~Economic~~level, ~~Area~~on January 12, 2025, Regulation No 2021/2282 on Health Technology Assessment (~~EEA~~HTA Regulation), ~~including~~entered ~~the~~into ~~health~~application through a phased implementation. The Regulation initially applies to new active substances for oncology and ~~medical~~ATMPs. ~~information~~It will be expanded to orphan medicinal products in January 2028, and to all centrally authorized medicinal products as of ~~these~~2030. ~~participants~~Select high-risk medical devices also came into scope in 2026. The ~~GDPR~~HTA Regulation is ~~directly~~intended ~~applicable~~to boost cooperation among Member States in ~~each~~assessing health technologies, including new medicinal products. The HTA Regulation establishes a framework for EU level joint clinical assessments, joint scientific consultations, and the early identification of emerging health technologies. The HTA Regulation permits EU Member States to use common tools, methodologies, and procedures and requires them to rely on EU level joint clinical assessment reports for the ~~twenty~~clinical components of their national HTA evaluations. Individual EU Member States will continue to be responsible for assessing non-~~seven~~clinical ~~member~~(e.g., ~~states~~economic, social, ethical) aspects of health technologies, and making decisions on pricing and reimbursement. However, under the ~~European~~HTA ~~Union~~Regulation, (EU Member States) will still be free to make their own pricing and reimbursement decisions. Moreover, ~~however~~EU Member States may, itand ~~provides~~do, ~~that~~choose to restrict the range of products for which their national health insurance systems or national healthcare systems provide reimbursement and to control the prices of such products. EU Member States may ~~introduce~~impose ~~further~~direct ~~conditions~~controls ~~that~~on ~~could~~pricing, ~~cause~~or ~~our~~otherwise ~~compliance~~adopt a system of direct or indirect controls on the profitability of the companies placing such products on the market. Other EU Member States allow companies to set their own prices but monitor and control prescription volumes and issue guidance to medical professionals to limit prescriptions of such products. The downward pressure on health care costs in general, particularly prescription drugs, has become very intense. As a result, increasingly high barriers are being erected to ~~increase~~the entry of new products. In addition, ~~ultimately~~in ~~having~~some ancountries, ~~adverse~~cross-border ~~impact~~imports from low-priced markets exert a commercial pressure on ~~our~~pricing ~~business~~within a country.

WeThe ~~are~~marketability ~~subject to the supervision~~ of ~~local~~any ~~data~~product ~~protection~~candidates ~~authorities~~for inwhich ~~those European Union jurisdictions where~~ we ~~are established~~ or ~~otherwise~~our ~~subject~~collaborators toreceive ~~the~~regulatory ~~GDPR.~~approval ~~Fines~~ for ~~certain~~commercial ~~breaches~~sale ofmay ~~the~~suffer ~~GDPR~~if ~~are significant: up to~~ the ~~greater~~government ofand ~~€20~~third-party ~~million~~payors orfail 4%to ofprovide ~~total~~adequate ~~global~~coverage ~~annual~~and ~~turnover~~reimbursement. ~~Further~~In addition, weemphasis ~~must~~on ~~comply~~managed ~~with~~care ~~both the GDPR and separately the GDPR as implemented~~ in the United ~~Kingdom~~States ~~(UK),~~has ~~each~~increased ~~regime~~and ~~having~~we ~~the~~expect ~~ability~~will tocontinue ~~fine up~~ to increase the ~~greater~~pressure ofon ~~€20~~pharmaceutical ~~million / £17 million or 4% of global turnover~~pricing. ACoverage ~~breach~~policies ~~of the GDPR or other applicable privacy~~ and ~~data~~third-party ~~protection~~reimbursement ~~laws~~rates ~~and~~may ~~regulations~~change ~~could~~at ~~result~~any intime. ~~regulatory~~Even ~~investigations,~~if ~~reputational~~favorable ~~damage,~~coverage ~~orders~~and toreimbursement ~~cease/change~~status ~~our~~is ~~use~~attained offor ~~data,~~one ~~enforcement notices,~~ or ~~potential~~more ~~civil~~products ~~claims~~for ~~including~~which ~~class~~we ~~action~~or ~~type litigation. In general, if~~ our ~~efforts~~collaborators toreceive ~~comply~~regulatory ~~with~~approval, ~~the~~less ~~GDPR~~favorable orcoverage ~~other~~policies ~~applicable European Union laws~~ and ~~regulations~~reimbursement ~~are~~rates ~~not~~may ~~successful,~~be itimplemented ~~could adversely affect our business~~ in the ~~European Union~~future.

InHealthcare the ordinary course of business, we may transfer personal data from Europe and other jurisdictions to the United States or other countries. Europe and other jurisdictions have enacted laws requiring data to be localized or limiting the transfer of personal data to other countries. In particular, the EEA and the UK have significantly restricted the transfer of personal data to the United States and other countries whose privacy laws it believes reform

39A primary trend in the U.S. healthcare industry and elsewhere is cost containment. Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medical products and services, implementing reductions in Medicare and other healthcare funding and applying new payment methodologies. For example, in March 2010, the ACA was enacted, which affected existing government healthcare programs and resulted in the development of new programs.

~~Table of Contents~~45

~~are~~Table ~~inadequate. Other jurisdictions may adopt similarly stringent interpretations~~ of their data localization and cross-border data transfer laws. Although there are currently various mechanisms that may be used to transfer personal data from the EEA and UK to the United States in compliance with law, such as the EEA and UK’s standard contractual clauses, these mechanisms are subject to legal challenges, and there is no assurance that we can satisfy or rely on these measures to lawfully transfer personal data to the United States.Contents

IfThere ~~there~~have isbeen ~~no lawful manner for us to transfer personal data from the EEA~~executive, ~~the~~judicial UKand orCongressional ~~other~~challenges ~~jurisdictions~~and amendments to ~~the~~certain ~~United~~aspects ~~States,~~of ~~or if~~ the ~~requirements~~ACA. ~~for~~For ~~a legally-compliant transfer are too onerous~~example, weon ~~could~~July ~~face significant adverse consequences~~4, ~~including the interruption or degradation of our operations~~2025, the ~~need~~One toBig ~~relocate~~Beautiful ~~part~~Bill ofAct or(OBBBA) ~~all~~was ofsigned ~~our~~into ~~business~~law, orwhich ~~data~~narrowed ~~processing~~access ~~activities~~ to ~~other~~ACA ~~jurisdictions~~marketplace atexchange ~~significant~~enrollment ~~expense,~~and ~~increased~~declined ~~exposure~~ to ~~regulatory~~extend ~~actions,~~the ~~substantial~~ACA ~~fines~~enhanced ~~and~~advanced ~~penalties,~~premium ~~the~~tax ~~inability~~credits tothat ~~transfer~~expired ~~data~~at ~~and~~the ~~work~~end ~~with~~of ~~partners~~2025, ~~vendors~~which, ~~and~~among other ~~third~~provisions ~~parties,~~in ~~and~~the ~~injunctions~~law, ~~against~~are ~~our~~anticipated ~~processing~~to orreduce ~~transferring~~the number of ~~personal~~Americans ~~data~~with ~~necessary~~health ~~to operate our business~~insurance. The ~~Additionally,~~OBBBA ~~companies~~also ~~that~~is ~~transfer~~expected ~~personal~~to ~~data~~reduce ~~out~~Medicaid ofspending ~~the EEA~~ and UKenrollment toby ~~other~~implementing ~~jurisdictions,~~work ~~particularly~~requirements tofor ~~the~~some ~~United States~~beneficiaries, ~~are~~capping ~~subject~~state-directed topayments, ~~increased~~reducing ~~scrutiny~~federal ~~from regulators~~funding, ~~individual litigants,~~ and ~~activist~~limiting ~~groups.~~provider ~~Some~~taxes ~~European~~used ~~regulators~~to ~~have~~fund ~~ordered~~the ~~certain~~program. ~~companies~~Congress tois ~~suspend~~considering orproposed ~~permanently~~legislation ~~cease~~intended ~~certain~~to ~~transfers~~further ~~out~~reduce ofhealthcare ~~Europe~~costs ~~for~~with ~~allegedly~~alternatives ~~violating~~to replace the ~~GDPR’s~~expired ~~cross-border~~ACA ~~data transfer limitations~~subsidies.

InOther ~~the~~legislative ~~United~~changes ~~States,~~have ~~the~~also ~~California~~been ~~Consumer~~proposed ~~Privacy~~and ~~Act~~adopted ~~(CCPA) creates individual privacy rights for California consumers (as defined~~ in the ~~law)~~United ~~and~~States ~~places~~since ~~increased~~the ~~privacy~~ACA ~~and~~was ~~security~~enacted. ~~obligations~~On onAugust ~~entities~~2, ~~handling~~2011, ~~certain~~the ~~personal~~Budget ~~data~~Control Act of ~~consumers~~2011, oramong ~~households.~~other ~~The~~things, ~~CCPA~~included ~~requires~~aggregate ~~covered~~reductions ~~companies~~ to ~~provide~~Medicare ~~new~~payments ~~disclosure~~ to ~~consumers~~providers ~~about~~of ~~such~~2% ~~companies’~~per ~~data~~fiscal ~~collection~~year, ~~use~~which ~~and~~went ~~sharing~~into ~~practices,~~effect ~~provide~~on ~~such~~April ~~consumers~~1, ~~new~~2013, ~~ways~~and towill ~~opt-out~~remain ofin ~~certain~~effect ~~sales~~through ~~or transfers of personal information~~2032, ~~and~~unless ~~provide consumers with~~ additional ~~causes~~Congressional of action. ~~The~~is ~~CCPA~~taken. ~~provides~~Additionally, ~~for~~on ~~civil~~March ~~penalties~~11, ~~for violations~~2021, ~~as well as a private right of action for certain data breaches that result in~~ the ~~loss~~American ofRescue ~~personal~~Plan ~~information.~~Act ~~This private right~~ of ~~action~~2021 ~~may~~was ~~increase~~signed ~~the~~into ~~likelihood of~~law, ~~and~~which ~~risks~~eliminated ~~associated~~the ~~with,~~statutory ~~data~~Medicaid ~~breach~~drug ~~litigation.~~rebate ~~The CCPA (a) allows enforcement by the California Attorney General~~cap, ~~with~~previously ~~fines~~ set at ~~$2,500~~100% ~~per~~of ~~violation~~a ~~(i.e.,~~drug’s ~~per~~average ~~person)~~manufacturer ~~or $7~~price,~~500~~ ~~per~~for ~~intentional~~single ~~violation~~source and ~~(b)~~innovator ~~authorizes~~multiple ~~private~~source ~~lawsuits~~drugs, toeffective ~~recover~~January ~~statutory~~1, ~~damages for certain data breaches~~2024.

InThe ~~addition,~~current ~~laws~~administration inis ~~all~~pursuing 50policies ~~U.S.~~to ~~states~~reduce ~~require~~regulations ~~businesses~~and toexpenditures ~~provide~~across ~~notice~~government toagencies ~~consumers~~including ~~whose~~at ~~personal~~HHS, ~~information~~the ~~has~~FDA, ~~been~~the ~~disclosed~~Centers asfor aMedicare ~~result~~& ofMedicaid aServices ~~data~~(CMS) ~~breach~~and related agencies. ~~State~~These ~~laws~~actions, ~~are~~presently ~~changing~~directed ~~rapidly~~by ~~and~~executive ~~there~~orders isor ~~discussion~~memoranda infrom the ~~U.S.~~Office ~~Congress~~ of aManagement ~~new~~and ~~comprehensive~~Budget, ~~federal~~may ~~data~~propose ~~privacy~~policy ~~law~~changes tothat ~~which~~create weadditional ~~would~~uncertainty ~~become~~for ~~subject~~our ifbusiness. itFor isexample, ~~enacted.~~the ~~The~~current ~~CCPA~~administration ~~may~~has ~~impact~~announced ~~our~~agreements ~~business~~with ~~activities~~pharmaceutical ~~and~~companies ~~exemplifies~~that require the ~~vulnerability~~drug ofmanufacturers ~~our business~~ to ~~the~~offer, ~~evolving~~through ~~regulatory~~a ~~environment~~direct-to-consumer ~~related~~platform to(TrumpRx), ~~personal~~U.S. ~~data~~patients and ~~protected~~Medicaid ~~health~~programs ~~information.~~prescription ~~Additionally,~~drug ~~the~~Most-Favored ~~California~~Nation ~~Privacy~~pricing ~~Rights~~equal ~~Act~~to ~~(CPRA)~~or ~~significantly~~lower ~~modifies~~than ~~the~~those ~~CCPA,~~paid ~~including~~in byother ~~expanding~~developed ~~consumers’~~nations, ~~rights~~ with ~~respect~~additional tomandates ~~certain~~for ~~sensitive~~direct-to-patient ~~personal~~discounts ~~information.~~and ~~The~~repatriation ~~CPRA~~of ~~also~~foreign ~~creates~~revenues. aOther ~~new~~recent ~~state~~actions, ~~agency~~for ~~that~~example, ~~will~~include be(1) ~~vested~~directing ~~with~~agencies ~~authority~~ to ~~implement~~reduce ~~and~~agency ~~enforce~~workforce ~~the CCPA~~ and ~~the~~cut ~~CPRA.~~programs; ~~New~~(2) ~~legislation~~directing ~~proposed~~HHS orand ~~enacted~~other inagencies ~~various~~to ~~other~~lower ~~states~~prescription ~~will~~drug ~~continue~~costs tothrough ~~shape~~a ~~the~~variety ~~data~~of ~~privacy~~initiatives; ~~environment~~(3) ~~nationally.~~imposing ~~For~~tariffs ~~example,~~on ~~Virginia,~~imported ~~Colorado,~~pharmaceutical ~~Utah,~~products; and ~~Connecticut~~(4) ~~have~~as ~~all~~part ~~enacted~~of ~~broad~~the ~~privacy~~Make ~~legislation.~~America ~~Certain~~Healthy ~~state~~Again ~~laws~~Commission’s ~~may~~Strategy beReport ~~more~~released ~~stringent or broader~~ in ~~scope~~September 2025, orworking ~~offer~~across ~~greater~~government ~~individual~~agencies ~~rights, with respect~~ to ~~confidential,~~increase ~~sensitive~~enforcement ~~and~~on ~~personal~~direct-to-consumer ~~information~~pharmaceutical ~~than~~advertising. ~~federal~~Additionally, ~~international~~the orcurrent ~~other~~administration ~~state~~recently ~~laws,~~called ~~and~~on ~~such~~Congress ~~laws~~to ~~may~~enact ~~differ~~“The ~~from~~Great ~~each~~Healthcare ~~other~~Plan,” ~~which~~to ~~may~~codify ~~complicate~~and ~~compliance~~expand ~~efforts.~~Most-Favored InNation ~~addition~~pricing, lower government subsidies to ~~the~~private ~~foregoing~~insurance companies, ~~any~~increase ~~breach~~healthcare ofprice ~~privacy~~transparency, ~~laws~~expand orpharmaceutical ~~data~~drugs ~~security~~available ~~laws,~~for ~~particularly~~over-the-counter ~~resulting~~purchase, inand aenact ~~significant~~restrictions ~~security~~on ~~incident~~pharmacy orbenefit ~~breach~~manager ~~involving~~payment ~~the misappropriation~~methodologies, ~~loss~~among or other ~~unauthorized~~things. ~~use~~These oractions ~~disclosure~~and ofpolicies ~~sensitive~~may orsignificantly ~~confidential~~reduce ~~patient~~U.S. ordrug ~~consumer information~~prices, ~~could~~potentially ~~have~~impacting amanufacturers’ ~~material~~global ~~adverse~~pricing ~~effect~~strategies onand ~~our business~~profitability, ~~reputation~~while ~~and~~increasing ~~financial~~their ~~condition.~~operational Ascosts aand ~~data~~compliance ~~controller,~~risks. In weJune ~~will~~2024, bein ~~accountable~~Loper ~~for~~Bright ~~any~~Enterprises ~~third-party~~v. ~~service~~Raimondo, ~~providers~~the weU.S. ~~engage~~Supreme toCourt ~~process~~greatly ~~personal~~reduced ~~data~~judicial ondeference ~~our~~to ~~behalf~~regulatory agencies, ~~including~~which ~~our~~could ~~contract~~increase ~~research~~successful ~~organizations~~legal ~~(CROs).~~challenges ~~We attempt~~ to ~~mitigate~~federal ~~the~~regulations ~~associated~~affecting ~~risks~~our ~~but~~operations. ~~there~~Congress ismay nointroduce ~~assurance~~and ~~that~~ultimately ~~privacy~~pass ~~and~~health ~~security-~~care related ~~safeguards~~legislation ~~will~~that ~~protect~~could usimpact ~~from~~the ~~all~~drug ~~risks~~approval ~~associated~~process ~~with~~and ~~the~~make ~~third-party~~changes ~~processing,~~to ~~storage~~the ~~and~~Medicare ~~transmission~~Drug ofPrice ~~such~~Negotiation ~~information~~Program.

~~Pharmaceutical~~At ~~coverage~~the state level, ~~pricing~~legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. Any such approved importation plans, when implemented, may result in lower drug prices for products covered by those programs.

~~Significant~~In ~~uncertainty~~addition, ~~exists~~it asis topossible ~~the~~that ~~coverage~~there ~~and~~will ~~reimbursement~~be ~~status~~further oflegislation ~~any~~or ~~product~~regulation ~~candidates~~that ~~for~~could ~~which~~harm ~~we or~~ our ~~collaborators~~business, ~~obtain~~financial ~~regulatory~~condition, ~~approval. In the United States~~ and ~~markets~~results ~~in other countries, sales~~ of ~~any products for which we or our collaborators receive regulatory approval for commercial sale will depend,~~ operations.

4046

Table of Contents

inThe ~~part, on the extent to which third-party payors provide coverage, and establish adequate reimbursement levels for such drug products~~U.S. InForeign ~~the~~Corrupt ~~United~~Practices ~~States, third-party payors include federal and state healthcare programs, government authorities, private managed care providers, private health insurers and other organizations.~~Act

~~Third-party~~The ~~payors~~U.S. ~~are~~Foreign ~~increasingly~~Corrupt ~~challenging~~Practices ~~the~~Act ~~price, examining the medical necessity and reviewing the cost-effectiveness~~ of ~~medical~~1977 ~~drug~~(FCPA) ~~products~~prohibits ~~and~~any ~~medical services, in addition to questioning their safety and efficacy~~U.S. ~~Such~~individual ~~payors~~or ~~may~~business ~~limit~~from ~~coverage to specific drug products on an approved list~~paying, ~~also known as a formulary~~offering, ~~which~~or ~~might~~authorizing ~~not~~payment ~~include~~or ~~all~~offering of ~~the~~anything ~~FDA-approved~~of ~~drugs~~value, ~~for~~directly ~~a particular indication. We~~ or ~~our~~indirectly, ~~collaborators may need~~ to ~~conduct~~any ~~expensive~~foreign ~~pharmaco-economic~~official, ~~studies~~political inparty ~~order~~or tocandidate ~~demonstrate~~for the ~~medical~~purpose ~~necessity and cost-effectiveness~~ of ~~our~~influencing ~~products,~~any inact ~~addition to the costs required to obtain the FDA approvals. Nonetheless, our product candidates may not be considered medically necessary~~ or ~~cost-effective.~~decision ~~Moreover,~~of the ~~process~~foreign ~~for~~entity ~~determining~~in ~~whether~~order ato ~~third-party~~assist ~~payor will provide coverage for a drug product may be separate from~~ the ~~process~~individual ~~for~~or ~~setting~~business ~~the~~in ~~price~~obtaining ~~of a drug product~~ or ~~for~~retaining ~~establishing~~business. ~~the~~The ~~reimbursement~~FCPA ~~rate~~also ~~that~~obligates ~~such~~companies awhose ~~payor~~securities ~~will~~are ~~pay~~listed ~~for~~in the ~~drug~~United ~~product.~~States ~~A payor’s decision~~ to ~~provide~~comply ~~coverage~~with ~~for~~accounting aprovisions ~~drug~~requiring ~~product~~the ~~does~~company ~~not imply that an adequate reimbursement rate will be approved. Further, one payor’s determination~~ to ~~provide~~maintain ~~coverage~~books ~~for~~and arecords ~~drug product does not assure~~ that ~~other~~accurately ~~payors~~and ~~will~~fairly ~~also~~reflect ~~provide~~all ~~coverage~~transactions ~~for~~of the ~~drug~~corporation, ~~product.~~including ~~Adequate~~international ~~third-party~~subsidiaries, ~~reimbursement~~and ~~may not be available~~ to ~~enable~~devise usand to maintain ~~price levels sufficient to realize~~ an ~~appropriate~~adequate ~~return~~system onof ~~our~~internal ~~investment~~accounting incontrols ~~product~~for ~~development~~international operations.

IfEurope we/ ~~elect~~rest to participate in certain governmental programs, we may be required to participate in discount and rebate programs, which may result in prices for our future products that will likely be lower than the prices we might otherwise obtain. For example, drug manufacturers participating under the Medicaid Drug Rebate Program must pay rebates on prescription drugs to state Medicaid programs. Under the Veterans Health Care Act (VHCA) drug companies are required to offer certain drugs at a reduced price to a number of ~~federal~~world agencies, including the U.S. Department of Veterans Affairs and Department of Defense, the Public Health Service and certain private Public Health Service designated entities in order to participate in other federal funding programs, including Medicare and Medicaid. Recent legislative changes require that discounted prices be offered for certain U.S. Department of Defense purchases for its TRICARE program via a rebate system. Participation under the VHCA also requires submission of pricing data and calculation of discounts and rebates pursuant to complex statutory formulas, as well as the entry into government procurement contracts governed by the Federal Acquisition Regulations. If our products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply.regulation

~~Different~~In ~~pricing~~addition ~~and~~to ~~reimbursement~~regulations ~~schemes exist~~ in ~~other countries. In~~ the ~~European~~United ~~Union~~States, ~~governments~~we ~~influence~~will the price of pharmaceutical products through their pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those products to consumers. Some jurisdictions operate positive and negative list systems under which products may only be ~~marketed~~subject once a reimbursement price has been agreed. 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 drug candidate to ~~currently available therapies. Across the European Union, member states carry out assessments of new pharmaceutical products from an economic, public health, and therapeutic perspective, through~~ a ~~Health~~variety ~~Technology Assessment (HTA) process, which is currently governed by the national laws~~ of EUregulations ~~Member~~in ~~States.~~other Injurisdictions ~~December 2021~~governing, ~~the~~among ~~European~~other ~~Parliament voted to implement a regulation regarding HTAs (the HTA Regulation). The HTA Regulation is scheduled to apply as of January 2025~~things, ~~and will provide a framework for pan-EU~~ clinical ~~assessments,~~trials ~~scientific consultations, identification of emerging health technologies,~~ and ~~further~~any ~~cooperation.~~commercial ~~Entry~~sales ~~into application of the Regulation could impose stricter~~ and ~~more~~distribution ~~detailed procedures to be followed by marketing authorization holders concerning conduct~~ of ~~HTAs~~our ~~in relation to their~~ products ~~which may influence related pricing and reimbursement decisions~~. ~~However,~~ ~~under~~Whether ~~the~~or ~~HTA~~not ~~Regulation,~~we EUor ~~Member~~our ~~States~~potential ~~will~~collaborators ~~still~~obtain beFDA ~~free~~approval tofor ~~make~~a ~~their own pricing and reimbursement decisions. Moreover~~product, EUwe ~~Member~~must ~~States~~obtain ~~may, and do, choose to restrict~~ the ~~range~~requisite ofapprovals ~~products~~from ~~for~~regulatory ~~which~~authorities ~~their~~in ~~national~~foreign ~~health~~countries ~~insurance~~prior ~~systems or national healthcare systems provide reimbursement and~~ to ~~control~~ the ~~prices~~commencement of ~~such~~clinical ~~products. EU~~trials ~~Member States may impose direct controls on pricing,~~ or ~~otherwise~~marketing ~~adopt a system~~ of ~~direct or indirect controls on~~ the ~~profitability~~product ofin ~~the~~those ~~companies placing such products on the market~~countries. ~~Other~~ ~~EU Member States allow companies to set their own prices but monitor and control prescription volumes and issue guidance to medical professionals~~

41Clinical trials in the EU

~~Table~~Certain countries outside of ~~Contents~~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. In the European Union, for example, clinical trials are governed by the Clinical Trials Regulation (EU) No 536/2014 (CTR), which entered into application on January 31, 2022 repealing and replacing the former Clinical Trials Directive 2001/20 (CTD). The CTR is intended to harmonize and streamline clinical trial authorizations, simplify adverse-event reporting procedures, improve the supervision of clinical trials and increase transparency. Specifically, the Regulation, which is directly applicable in all EU Member States, introduces a streamlined application procedure through a single-entry point, the "EU portal", the Clinical Trials Information System (CTIS); a single set of documents to be prepared and submitted for the application; as well as simplified reporting procedures for clinical trial sponsors. A harmonized procedure for the assessment of applications for clinical trials has been introduced and is divided into two parts. Part I assessment is led by the competent authorities of a reference Member State selected by the trial sponsor and relates to clinical trial aspects that are considered to be scientifically harmonized across EU Member States. This assessment is then submitted to the competent authorities of all concerned EU Member States in which the trial is to be conducted for their review. Part II is assessed separately by the competent authorities and Ethics Committees in each concerned EU Member State. Individual EU Member States retain the power to authorize the conduct of clinical trials on their territory. The CTR foresaw a three-year transition period that ended on January 31, 2025. Since this date, all new or ongoing trials are subject to the provisions of the CTR.

toThe ~~limit~~requirements ~~prescriptions~~and ofprocesses ~~such~~governing ~~products.~~the ~~The~~conduct ~~downward~~of ~~pressure~~clinical ontrials, ~~health~~product ~~care costs in general~~licensing, ~~particularly~~pricing ~~prescription~~and ~~drugs,~~reimbursement ~~has~~vary ~~become~~from ~~very~~country ~~intense~~to country. AsIn aall ~~result~~major territories, ~~increasingly~~including ~~high~~the ~~barriers~~European ~~are~~Union, ~~being~~clinical ~~erected~~trials tomust ~~the~~be ~~entry~~conducted ofin ~~new~~accordance ~~products.~~with InGCP ~~addition,~~and inthe ~~some~~applicable ~~countries,~~regulatory ~~cross-border~~requirements ~~imports~~and ~~from~~the ~~low-priced~~ethical ~~markets~~principles ~~exert~~that ahave ~~commercial~~their ~~pressure~~origin onin ~~pricing~~the ~~within~~Declaration aof ~~country~~Helsinki.

~~The~~Review ~~marketability of any product candidates for which we or our collaborators receive regulatory approval for commercial sale may suffer if the government~~ and ~~third-party~~authorization ~~payors~~process ~~fail to provide adequate coverage and reimbursement. In addition, emphasis on managed care~~ in the ~~United~~EU States has increased and we expect will continue to increase the pressure on pharmaceutical pricing. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which we or our collaborators receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

~~Healthcare~~In ~~reform~~the EU, medicinal products can only be commercialized after a related marketing authorization (MA), has been granted. To obtain an MA for a product in the EU, an applicant must submit a Marketing Authorization Application (MAA), either under a centralized procedure administered by the European Medicines Agency (EMA), or one of the procedures administered by the competent authorities of EU Member States (decentralized procedure, national procedure or mutual recognition procedure). An MA may be granted only to an applicant established in the EU.

A primary trend in the U.S. healthcare industry and elsewhere is cost containment. Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medical products and services, implementing reductions in Medicare and other healthcare funding and applying new payment methodologies. For example, in March 2010, the ACA was enacted, which affected existing government healthcare programs and resulted in the development of new programs.47

~~There~~Table ~~have been executive, judicial and Congressional challenges and amendments to certain aspects~~ of the ACA. For example, on August 16, 2022, the Inflation Reduction Act of 2022 (IRA) was signed into law, which 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. It is possible that the ACA will be subject to judicial or Congressional challenges in the future. It is unclear how such challenges and the healthcare reform measures of the current administration will impact the ACA and our business.Contents

~~Other~~The ~~legislative~~European ~~changes~~Union ~~have also been proposed~~ and ~~adopted in~~ the ~~United~~European ~~States~~Economic ~~since~~Area ~~the~~consist ~~ACA~~of ~~was enacted. On August 2, 2011,~~ the ~~Budget~~EU ~~Control~~Member ~~Act of 2011~~States, ~~among~~plus ~~other things~~Norway, ~~included aggregate reductions to Medicare payments to providers of 2% per fiscal year~~Iceland, ~~which went into effect on April 1, 2013,~~ and ~~will~~Liechtenstein ~~remain~~which inare ~~effect~~member ~~through~~states ~~2032,~~of ~~unless~~the ~~additional~~European ~~Congressional~~Economic ~~action is taken~~Area. ~~Additionally,~~To onobtain ~~March~~regulatory ~~11,~~approval ~~2021, the American Rescue Plan Act~~ of ~~2021~~an ~~was~~investigational ~~signed~~drug ~~into~~or ~~law,~~biological ~~which~~product ~~eliminated~~under ~~the~~European ~~statutory~~Union ~~Medicaid~~regulatory ~~drug rebate cap~~systems, ~~previously~~we ~~set~~must atsubmit ~~100% of~~ a ~~drug’s~~marketing ~~average~~authorization ~~manufacturer~~application ~~price,~~either ~~for~~under ~~single~~the ~~source~~so-called ~~and~~centralized ~~innovator~~or ~~multiple~~national ~~source~~authorization ~~drugs, effective January 1, 2024~~procedures.

•

~~There~~The ~~has~~Centralized ~~been~~marketing ~~heightened~~authorization, ~~governmental~~which ~~scrutiny~~is ~~recently~~issued ~~over~~by the ~~manner~~European inCommission ~~which~~through ~~pharmaceutical~~the ~~companies~~Centralized ~~set prices for their marketed products~~Procedure, ~~which~~based ~~has~~on ~~resulted~~the inscientific ~~several~~opinion ~~Presidential~~of ~~executive~~the ~~orders,~~EMA’s ~~Congressional~~Committee ~~inquiries~~for ~~and~~Medicinal ~~proposed~~Products ~~federal~~for ~~legislation,~~Human ~~as well as state efforts~~Use, ~~designed~~and ~~to,~~which ~~among~~is ~~other~~valid ~~things,~~throughout ~~bring~~the ~~more~~entire ~~transparency~~territory toof ~~product pricing, reduce~~ the ~~cost~~European ofEconomic ~~prescription~~Area ~~drugs~~(which ~~under~~is ~~Medicare,~~compromised ~~review~~of the ~~relationship~~27 ~~between~~EU ~~pricing~~Member ~~and~~States ~~manufacturer~~plus ~~patient programs~~Iceland, Liechtenstein and ~~reform~~Norway). ~~government~~The ~~program~~Centralized ~~reimbursement~~Procedure ~~methodologies~~is mandatory for ~~drug~~certain ~~products.~~types ~~For~~of ~~example~~products, ~~the~~such ~~IRA,~~as ~~among other things,~~ (1i) ~~directs~~biotechnology ~~the~~medicinal ~~U.S.~~products ~~Department~~such ofas ~~Health~~genetic ~~and~~engineering, ~~Human Services~~ (~~HHS~~ii), toorphan ~~negotiate~~medicinal ~~the~~products, ~~price~~(iii) ofmedicinal ~~certain~~products ~~high-expenditure,~~containing ~~single-source~~a ~~drugs~~new ~~that~~active ~~have~~substance ~~been~~indicated onfor the ~~market~~treatment ~~for~~of atAIDS, ~~least~~cancer, ~~seven~~neurodegenerative ~~years~~disorders, ~~covered under Medicare~~diabetes, ~~the~~autoimmune ~~Medicare~~and ~~Drug~~viral ~~Price~~diseases ~~Negotiation Program,~~ and (2iv) ~~imposes~~advanced-therapy ~~rebates~~medicines, ~~under~~such ~~Medicare~~as ~~Part~~gene Btherapy, ~~and~~somatic ~~Medicare~~cell ~~Part~~therapy Dor totissue-engineered ~~penalize~~medicines. ~~price~~The ~~increases~~Centralized ~~that~~Procedure ~~outpace~~is ~~inflation.~~optional ~~These~~for ~~provisions~~products ~~began~~containing toa ~~take~~new ~~effect~~active ~~progressively~~substance innot ~~fiscal~~yet ~~year~~authorized ~~2023.~~in Onthe ~~August~~European 15Union, ~~2024,~~or ~~HHS~~for ~~announced~~products ~~the~~that ~~agreed-upon~~constitute ~~prices~~a ofsignificant ~~the~~therapeutic, ~~first~~scientific ~~ten~~or ~~drugs~~technical ~~that~~innovation ~~were~~or ~~subject~~which toare ~~price~~in ~~negotiations, although~~ the ~~Medicare~~interest ~~Drug~~of ~~Price~~public ~~Negotiation~~health ~~Program~~in isthe ~~currently~~European ~~subject~~Union. toUnder ~~legal~~the ~~challenges.~~centralized Onprocedure, ~~January~~the ~~17,~~EMA’s ~~2024,~~Committee ~~HHS~~for ~~selected~~Medicinal ~~fifteen~~Products ~~additional~~for ~~products~~Human ~~covered~~Use ~~under~~(CHMP), ~~Part~~conducts Dthe ~~for~~initial ~~price~~assessment ~~negotiation~~of ina ~~2025~~product. ~~Each~~The ~~year~~CHMP ~~thereafter,~~is ~~more~~also ~~Part~~responsible Bfor ~~and~~several ~~Part~~post-authorization Dand ~~products~~maintenance ~~will~~activities, ~~become~~such ~~subject~~as to the ~~Medicare~~assessment ~~Drug~~of ~~Price~~modifications ~~Negotiation~~or ~~Program.~~extensions ~~Further,~~to onan ~~December~~existing 7,MA. ~~2023,~~The anmaximum ~~initiative~~timeframe tofor ~~control~~ the ~~price~~evaluation of ~~prescription~~an ~~drugs~~MAA ~~through~~under the ~~use~~centralized ofprocedure ~~march-in~~is ~~rights~~210 ~~under~~days, ~~the~~excluding ~~Bayh-Dole~~clock ~~Act~~stops ~~was~~when ~~announced.~~additional Oninformation ~~December~~or 8,written ~~2023,~~or ~~the~~oral ~~National~~explanation ~~Institute~~is ofto ~~Standards~~be ~~and~~provided ~~Technology~~by ~~published~~the ~~for~~applicant ~~comment~~in aresponse ~~Draft~~to ~~Interagency~~questions ~~Guidance~~of the CHMP.

•

42Decentralized Procedure marketing authorizations are available for products not falling within the mandatory scope of the Centralized Procedure. An identical dossier is submitted to the competent authorities of each of the EU Member States in which the marketing authorization is sought, one of which is selected by the applicant as the Reference Member State (RMS), to lead the evaluation of the regulatory submission. The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics (SmPC), and a draft of the labeling and package leaflet as distilled from the preliminary evaluation, which are sent to the other concerned EU Member States (referred to as the Concerned Member States) for their approval. If the Concerned Member States raise no objections, based on a potential serious risk to public health, to the assessment, SmPC, labeling, or packaging proposed by the RMS, the RMS records the agreement, closes the procedure and informs the applicant accordingly. If a concerned Member State cannot approve the assessment report and related materials due to concerns relating to a potential serious risk to public health, disputed elements are referred to the Heads of Medicines Agencies’ Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), for review. If the CMDh fails to reach a consensus, the matter escalates to the European Commission who’s decision is binding on all EU Member States. Each Member State concerned by the procedure is required to adopt a national decision to grant a national marketing authorization in conformity with the approved assessment report, SmPC and the labeling and package leaflet as approved.

•

~~Table~~Where a product has already been authorized for marketing in an EU Member, the granted national marketing authorization can be used for mutual recognition in other EU Member States through the Mutual Recognition Procedure (MRP), resulting in progressive national approval of ~~Contents~~the product in the EU.

•

~~Framework~~National ~~for~~marketing ~~Considering~~authorizations, ~~the Exercise of March-In Rights~~ which ~~for~~are ~~the~~issued ~~first~~by ~~time~~a ~~includes~~single ~~the~~competent ~~price~~authority of athe ~~product~~EU asMember ~~one~~States ~~factor~~and anonly ~~agency~~covers ~~can~~such ~~use~~authority’s ~~when~~respective ~~deciding~~territory, toare ~~exercise~~also ~~march-in~~available ~~rights.~~for ~~While~~products ~~march-in rights have~~ not ~~previously~~falling ~~been~~within ~~exercised,~~the itmandatory isscope ~~uncertain~~of ~~if that will continue under~~ the ~~new~~Centralized ~~framework~~Procedure. AtOnce ~~the~~a ~~state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological~~ product ~~pricing,~~has ~~including~~been ~~price~~authorized orfor ~~patient reimbursement constraints, discounts, restrictions on certain product access and~~ marketing ~~cost disclosure and transparency measures, and,~~ in ~~some~~an ~~cases,~~EU ~~designed~~Member toState ~~encourage~~through ~~importation~~the ~~from~~National ~~other countries and bulk purchasing. For example~~Procedure, ~~on January 5, 2024, the FDA approved Florida’s Section 804 Importation Program (SIP) proposal to import certain drugs from Canada for specific state healthcare programs. It is unclear how~~ this ~~program~~National ~~will~~marketing beauthorization ~~implemented,~~can ~~including which drugs will~~ be ~~chosen,~~recognized ~~and whether it will be subject to legal challenges~~ in ~~the~~other ~~United~~Member States orthrough ~~Canada. Other states have also submitted SIP proposals that are pending review by~~ the ~~FDA.~~Mutual ~~Any~~Recognition ~~such approved importation plans, when implemented, may result in lower drug prices for products covered by those programs~~Procedure.

~~In addition, it is possible that there will be further legislation or regulation that could harm our business, financial condition, and results of operations.~~48

~~The~~Table ~~U.S.~~of ~~Foreign Corrupt Practices Act~~Contents

~~The~~An ~~U.S.~~MA ~~Foreign~~has, ~~Corrupt~~in ~~Practices~~principle, ~~Act~~an ofinitial ~~1977~~validity ~~(FCPA)~~of ~~prohibits~~five ~~any U~~years.S. ~~individual~~The orMA ~~business~~may ~~from~~be ~~paying,~~renewed ~~offering,~~after orfive ~~authorizing~~years ~~payment~~on orthe ~~offering~~basis of ~~anything~~a re-evaluation of ~~value,~~the ~~directly~~risk-benefit balance by the EMA or ~~indirectly,~~by tothe ~~any~~competent ~~foreign~~authority ~~official,~~of ~~political~~the ~~party~~EU orMember ~~candidate~~State ~~for~~in which the ~~purpose~~original ofMA ~~influencing~~was ~~any~~granted. ~~act~~To support the application, the MA holder must provide the EMA or ~~decision~~the competent authority with a consolidated version of the ~~foreign~~Common ~~entity~~Technical inDocument ~~order~~providing up-to-date ~~assist~~data concerning the ~~individual~~quality, orsafety ~~business~~and inefficacy ~~obtaining~~of orthe ~~retaining~~product, ~~business.~~including ~~The~~all ~~FCPA~~variations ~~also~~introduced ~~obligates~~since ~~companies~~the ~~whose~~MA ~~securities~~was ~~are~~granted, ~~listed~~at inleast nine months before the ~~United~~MA ~~States~~ceases to ~~comply~~be ~~with~~valid. ~~accounting~~The ~~provisions~~European ~~requiring~~Commission or the ~~company~~competent toauthorities ~~maintain~~of ~~books~~the ~~and~~EU ~~records~~Member ~~that~~States ~~accurately~~may ~~and~~decide ~~fairly~~on ~~reflect~~justified ~~all~~grounds ~~transactions~~relating ofto pharmacovigilance, to proceed with one further five year renewal period for the ~~corporation,~~MA. ~~including~~Once ~~international~~subsequently ~~subsidiaries~~definitively renewed, ~~and~~the toMA ~~devise~~shall ~~and~~be ~~maintain~~valid for an ~~adequate~~unlimited ~~system~~period. Any authorization which is not followed by the actual placing of ~~internal~~the ~~accounting~~medicinal ~~controls~~product on the EU market (for ~~international~~a ~~operations~~centralized MA) or on the market of the authorizing EU Member State within three years after authorization ceases to be valid (the so-called sunset clause).

~~Europe~~Accelerated /and ~~rest~~alternative ofmarketing ~~world~~authorization ~~government~~mechanisms ~~regulation~~in the EU

InInnovative ~~addition~~products that target an unmet medical need and are expected to ~~regulations~~be inof ~~the~~major ~~United~~public ~~States,~~health weinterest ~~will~~may be ~~subject~~eligible tofor a ~~variety~~number of ~~regulations~~expedited indevelopment ~~other~~and ~~jurisdictions~~review ~~governing~~programs, ~~among~~such ~~other~~as ~~things~~the Priority Medicines (PRIME), ~~clinical~~scheme, ~~trials~~which ~~and~~provides ~~any~~incentives ~~commercial~~similar ~~sales~~to ~~and~~the ~~distribution~~breakthrough therapy designation in the U.S. PRIME is a voluntary scheme aimed at enhancing the EMA’s support for the development of ~~our~~medicinal products that target unmet medical needs. ~~Whether~~Eligible products must target conditions for which there is an unmet medical need (there is no satisfactory method of diagnosis, prevention or ~~not~~treatment wein the EU or, ~~our~~if ~~potential~~there ~~collaborators~~is, ~~obtain~~the ~~FDA~~new ~~approval~~medicinal ~~for~~product will bring a ~~product,~~major wetherapeutic advantage) and they must ~~obtain~~demonstrate the ~~requisite~~potential ~~approvals~~to ~~from~~address ~~regulatory~~the ~~authorities~~unmet inmedical ~~foreign~~need ~~countries~~by ~~prior~~introducing new methods of therapy or improving existing ones. Benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the ~~commencement~~EMA, offrequent discussions on clinical ~~trials~~trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted. Importantly, a dedicated contact and rapporteur from CHMP, or ~~marketing~~Committee for Advanced Therapies, are appointed early in the PRIME scheme facilitating increased understanding of the product inat ~~those~~EMA’s ~~countries~~Committee level. A kick-off meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies. Where, during the course of development, a medicine no longer meets the eligibility criteria, support under the PRIME scheme may be withdrawn.

~~Certain~~A ~~countries~~“conditional” ~~outside~~MA ofmay ~~the~~be ~~United~~granted ~~States~~in ~~have~~cases awhere ~~similar~~all ~~process that requires~~ the ~~submission~~required ofsafety aand ~~clinical~~efficacy ~~trial~~data ~~application~~are ~~much~~not ~~like~~yet ~~the~~available. ~~IND~~The ~~prior~~European toCommission ~~the~~may ~~commencement~~grant ofa ~~human~~conditional ~~clinical~~MA ~~trials.~~for Ina ~~the~~medicinal ~~European~~product ~~Union,~~if ~~for~~it ~~example,~~is ~~clinical~~demonstrated ~~trials~~that ~~are~~all ~~governed~~of by the ~~Clinical~~following ~~Trials~~criteria ~~Regulation~~are ~~(EU)~~met: ~~No 536/2014~~ (~~CTR~~i), ~~which~~the ~~entered~~benefit-risk ~~into~~balance ~~application~~of ~~on January 31, 2022 repealing and replacing~~ the ~~former~~medicinal ~~Clinical~~product ~~Trials~~is ~~Directive~~positive; ~~2001/20~~ (~~CTD~~ii). ~~The~~it ~~CTR~~ is ~~intended~~likely tothat ~~harmonize~~the ~~and~~applicant ~~streamline~~will ~~clinical~~be ~~trial~~able ~~authorizations,~~to ~~simplify~~provide ~~adverse-event~~comprehensive ~~reporting~~data ~~procedures,~~post-authorization; ~~improve~~(iii) the ~~supervision~~medicinal ofproduct ~~clinical~~fulfils ~~trials~~an ~~and~~unmet ~~increase~~medical ~~transparency.~~need; ~~Specifically,~~and (iv) the ~~Regulation,~~benefit ~~which~~of isthe ~~directly~~immediate ~~applicable~~availability into ~~all~~patients EUof ~~Member~~the ~~States,~~medicinal ~~introduces~~product ais ~~streamlined~~greater ~~application~~than ~~procedure~~the ~~through~~risk ainherent ~~single-entry~~in ~~point,~~ the ~~"EU~~fact ~~portal",~~that ~~the~~additional ~~Clinical~~data ~~Trials~~are ~~Information~~still ~~System~~required. ~~(CTIS);~~The aconditional ~~single~~MA ~~set~~is ofsubject ~~documents~~to conditions to be ~~prepared~~fulfilled ~~and submitted~~ for generating the ~~application;~~missing asdata ~~well~~or asensuring ~~simplified~~increased ~~reporting~~safety ~~procedures for clinical trial sponsors~~measures. AIt ~~harmonized~~is ~~procedure~~valid for ~~the~~one ~~assessment~~year ofand ~~applications~~must ~~for~~be ~~clinical~~renewed ~~trials~~annually ~~has~~until ~~been~~all ~~introduced~~related ~~and~~conditions ishave ~~divided~~been ~~into two parts~~fulfilled. ~~Part~~Once Iany ~~assessment~~pending isstudies ~~led~~are byprovided, the ~~competent~~conditional ~~authorities~~MA ofcan ~~a reference Member State selected by the trial sponsor and relates to clinical trial aspects that are considered to~~ be ~~scientifically~~converted ~~harmonized~~into ~~across~~a EUtraditional ~~Member States~~MA. ~~This~~However, ~~assessment~~if ~~is then submitted to~~ the ~~competent~~conditions ~~authorities~~are ofnot ~~all~~fulfilled ~~concerned~~within ~~EU Member States in which~~ the ~~trial~~timeframe isset ~~to be conducted for their review. Part II is assessed separately~~ by the ~~competent~~EMA ~~authorities~~ and ~~Ethics~~approved ~~Committees~~by ~~in each concerned EU Member State. Individual EU Member States retain~~ the ~~power~~European toCommission, ~~authorize~~ the ~~conduct~~MA ofwill ~~clinical~~cease ~~trials on their territory. The CTR foresaw a three-year transition period that ended on January 31, 2025. Since this date, all new or ongoing trials are subject~~ to ~~the~~be ~~provisions of the CTR~~renewed.

43An MA may also be granted “under exceptional circumstances” where the applicant can show that it is unable to provide comprehensive data on efficacy and safety under normal conditions of use even after the product has been authorized and subject to specific procedures being introduced. These circumstances may arise in particular when the intended indications are very rare and, in the state of scientific knowledge at that time, it is not possible to provide comprehensive information, or when generating data may be contrary to generally accepted ethical principles. Like a conditional MA, an MA granted in exceptional circumstances is reserved to medicinal products intended to be authorized for treatment of rare diseases or unmet medical needs for which the applicant does not hold a complete data set that is required for the grant of a standard MA. However, unlike the conditional MA, an applicant for authorization in exceptional circumstances is not subsequently required to provide the missing data. Although the MA “under exceptional circumstances” is granted definitively, the risk-benefit balance of the medicinal product is reviewed annually, and the MA will be withdrawn if the risk-benefit ratio is no longer favorable.

~~Table of Contents~~49

~~The~~Table ~~requirements and processes governing the conduct~~ of clinical trials, product licensing, pricing and reimbursement vary from country to country. In all major territories, including the European Union, clinical trials must be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.Contents

~~The~~Pediatric ~~European~~development ~~Union~~in ~~and~~ the ~~European Economic Area consist, at the time of writing, of the~~ EU Member States, plus Norway, Iceland, and Liechtenstein which are member states of the European Economic Area. To obtain regulatory approval of an investigational drug or biological product under European Union regulatory systems, we must submit a marketing authorization application either under the so-called centralized or national authorization procedures. There are three procedures for a marketing authorization (MA) to be obtained:

~~The~~In ~~Centralized~~the ~~marketing authorization~~EU, ~~which~~Regulation is(EC) ~~issued~~No by1901/2006 ~~the~~provides ~~European~~that ~~Commission~~all ~~through~~MAAs ~~the~~for ~~Centralized~~new ~~Procedure,~~medicinal ~~based~~products onhave ~~the~~to ~~scientific~~include ~~opinion of~~ the ~~EMA’s~~results ~~Committee~~of ~~for~~trials ~~Medicinal~~conducted ~~Products~~in ~~for~~the ~~Human~~pediatric ~~Use~~population, ~~and~~in ~~which~~compliance iswith ~~valid~~a ~~throughout~~pediatric ~~the~~investigation ~~entire~~plan ~~territory~~(PIP), ofagreed with the ~~European~~EMA’s ~~Economic~~Pediatric ~~Area~~Committee (PDCO). The ~~Centralized~~PIP ~~Procedure~~sets isout ~~mandatory~~the ~~for~~timing ~~certain~~and ~~types~~measures ofproposed ~~products,~~to ~~such~~generate asdata ~~(i)~~to ~~biotechnology~~support ~~medicinal~~a ~~products~~pediatric ~~such~~indication asof ~~genetic~~the ~~engineering, (ii) orphan~~ medicinal ~~products,~~product ~~(iii)~~for ~~medicinal~~which ~~products~~MA ~~containing~~is abeing ~~new~~sought. ~~active~~The ~~substance~~PDCO ~~indicated~~can ~~for~~grant ~~the~~a ~~treatment~~deferral of ~~AIDS,~~the ~~cancer,~~obligation ~~neurodegenerative~~to ~~disorders,~~implement ~~diabetes,~~some ~~autoimmune~~or ~~and~~all ~~viral~~of ~~diseases~~the ~~and~~measures ~~(iv)~~provided ~~advanced-therapy~~in ~~medicines,~~the ~~such~~PIP asuntil ~~gene~~there ~~therapy,~~are ~~somatic~~sufficient ~~cell~~data ~~therapy~~to ordemonstrate ~~tissue-engineered~~the ~~medicines.~~efficacy ~~The~~and ~~Centralized~~safety ~~Procedure~~of isthe ~~optional~~product ~~for~~in ~~products~~adults. ~~containing~~Further, athe ~~new~~obligation ~~active~~to ~~substance~~provide ~~not~~pediatric ~~yet~~clinical ~~authorized~~trial indata ~~the~~can ~~European~~be ~~Union,~~waived orby ~~for~~the ~~products~~PDCO ~~that~~when ~~constitute~~these adata ~~significant~~are ~~therapeutic,~~not ~~scientific~~needed or ~~technical~~appropriate ~~innovation~~because orthe ~~which~~product ~~are~~is inlikely ~~the~~to ~~interest~~be ofineffective ~~public~~or ~~health~~unsafe in children, the ~~European~~disease ~~Union.~~or ~~Under~~condition ~~the~~for ~~centralized~~which ~~procedure,~~ the ~~EMA’s~~product ~~Committee~~is ~~for~~intended ~~Medicinal~~occurs ~~Products~~only ~~for~~in ~~Human~~adult ~~Use (CHMP)~~populations, ~~conducts~~or when the ~~initial~~product ~~assessment~~does ofnot represent a ~~product.~~significant ~~The~~therapeutic ~~CHMP~~benefit isover ~~also~~existing ~~responsible~~treatments for ~~several~~pediatric ~~post-authorization~~patients. ~~and~~Once ~~maintenance activities, such as~~ the ~~assessment~~MA ofis ~~modifications~~obtained orin ~~extensions~~all toEU anMember ~~existing~~States ~~MA.~~and ~~The~~study ~~maximum~~results ~~timeframe~~are ~~for~~included in the ~~evaluation~~product ofinformation, aneven ~~MAA~~when ~~under~~negative, the ~~centralized~~product ~~procedure~~ is ~~210~~eligible ~~days,~~for ~~excluding~~a ~~clock~~six-month ~~stops~~extension ~~when~~to ~~additional~~the ~~information~~Supplementary orProtection ~~written~~Certificate, or ~~oral~~SPC, ~~explanation~~if any is toin beeffect ~~provided~~at by the ~~applicant~~time of authorization or, in ~~response~~the tocase ~~questions~~of orphan medicinal products, a two-year extension of ~~the~~orphan ~~CHMP~~market exclusivity.

~~Decentralized~~Data Procedure marketing authorizations are available for products not falling within the mandatory scope of the Centralized Procedure. An identical dossier is submitted to the competent authorities of each of the Member States in which the marketing authorization is sought, one of which is selected by the applicant as the Reference Member State (RMS), to lead the evaluation of the regulatory submission. The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics (SmPC), and amarket ~~draft~~exclusivity of the labeling and package leaflet as distilled from the preliminary evaluation, which are sent to the other Member States (referred to as the Concerned Member States) for their approval. If the Concerned Member States raise no objections, based on a potential serious risk to public health, to the assessment, SmPC, labeling, or packaging proposed by the RMS, the RMS records the agreement, closes the procedure and informs the applicant accordingly. Each Member State concerned by the procedure is required to adopt a national decision to grant a national marketing authorization in ~~conformity with~~ the ~~approved~~EU assessment report, SmPC and the labeling and package leaflet as approved. Where a product has already been authorized for marketing in a Member State of the European Economic Area, the granted national marketing authorization can be used for mutual recognition in other Member States through the Mutual Recognition Procedure (MRP), resulting in progressive national approval of the product in the European Economic Area.

~~National~~The ~~marketing~~EU ~~authorizations~~provides opportunities for data and market exclusivity related to MAs. Upon receiving an MA, ~~which~~innovative medicinal products are ~~issued~~generally byentitled ato ~~single~~receive ~~competent~~eight ~~authority~~years of ~~the~~data ~~member~~exclusivity ~~states~~and 10 years of ~~the~~market ~~European~~exclusivity. ~~Economic~~Data ~~Area~~exclusivity, ~~and~~if ~~only~~granted, ~~covers~~prevents ~~such~~regulatory ~~authority~~authorities in the EU from referencing the innovator’s ~~respective~~data ~~territory,~~to ~~are~~assess ~~also~~a ~~available~~generic ~~for~~application ~~products~~or ~~not~~biosimilar ~~falling~~application ~~within~~for eight years from the ~~mandatory~~date ~~scope~~of authorization of the ~~Centralized~~innovative ~~Procedure~~product, after which a generic or biosimilar MAA can be submitted, and the innovator’s data may be referenced. ~~Once~~The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product ~~has~~in ~~been~~the ~~authorized~~EU ~~for~~until ~~marketing~~10 years have elapsed from the initial MA of the reference product in the EU. The overall ten-year period may, occasionally, be extended for a ~~Member~~further ~~State~~year to a maximum of 11 years if, during the ~~European~~first ~~Economic~~eight ~~Area~~years ~~through~~of those ten years, the ~~National~~MA ~~Procedure~~holder obtains an authorization for one or more new therapeutic indications which, ~~this~~during ~~National~~the ~~marketing~~scientific evaluation prior to their authorization, ~~can~~are ~~also~~held beto ~~recognized~~bring a significant clinical benefit in ~~other~~comparison ~~Member~~with ~~States~~existing ~~through~~therapies. However, there is no guarantee that a product will be considered by the ~~Mutual~~EU’s ~~Recognition~~regulatory ~~Procedure~~authorities to be a new chemical/biological entity, and products may not qualify for data exclusivity.

AnOrphan MAdesignation ~~has,~~ in ~~principle, an initial validity of five years. The MA may be renewed after five years on~~ the ~~basis of a re-evaluation of the risk-benefit balance by the EMA or by the competent authority of the~~ EU ~~Member State~~

44The European Commission may also grant orphan drug designation to promote the development of products that may offer therapeutic benefits for life-threatening or chronically debilitating conditions affecting not more than five in 10,000 people in the European Union. In addition, orphan drug designation can be granted if the drug is intended for a life threatening, seriously debilitating or serious and chronic condition in the European Union and without incentives it is unlikely that sales of the drug in the European Union would be sufficient to justify developing the drug. Orphan drug designation is only available if there is no other satisfactory method approved in the European Union of diagnosing, preventing or treating the condition, or if such a method exists, the proposed orphan drug will be of significant benefit to patients. Orphan drug designation provides opportunities for free protocol assistance, fee reductions for access to the centralized regulatory procedures and ten years of market exclusivity following drug approval, which can be extended to 12 years if trials are conducted in accordance with an agreed-upon pediatric investigational plan. The exclusivity period may be reduced to six years if the designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.

~~Table~~Pricing ofand ~~Contents~~reimbursement in the EU

in which the original MA was granted. To support the application, the MA holder must provide the EMA or the competent authority with a consolidated version of the Common Technical Document providing up-to-date data concerning the quality, safety and efficacy of the product, including all variations introduced since the MA was granted, at least nine months before the MA ceases to be valid. The European Commission or the competent authorities of the EU Member States may decide on justified grounds relating to pharmacovigilance, to proceed with one further five year renewal period for the MA. Once subsequently definitively renewed, the MA shall be valid for an unlimited period. Any authorization which is not followed by the actual placing of the medicinal product on the EU market (for a centralized MA) or on the market of the authorizing EU Member State within three years after authorization ceases to be valid (the so-called sunset clause).50

~~The~~Table ~~EU provides opportunities for data and market exclusivity related to MAs. Upon receiving an MA, innovative medicinal products are generally entitled to receive eight years~~ of data exclusivity and 10 years of market exclusivity. Data exclusivity, if granted, prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic application or biosimilar application for eight years from the date of authorization of the innovative product, after which a generic or biosimilar MAA can be submitted, and the innovator’s data may be referenced. The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from the initial MA of the reference product in the EU. The overall ten-year period may, occasionally, be extended for a further year to a maximum of 11 years if, during the first eight years of those ten years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies. However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical/biological entity, and products may not qualify for data exclusivity.Contents

~~The~~In ~~European Commission may also grant orphan drug designation to promote~~ the ~~development~~EU, ofpricing ~~products~~and ~~that~~reimbursement ~~may~~schemes ~~offer~~vary ~~therapeutic~~widely ~~benefits~~from ~~for~~country ~~life-threatening~~to ~~or chronically debilitating conditions affecting not more than five in 10,000 people in the European Union~~country. InSome ~~addition,~~EU ~~orphan~~Member ~~drug~~States ~~designation~~may ~~can~~approve bea ~~granted~~specific ifprice ~~the drug is intended~~ for a ~~life threatening~~product, ~~seriously debilitating~~ or ~~serious~~they ~~and~~may ~~chronic~~instead ~~condition~~adopt ina ~~the~~system ~~European~~of ~~Union~~direct ~~and~~or ~~without~~indirect ~~incentives~~controls iton isthe ~~unlikely~~profitability ~~that sales~~ of the ~~drug~~company inplacing the ~~European~~product ~~Union~~on ~~would be sufficient to justify developing~~ the ~~drug~~market. ~~Orphan~~Other ~~drug~~EU ~~designation~~Member isStates ~~only~~allow ~~available~~companies if there is no other satisfactory method approved in the European Union of diagnosing, preventing or treating the condition, or if such a method exists, the proposed orphan drug will be of significant benefit to ~~patients.~~fix ~~Orphan~~their ~~drug~~own ~~designation~~prices ~~provides opportunities~~ for ~~free~~products ~~protocol~~but ~~assistance,~~monitor ~~fee~~and ~~reductions~~control ~~for~~prescription ~~access~~volumes ~~to the centralized regulatory procedures~~ and ~~ten~~issue ~~years~~guidance ~~of market exclusivity following drug approval, which can be extended~~ to 12physicians ~~years if trials are conducted in accordance with an agreed-upon pediatric investigational plan. The exclusivity period may be reduced~~ to ~~six~~limit ~~years if the designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity~~prescriptions.

In ~~the~~addition, some EU Member States may require the completion of additional studies that compare the cost-effectiveness of a particular medicinal product candidate to currently available therapies. This Health Technology Assessment (HTA), ~~pricing~~process is the procedure according to which the assessment of the public health impact, therapeutic impact and ~~reimbursement~~the ~~schemes~~economic ~~vary~~and ~~widely~~societal ~~from~~impact ~~country~~of touse of a given medicinal product in the national healthcare systems of the individual country is conducted. ~~Some~~The outcome of HTA regarding specific medicinal products will often influence the pricing and reimbursement status granted to these medicinal products by the competent authorities of individual EU Member States. At ~~may~~the ~~approve~~EU level, on January 12, 2025,the HTA Regulation entered into application through a ~~specific~~phased ~~price~~implementation. The Regulation initially applies to new active substances for aoncology ~~product~~and ATMPs. It will be expanded to orphan medicinal products in January 2028, orand ~~they~~to ~~may~~all ~~instead~~centrally ~~adopt~~authorized amedicinal ~~system~~products as of ~~direct~~2030. orSelect ~~indirect~~high-risk ~~controls~~medical ondevices also came into scope in 2026. The HTA Regulation is intended to boost cooperation among EU Member States in assessing health technologies, including new medicinal products. The HTA Regulation establishes a framework for cooperation at EU level for joint clinical assessments, joint scientific consultations, and the ~~profitability~~early identification of ~~the~~emerging ~~company~~health ~~placing~~technologies. ~~the~~The ~~product~~HTA Regulation permits EU Member States to use common tools, methodologies, and procedures and requires them to rely on EU level joint clinical assessment reports for the ~~market~~clinical components of their national HTA evaluations. ~~Other~~Individual EU Member States ~~allow~~will ~~companies~~continue to ~~fix~~be ~~their~~responsible ~~own~~for ~~prices~~assessing ~~for~~non-clinical ~~products~~(e.g., ~~but~~economic, ~~monitor~~social, ~~and~~ethical) ~~control~~aspects ~~prescription~~of ~~volumes~~health technologies, and ~~issue~~making ~~guidance~~decisions toon ~~physicians~~pricing toand ~~limit prescriptions~~reimbursement.

InOther ~~addition,~~compliance ~~some~~requirements EU Member States may require the completion of additional studies that compare the cost-effectiveness of a particular medicinal product candidate to currently available therapies. This Health Technology Assessment (HTA), process is the procedure according to which the assessment of the public health impact, therapeutic impact and the economic and societal impact of use of a given medicinal product in the national healthcare systems of the individual country is conducted. The outcome of HTA regarding specific medicinal products will often influence the pricing and reimbursement status granted to these medicinal products by the competent authorities of individual EU Member States. In December 2021, Regulation No 2021/2282 on Health Technology Assessment, or HTA Regulation, was adopted. The HTA Regulation is intended to boost cooperation among EU Member States in assessing health technologies, including new medicinal products, and providing the basis for cooperation at EU level for joint clinical assessments in these areas. The HTA Regulation has applied from January 12, 2025 although it will enter into force iteratively and

45Much like the Anti-Kickback Statute prohibition in the United States, as described below, the provision of benefits or advantages to physicians and other health care professionals to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the E.U. Interactions between pharmaceutical companies and health care professionals are governed by strict laws, such as national anti-bribery laws of European countries, national sunshine rules, regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment. Infringement of related laws could result in substantial fines and imprisonment.

~~Table~~Payments made to physicians and other health care professionals in certain EU Member States must be publicly disclosed. Moreover, agreements with health care professionals may require prior notification or approval by the health care professional’s employer, his or her competent professional organization and/or the regulatory authorities of ~~Contents~~the individual EU Member States. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

~~initially~~Regulatory ~~apply~~framework ~~to new active substances to treat cancer and to all advanced therapy medicinal products (ATMPs), it will then be expanded to orphan medicinal products~~ in ~~January 2028, and to all centrally authorized medicinal products as of 2030. Selected high-risk medical devices will also be assessed under~~ the ~~HTA~~United ~~Regulation~~Kingdom ~~as of 2026. The HTA Regulation is intended to harmonize the clinical benefit assessment of HTA across the European Union.~~

~~Much~~The ~~like~~Medicines ~~the Anti-Kickback Statute prohibition in the United States, as described below, the provision of benefits or advantages to physicians~~ and ~~other~~Healthcare ~~health~~products ~~care~~Regulatory ~~professionals~~Agency to(MHRA) ~~induce~~is ~~or encourage~~ the ~~prescription,~~United ~~recommendation,~~Kingdom’s ~~endorsement,~~standalone ~~purchase,~~regulator ~~supply,~~for ~~order or use of~~ medicinal products ~~is also prohibited in the E.U. Interactions between pharmaceutical companies~~ and ~~health~~medical care professionals are governed by strict laws, such as national anti-bribery laws of European countries, national sunshine rules, regulations, industry self-regulation codes of conduct and physicians’ codes of professional conductdevices. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment. Infringement of related laws could result in substantial fines and imprisonment.

Payments made to physicians and other health care professionals in certain EU Member States must be publicly disclosed. Moreover, agreements with health care professionals may require prior notification or approval by the health care professional’s employer, his or her competent professional organization and/or the regulatory authorities of the individual EU Member States. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.51

~~The~~Table ~~United~~of ~~Kingdom’s, or UK, withdrawal from the EU on January 31, 2020, commonly referred to as Brexit,~~ Contents

~~has~~While ~~changed~~ the ~~regulatory~~United ~~relationship between the UK and the EU. The Medicines and Healthcare products Regulatory Agency, or MHRA, is now the UK~~Kingdom’s ~~standalone regulator for medicinal products and medical devices. The United Kingdom is now a third country to the EU. The UK~~ regulatory framework infor ~~relation to~~ clinical trials iswas ~~governed~~historically bybased on the Medicines for Human Use (Clinical Trials) Regulations 2004, ~~as amended,~~ which isimplemented ~~derived from~~ the ~~CTD,~~former asEU ~~implemented~~Clinical ~~into~~Trials ~~UK national law through secondary legislation. On January 17~~Directive, ~~2022,~~this ~~the~~has ~~MHRA~~been ~~launched~~significantly anreformed ~~eight-week~~by ~~consultation on reframing~~ the UKMedicines ~~legislation~~ for ~~clinical~~Human ~~trials,~~Use ~~and~~(Clinical ~~which~~Trials) ~~aimed~~(Amendment) toRegulations ~~streamline~~2024. ~~clinical~~The ~~trials~~new ~~approvals~~legislation, ~~enable~~which ~~innovation,~~was ~~enhance~~adopted ~~clinical~~in ~~trials~~April ~~transparency~~2025, ~~enable~~modernizes ~~greater~~the ~~risk~~United ~~proportionality,~~Kingdom's ~~and~~approach ~~promote~~to ~~patient~~make ~~and~~it ~~public~~a ~~involvement~~more inattractive ~~clinical~~location ~~trials.~~for ~~The~~research, UKand ~~Government~~includes ~~published~~key ~~its~~features ~~response~~such toas: ~~the~~(i) ~~consultation~~a onrisk-proportionate ~~March 21~~approach, ~~2023~~including ~~confirming~~a ~~that~~notification itscheme ~~would~~for ~~bring~~lower-risk ~~forward~~trials; ~~changes~~(ii) toa ~~the~~combined ~~legislation.~~review ~~The~~process UKintegrating ~~Government~~ethics ~~published~~committee ~~its~~and ~~response~~regulatory toapprovals ~~the~~into ~~consultation~~a ~~on March 21~~single, ~~2023~~streamlined ~~confirming~~pathway; ~~that~~(iii) itenhanced ~~would~~transparency ~~bring~~requirements ~~forward~~mandating ~~changes~~registration toof ~~the~~clinical ~~legislation~~trials ~~and such changes were laid~~ in ~~parliament~~a onpublic ~~December~~registry ~~12,~~and ~~2024.~~publication ~~These~~of ~~resulting~~trial ~~legislative~~results ~~amendments~~within ~~will,~~12 ifmonths ~~implemented~~of intrial ~~their~~completion ~~current form, bring the UK into closer alignment~~ (with ~~the~~scope ~~CTR.~~for Indeferrals ~~October~~in ~~2023,~~certain ~~the~~circumstances); ~~MHRA~~(iv) ~~announced~~greater aflexibility ~~new~~to ~~Notification~~support ~~Scheme~~innovation ~~for~~in clinical ~~trials~~trial ~~which~~design; ~~enables~~and a(v) ~~more~~measures ~~streamlined~~to ~~and~~promote ~~risk-proportionate~~patient ~~approach~~and topublic ~~initial~~involvement. ~~clinical~~The ~~trial~~amendments ~~applications~~will ~~for~~become ~~Phase~~applicable 4on ~~and~~April ~~low-risk~~28, ~~Phase~~2026 3following ~~clinical~~a ~~trial~~one-year ~~applications.~~transition period.

Marketing authorizations in the United Kingdom are governed by the Human Medicines Regulations (SI 2012/1916), as amended. In order to obtain a United Kingdom MA to commercialize products in the United Kingdom, an applicant must be established in the United Kingdom and must follow one of the United Kingdom national authorization procedures or one of the remaining post-Brexit international cooperation procedures. Applications are governed by the Human Medicines Regulations (SI 2012/1916) and are made electronically through the MHRA Submissions Portal. The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, a 150-day assessment (subject to clock-stops) and a rolling review procedure. The rolling-review procedure permits the separate or joint submission of quality, non-clinical, and clinical data to the MHRA which can be reviewed on a rolling basis. After an application under the rolling-review procedure has been validated, the decision should be received within 100 days (subject to clock-stops).

~~2012/1916~~In addition, since January 1, 2024, the MHRA may rely on the International Recognition Procedure (IRP), aswhen ~~amended~~reviewing certain types of MAAs. ~~Since~~Pursuant ~~January~~to 1the IRP, ~~2021~~the MHRA will take into account the expertise and decision-making of trusted regulatory partners (e.g., anthe ~~applicant~~regulatory ~~for~~in Australia, Canada, Switzerland, Singapore, Japan, the U.S.A. and the EU). The MHRA will conduct a targeted assessment of IRP applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust. The IRP allows medicinal products approved by such trusted regulatory partners that meet certain criteria to undergo a fast-tracked MHRA review to obtain and/or update a MA in the United Kingdom. Applications should be decided within a maximum of 60 days if there are no major objections identified that cannot be resolved within such 60 day period and the approval from the trusted regulatory partner selected has been granted within the previous 2 years or if there are such major objections identified or such approval hasn’st ~~centralized~~been granted within the previous 2 years within 110 days. Applicants can submit initial MAAs to the IRP but the procedure ~~marketing~~can also be used throughout the lifecycle of a product for post-authorization procedures including line extensions, variations and renewals.

~~authorization~~Existing ~~can~~EU nomarketing ~~longer~~authorizations befor ~~established~~centrally inauthorized ~~the~~products were automatically converted into United Kingdom.’s Asmarketing aauthorizations, ~~result~~effective in Great Britain only, ~~since~~free of charge on January 1, 2021, unless the marketing authorization holder opted-out of this ~~date~~possibility. On January 1, ~~companies~~2025, the Windsor Framework came into effect, reintegrating Northern Ireland under the regulatory authority of the MHRA with respect to medicinal products and introducing a United Kingdom-wide licensing process for medicines.

~~established~~There is no pre-marketing authorization orphan designation for medicinal products in the UK. Instead, the MHRA reviews applications for orphan designation in parallel to the corresponding marketing authorization application. The criteria are essentially the same as those in the EU, but have been tailored for the market. This includes the criterion that prevalence of the condition in the United Kingdom, ~~cannot~~rather ~~use~~than the EU’s, ~~centralized~~must ~~procedure~~not be more than five in 10,000. InUpon ~~order~~the togrant ~~obtain~~of a marketing authorization with orphan status, the medicinal product will benefit from up to 10 years of market exclusivity from similar products in the approved orphan indication. The start of this market exclusivity period will be set from the date of first approval of the product in the United Kingdom.

~~Kingdom MA to commercialize products in the United Kingdom, an applicant must be established in the~~ 52

~~United~~Table ~~Kingdom and must follow one~~ of ~~the United Kingdom national authorization procedures or one of the~~ Contents

~~remaining~~For ~~post-Brexit~~other ~~international~~countries ~~cooperation~~outside ~~procedures~~of the European Union, 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. ~~Applications~~In ~~are~~all ~~governed~~major byterritories, clinical trials must be conducted in accordance with GCP and the ~~Human~~applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki. If we or our potential collaborators fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

MedicinesEmployees Regulations (SI 2012/1916) and areHuman made electronically through the MHRA Submissions Portal. Capital

~~The~~Our ~~MHRA~~commitment ~~has introduced changes~~ to ~~national~~innovation ~~licensing~~begins ~~procedures,~~with ~~including~~the ~~procedures~~dedication to ~~prioritize~~creating ~~access~~an toenvironment ~~new medicines~~ that ~~will~~attracts ~~benefit patients, a 150-day assessment (subject to clock-stops)~~ and aretains ~~rolling~~highly ~~review~~skilled ~~procedure. The rolling-review procedure permits the separate or joint submission of quality~~people, ~~non-clinical,~~including ~~and~~top ~~clinical~~scientific ~~data~~talent. toThis ~~the~~is ~~MHRA which can be reviewed on~~ a ~~rolling~~critical ~~basis.~~factor ~~After~~for anus ~~application~~in ~~under~~delivering ~~the~~on ~~rolling-review~~our ~~procedure~~mission ~~has~~and ~~been~~creating ~~validated,~~value ~~the~~for ~~decision~~our ~~should be received within 100 days (subject to clock-stops)~~stakeholders.

InWe ~~addition,~~have grown significantly since ~~January~~our 1initial public offering in November 2020 and have since built a diverse organization, ~~2024~~both in our Board of Directors where three global biotech female leaders are seated, ~~the~~and ~~MHRA~~across ~~may~~our ~~rely~~employee onbase. We have been successful in hiring employees with broad experience and backgrounds while facing significant competition for biotechnology talent from both established and early-stage biotechnology companies. Further, we are headquartered in the ~~International~~San ~~Recognition~~Francisco ~~Procedure~~Bay ~~(“IRP”)~~area and have operations in Cambridge, Massachusetts—both of which are global biotechnology hubs with many employment choices. Despite the competition, we have been successful in hiring highly qualified staff to join Olema.

~~when~~As ~~reviewing~~of ~~certain~~January ~~types~~31, of2026, ~~MAAs.~~we ~~Pursuant~~had to131 ~~the IRP~~employees, ~~the~~all ~~MHRA~~of ~~will~~whom ~~take~~were ~~into~~full ~~account~~time, ~~the~~consisting ~~expertise~~of clinical, research, operations, regulatory, and ~~decision~~administrative personnel. Thirty-~~making~~eight of ~~trusted~~our ~~regulatory~~employees ~~partners~~hold (ePh.gD., ~~the~~or ~~regulatory~~M.D. indegrees. ~~Australia,~~None ~~Canada,~~of ~~Switzerland,~~our employees is subject to a collective bargaining agreement. We consider our relationship with our employees to be good.

46We strive to create a positive employee experience and we are committed to the health, safety, and well-being of our employees. This commitment is reflected in our ability to attract and retain high performers. We believe we have a robust employment package that promotes well-being across all aspects of our employees’ lives, including healthcare, paid time-off, retirement savings with a company match through a 401(k) plan, our equity incentive plans, and our employee stock purchase plan. The principal purposes of our equity incentive plans are to attract, motivate, and retain our employees and directors through the granting of stock-based compensation awards. From time to time, we may offer additional stock-based compensation awards to our employees to continue to motivate them and support retention, particularly at times when our stock price, or the stock price of biotechnology companies generally, is volatile. We grant stock options to all full-time employees to foster alignment and promote a spirit of ownership.

TableCorporate of ContentsInformation

~~Singapore,~~We ~~Japan,~~were ~~the~~incorporated ~~U.S.A.~~in ~~and~~Delaware ~~the~~on ~~EU).~~August ~~The~~7, ~~MHRA~~2006, ~~will~~under ~~conduct~~the alegal ~~targeted~~name ~~assessment~~ of ~~IRP~~CombiThera, ~~applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust~~Inc., ~~The IRP allows medicinal products approved by such trusted regulatory partners that meet certain criteria to undergo a fast-tracked MHRA review to obtain~~ and~~/or~~, ~~update~~on aMarch MA25, in2009, ~~the~~were ~~United~~renamed ~~Kingdom.~~Olema Applications should be decided within a maximum of 60 days if there are no major objections identified that cannot be resolved within such 60 day period and the approval from the trusted regulatory partner selected has been granted within the previous 2 years or if there are such major objections identified or such approval hasn’t been granted within the previous 2 years within 110 days. 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 extensionsPharmaceuticals, ~~variations and renewals~~Inc.

~~There~~Available ~~is no pre-marketing authorization orphan designation for medicinal products in the UK. Instead, the~~ Information

~~MHRA~~Our ~~reviews~~Annual ~~applications~~Report ~~for~~on ~~orphan~~Form ~~designation~~10-K, inQuarterly ~~parallel~~Reports on Form 10-Q, Current Reports on Form 8-K, and amendments to reports filed pursuant to Sections 13(a) and 15(d) of the ~~corresponding~~Exchange ~~marketing~~Act, ~~authorization~~are filed with the SEC. Such reports and other information filed by us with the SEC are available free of charge on the Investors section of our website, www.olema.com, when such reports are available on the SEC’s website. The SEC maintains an internet site that contains reports, proxy and information statements and other information regarding issuers that file electronically with the SEC at www.sec.gov. The information contained on the websites referenced in this Annual Report is not incorporated by reference into this filing. Further, any references to website URLs are intended to be inactive textual references only.

~~application. The criteria are essentially the same as those in the EU, but have been tailored for the market.~~ 53

~~This~~Table ~~includes the criterion that prevalence~~ of the condition in the United Kingdom, rather than the EU, must not be more than five in 10,000. Upon the grant of a marketing authorization with orphan status, the medicinal product will benefit from up to 10 years of market exclusivity from similar products in the approved orphan indication. The start of this market exclusivity period will be set from the date of first approval of the product in the United Kingdom. Contents

~~For~~Item other countries outside of the European Union, 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 country1A. InRisk all major territories, clinical trials must be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of HelsinkiFactors. If we or our potential collaborators fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

~~Employees~~Risks related to our financial position and ~~Human~~the ~~Capital~~need for additional capital

~~Our~~We ~~commitment~~have tono ~~innovation~~products ~~begins~~approved ~~with~~for ~~the~~commercial ~~dedication to creating an environment that attracts and retains highly skilled people~~sale, ~~including~~which ~~top~~may ~~scientific~~make ~~talent.~~it ~~This~~difficult ~~is a critical factor~~ for usyou into ~~delivering~~evaluate on our ~~mission~~current business and ~~creating~~predict ~~value~~our ~~for~~future ~~our~~success ~~stakeholders~~and viability.

We are a clinical-stage biopharmaceutical company, and we have ~~grown~~no ~~significantly~~products ~~since~~approved ~~our~~for ~~initial~~commercial ~~public~~sale, ~~offering~~have innot ~~November~~generated ~~2020~~any revenue from product sales and have ~~since~~incurred ~~built~~losses asince ~~diverse~~inception. ~~organization~~To date, ~~both~~we inhave ~~our~~devoted ~~Board~~substantially all of ~~Directors~~our ~~where~~resources ~~three~~and ~~global~~efforts ~~biotech~~to ~~female~~organizing ~~leaders~~and ~~are~~staffing ~~seated~~our company, business planning, executing partnerships, raising capital, discovering, identifying and ~~across~~developing our ~~employee~~lead ~~base.~~product Wecandidate, ~~have~~palazestrant, ~~been~~securing ~~successful~~related inintellectual ~~hiring~~property ~~employees~~rights, ~~with~~conducting ~~broad~~non-clinical ~~experience~~studies and ~~backgrounds~~clinical ~~while~~trials, ~~facing~~including ~~significant~~conducting ~~competition~~multiple ~~for~~Phase ~~biotechnology~~1/2 ~~talent~~studies ~~from~~of ~~both~~palazestrant, ~~established~~initiating and ~~early-stage~~conducting ~~biotechnology~~Phase ~~companies.~~3 ~~Further~~clinical trials of palazestrant, weconducting ~~are~~non-clinical ~~headquartered~~studies inof ~~the~~OP-3136, ~~San~~and ~~Francisco~~conducting ~~Bay~~a ~~area~~Phase ~~and~~1 study of OP-3136. We have ~~operations~~not inyet ~~Cambridge~~demonstrated our ability to obtain marketing approvals, ~~Massachusetts~~manufacture a commercial-scale ~~both~~product ofor ~~which~~arrange ~~are~~for ~~global~~a ~~biotechnology~~third ~~hubs~~party ~~with~~to ~~many~~do ~~employment~~so ~~choices.~~on ~~Despite~~our ~~the competition~~behalf, weor ~~have~~conduct ~~been~~sales and marketing activities necessary for successful inproduct ~~hiring~~commercialization. ~~highly~~As ~~qualified~~a ~~staff~~result, it may be more difficult for you to ~~join~~accurately ~~Olema.~~predict our future success or viability than it would be if we had a longer operating history.

AsIn ofaddition, ~~January~~we 31may encounter unforeseen expenses, ~~2025~~difficulties, wecomplications, ~~had~~delays 96and ~~employees,~~other ~~all~~known ofand ~~whom~~unknown ~~were~~factors ~~full~~and ~~time,~~risks ~~consisting~~frequently ofexperienced by clinical,-stage ~~research,~~biopharmaceutical ~~operations,~~companies ~~regulatory,~~in ~~and~~rapidly ~~administrative~~evolving ~~personnel~~fields. ~~Twenty~~We ~~eight~~also ofmay ~~our~~need ~~employees~~to ~~hold~~transition ~~Ph.D.~~from ora ~~M.D.~~company ~~degrees;~~with ~~41%~~a research focus to a company capable of ~~our~~successfully ~~employee~~executing ~~population~~drug isdevelopment ~~male~~activities and ~~59%~~supporting iscommercial ~~female~~operations, if approved. ~~None~~If ofwe ~~our~~do ~~employees~~not isadequately ~~subject~~address tothese arisks ~~collective~~and ~~bargaining~~difficulties ~~agreement.~~or Wesuccessfully ~~consider~~make ~~our~~such ~~relationship~~a ~~with~~transition, our ~~employees~~business, tofinancial condition, results of operations, and prospects will be ~~good~~significantly harmed.

We ~~strive~~require tosubstantial ~~create~~additional acapital ~~positive employee experience and we are committed~~ to ~~the~~finance ~~health, safety, and well-being of~~ our ~~employees~~operations. ~~This~~If ~~commitment~~we isare ~~reflected~~unable ~~in our ability~~ to ~~attract~~raise ~~and~~such ~~retain~~capital ~~high~~when ~~performers. We believe we have a robust employment package that promotes well-being across all aspects of our employees’ lives~~needed, ~~including~~or ~~healthcare,~~on ~~paid~~acceptable ~~time-off~~terms, ~~retirement~~we ~~savings~~may ~~with~~be aforced ~~company~~to ~~match through a 401(k) plan~~delay, ~~our equity incentive plans~~reduce, and/or ~~our~~eliminate ~~employee~~one ~~stock~~or ~~purchase~~more ~~plan. The principal purposes~~ of our ~~equity~~research ~~incentive plans are to attract, motivate,~~ and ~~retain~~drug ~~our~~development ~~employees~~programs ~~and directors through the granting~~ of ~~stock-based compensation awards. From time to time, we may offer additional stock-based compensation awards to~~ our ~~employees~~product tocandidates ~~continue~~or tofuture ~~motivate~~commercialization ~~them and support retention, particularly at times when our stock price, or~~ efforts.

47Developing pharmaceutical products, including conducting non-clinical studies and clinical trials, is a very time-consuming, expensive and uncertain process that takes years to complete. Our operations have consumed substantial amounts of cash since inception, and we expect our expenses will increase in connection with our ongoing activities, particularly as we initiate and conduct clinical trials of, and seek marketing approval for, palazestrant. We anticipate incurring significant costs associated with the development of our lead product candidate, palazestrant, OP-3136, and any future product candidates we may develop. Our expenses could increase beyond expectations if we are required by the FDA, the European Medicines Agency (EMA), or other regulatory authorities to perform clinical trials or non-clinical studies in addition to those that we currently anticipate. Other unanticipated costs may also arise. In addition, if we obtain marketing approval for palazestrant, OP-3136, or future product candidates we may develop, we expect to incur significant commercialization expenses related to drug sales, marketing, manufacturing and distribution. Our estimates as to how long until we are able to commercialize one or more of our product candidates are based on assumptions that may prove to be wrong, and we may require more time and resources than we currently anticipate, and may exhaust our available capital resources before we are able to generate any revenue from product sales. In addition, because the design and outcome of our planned and anticipated clinical trials are highly uncertain, we cannot reasonably estimate the actual amounts necessary to successfully complete the development and commercialization of any product candidate we develop. We also incur costs associated with operating as a public company. Accordingly, we will need to obtain substantial additional funding in order to maintain our continuing operations.

~~Table of Contents~~54

~~the~~Table ~~stock price~~ of ~~biotechnology companies generally, is volatile. We grant stock options to all full-time employees to foster alignment and promote a spirit of ownership.~~Contents

~~Corporate~~Our ~~Information~~estimate as to how long we expect our existing cash, cash equivalents and marketable securities to be able to continue to fund our operating expenses and capital expenditures requirements is based on assumptions that may prove to be wrong, and we could use our available capital resources sooner than we currently expect. Changing circumstances, some of which may be beyond our control, including a negative return on our cash and cash equivalents, could cause us to consume capital significantly faster than we currently anticipate, and we may need to seek additional funds sooner than planned. Moreover, it is particularly difficult to estimate with certainty our future expenses given the dynamic nature of our business and the geopolitical and macroeconomic environment, generally, including economic and geopolitical uncertainty, market volatility, labor shortages, evolving trade and tariff policies, including related legal challenges, trade tensions and retaliatory measures by other countries, supply chain disruptions, military conflicts, as well as any related political or economic responses or counter-responses by various global actors, inflationary pressures, monetary supply shifts, increased recession risk, and related financial instability. Advancing the development of palazestrant, OP-3136, and any future product candidates we may develop will require a significant amount of capital, and our existing cash, cash equivalents and marketable securities will not be sufficient to fund all of the activities that are necessary to complete the development of palazestrant and OP-3136.

We ~~were~~will ~~incorporated~~be inrequired ~~Delaware~~to obtain additional funding through public or private equity offerings, debt financings, collaborations and licensing arrangements or other sources, which may dilute our stockholders, cause our stock price to decline, or restrict our operating activities. Adequate additional financing may not be available to us on ~~August~~acceptable 7terms, ~~2006~~or at all. Market volatility, ~~under~~including ~~the~~as ~~legal~~a ~~name~~result of ~~CombiThera~~geopolitical and macroeconomic events discussed above, ~~Inc~~could adversely increase our need to access capital and, likewise, adversely impact our ability to access capital as and when needed. For example, inflation rates, particularly in the United States, in recent past increased to levels not seen in years, and increased inflation may result in increases in our operating costs (including our labor costs), reduced liquidity and limits on ~~March~~our 25ability to access credit or otherwise raise capital on acceptable terms, ~~2009~~if at all. In addition, ~~were~~the ~~renamed~~U.S. ~~Olema~~Federal ~~Pharmaceuticals~~Reserve had previously raised, ~~Inc~~and may again raise in the future, interest rates in response to concerns about inflation, which, coupled with reduced government spending and volatility in financial markets, may have the effect of heightening these risks and further increasing economic uncertainty.

~~Available~~Our ~~Information~~failure to raise capital as and when needed or on acceptable terms would have a negative impact on our financial condition and our ability to pursue our business strategy, and we may have to delay, reduce the scope of, suspend or eliminate one or more of our research-stage programs, clinical trials, or future commercialization efforts. We also could be required to seek collaborators for palazestrant, OP-3136, or any future product candidates we may develop at an earlier stage than otherwise would be desirable or on terms that are less favorable than might otherwise be available or relinquish or license on unfavorable terms our rights to our product candidates in markets where we otherwise would seek to pursue development or commercialization ourselves. Any of the above events could significantly harm our business, financial condition, results of operations, and prospects and cause the price of our common stock to decline.

~~Our~~We ~~Annual~~have ~~Report~~incurred onnet ~~Form~~losses ~~10-K,~~since ~~Quarterly Reports on Form 10-Q~~inception, ~~Current Reports on Form 8-K,~~ and ~~amendments~~we expect to ~~reports~~continue ~~filed pursuant~~ to ~~Sections~~incur ~~13(a)~~net ~~and~~losses ~~15(d)~~for of the ~~Exchange~~foreseeable ~~Act, are filed with the SEC~~future. ~~Such~~In ~~reports and other information filed by us with the SEC are available free of charge on the Investors section of our website~~addition, ~~www.olema.com,~~we ~~when~~may ~~such~~be ~~reports~~unable ~~are~~to ~~available~~continue onas ~~the~~a ~~SEC’s~~going ~~website.~~concern ~~The~~over ~~SEC maintains an internet site that contains reports, proxy and information statements and other information regarding issuers that file electronically with~~ the ~~SEC~~long ~~at www~~term.sec.gov. The information contained on the websites referenced in this Annual Report on Form 10-K is not incorporated by reference into this filing. Further, any references to website URLs are intended to be inactive textual references only.

~~Item~~We 1Ahave incurred net losses in each reporting period since our inception, have not generated any revenue from product sales to date, and have financed our operations principally through sales of our equity securities, including sales of our common stock and pre-funded warrants to purchase our common stock to selected institutional and accredited investors in private placement transactions, at-the-market offerings, our initial public offering and other public offerings and private financings. ~~Risk~~We ~~Factors~~have incurred net losses of $162.5 million and $129.5 million for the years ended December 31, 2025 and 2024, respectively. We had an accumulated deficit of $597.6 million as of December 31, 2025. Our losses have resulted principally from expenses incurred in research and development of palazestrant, OP-3136 and from management and administrative costs and other expenses that we have incurred while building our business infrastructure. Our lead product candidate, palazestrant, and OP-3136 are both in clinical trials. As a result, we expect that it will be several years, if ever, before we have a commercialized product and generate revenue from product sales. Even if we succeed in receiving marketing approval for palazestrant or OP-3136 in one of our lead indications and proceed to commercializing palazestrant or OP-3136, we expect that we will continue to incur substantial research and

~~Risks related to our financial position and the need for additional capital~~55

WeTable ~~have~~of ~~no products approved for commercial sale, which may make it difficult for you to evaluate our current business and predict our future success and viability.~~Contents

Wedevelopment ~~are a clinical-stage biopharmaceutical company,~~ and weother ~~have~~expenses noas ~~products approved for commercial sale, have not generated any revenue from product sales and have incurred losses since inception. To date,~~ we ~~have~~continue ~~devoted~~the substantially all of our resources and efforts to organizing and staffing our company, business planning, executing partnerships, raising capital, discovering, identifying and developing our lead product candidate, palazestrant (OP-1250), securing related intellectual property rights, conducting non-clinical ~~studies,~~development ~~conducting~~programs afor ~~Phase 1/2 clinical study of~~ palazestrant, ~~initiating~~in ~~and~~other ~~conducting~~indications aor ~~Phase 3 clinical trial of palazestrant, conducting non-clinical studies of OP-3136, and preparing~~ for ~~the anticipated clinical development of~~ OP-3136. We have not yet demonstrated our ability to obtain marketing 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. As a result, it may be more difficult for you to accurately predict our future success or viability than it could be if we had a longer operating history.

InWhile ~~addition,~~our weexpenses may ~~encounter~~fluctuate ~~unforeseen~~from ~~expenses,~~period ~~difficulties,~~to ~~complications~~period, ~~delays~~we ~~and~~generally ~~other~~expect ~~known~~to continue to incur increased expenses and ~~unknown~~operating ~~factors~~losses for the foreseeable future as we continue our research and ~~risks~~development ~~frequently~~efforts ~~experienced~~and byseek ~~clinical-stage~~to ~~biopharmaceutical~~obtain ~~companies~~regulatory inapproval ~~rapidly~~for ~~evolving~~palazestrant ~~fields~~or OP-3136. WeThe ~~also~~net losses we incur may ~~need~~fluctuate significantly from quarter to ~~transition~~quarter ~~from~~such that a ~~company~~period-to-period ~~with~~comparison aof ~~research~~our ~~focus~~results toof operations may not be a ~~company~~good ~~capable~~indication of ~~successfully~~our ~~executing~~future ~~drug~~performance. ~~development~~The ~~activities~~size of our future net losses will depend, in part, on the rate of future growth of our expenses and ~~supporting~~our ~~commercial~~ability ~~operations~~to generate revenue. IfOur weprior dolosses ~~not~~and ~~adequately~~expected ~~address~~future ~~these~~losses ~~risks~~have had, and ~~difficulties~~will orcontinue ~~successfully~~to ~~make~~have, ~~such~~an aadverse ~~transition,~~effect on our ~~business,~~working ~~financial~~capital. ~~condition~~In any particular period, our operating results could be below the expectations of ~~operations~~securities ~~and~~analysts ~~prospects~~or ~~will~~investors, bewhich ~~significantly~~could ~~harmed~~cause our stock price to decline.

WeIn ~~require~~addition, ~~substantial~~our ~~additional~~consolidated ~~capital~~financial tostatements ~~finance~~for ~~our~~the ~~operations.~~years Ifended weDecember ~~are~~31, ~~unable~~2025 toand ~~raise~~2024 ~~such~~included ~~capital~~elsewhere ~~when~~in ~~needed,~~this orAnnual onReport ~~acceptable~~have ~~terms~~been prepared assuming we will continue as a going concern. However, we ~~may~~have beincurred ~~forced~~losses toand ~~delay~~negative cash flows from operations. As a development stage company, ~~reduce~~we expect to incur significant and~~/or~~ ~~eliminate~~increasing ~~one~~losses until regulatory approval is granted for palazestrant or ~~more~~OP-3136. ofRegulatory ~~our~~approval ~~research~~is not guaranteed and ~~drug~~may ~~development~~never ~~programs~~be ofobtained. As a result, these conditions raise substantial doubt about our ~~product~~ability ~~candidates~~to orcontinue ~~future~~as ~~commercialization~~a ~~efforts~~going concern over the long term.

~~Developing~~We ~~pharmaceutical products, including conducting non-clinical studies and clinical trials, is a very time-consuming, expensive and uncertain process that takes years to complete. Our operations~~ have ~~consumed~~never ~~substantial~~generated ~~amounts~~revenue offrom ~~cash~~product ~~since~~sales ~~inception,~~ and wemay ~~expect~~never ~~our~~be ~~expenses will increase in connection with our ongoing activities, particularly as we initiate and conduct clinical trials of, and seek marketing approval for, palazestrant~~profitable. ~~We anticipate incurring significant costs associated with the development of our lead product~~

48Our ability to generate revenue from product sales and achieve profitability depends on our ability, alone or with our collaboration partners, to successfully complete the development of, and obtain the regulatory approvals necessary to commercialize, palazestrant, OP-3136, and any future product candidates we may develop. We do not anticipate generating revenue from product sales for the next several years, if ever. Our ability to generate revenue from product sales depends heavily on our and our current and potential future collaborators’ success in:

•

~~Table~~completing clinical and non-clinical development of ~~Contents~~our product candidates and programs and identifying and developing new product candidates;

•

~~candidate,~~seeking ~~palazestrant, OP-3136~~ and ~~any~~obtaining future product candidates we may develop. Our expenses could increase beyond expectations if we are required by the FDA, the European Medicines Agency (EMA), or other regulatory authorities to perform clinical trials or non-clinical studies in addition to those that we currently anticipate. Other unanticipated costs may also arise. In addition, if we obtain marketing ~~approval~~approvals for ~~palazestrant,~~any ~~OP-3136 or other~~ product candidates, wethat expect to incur significant commercialization expenses related to drug sales, marketing, manufacturing and distribution. Because the design and outcome of our planned and anticipated clinical trials are highly uncertain, we ~~cannot reasonably estimate the actual amounts necessary to successfully complete the development and commercialization of any product candidate we~~ develop~~. We also incur costs associated with operating as a public company. Accordingly, we will need to obtain substantial additional funding in order to maintain our continuing operations.~~;

•

~~Our~~launching ~~estimate as to how long we expect our existing cash, cash equivalents~~ and ~~marketable~~commercializing ~~securities~~product tocandidates befor ~~able~~which ~~to continue to fund our operating expenses and capital expenditures requirements is based on assumptions that may prove to be wrong, and~~ we ~~could~~obtain ~~use~~marketing ~~our~~approval ~~available~~by ~~capital~~establishing ~~resources sooner than we currently expect. Changing circumstances, some of which may be beyond our control including~~ a ~~negative~~sales ~~return on~~force, ~~our cash and cash equivalents~~marketing, ~~could~~medical ~~cause~~affairs ~~us to consume capital significantly faster than we currently anticipate,~~ and wedistribution ~~may~~infrastructure need to seek additional funds sooner than planned. Moreover, it is particularly difficult to estimate with certainty our future expenses given the dynamic nature of our business and the geopolitical and macroeconomic environment, generally, including economic uncertainty, market volatility, labor shortages, tariffs and trade tensions, the ongoing conflicts between Ukraine and Russia and in the Middle East, as well as any related political or ~~economic responses and counter-responses or otherwise by various global actors~~, ~~inflation rates and the responses by central banking authorities to control such inflation~~alternatively, ~~monetary~~collaborating ~~supply~~with ~~shifts and related financial instability. Advancing the development of palazestrant, OP-3136 and any future product candidates we may develop will require~~ a ~~significant~~commercialization amount of capital, and our existing cash, cash equivalents and marketable securities will not be sufficient to fund all of the activities that are necessary to complete the development of palazestrant and OP-3136.partner;

•

Weachieving ~~will~~adequate be required to obtain additional funding through public or private equity offerings, debt financings, collaborations and licensing arrangements or other sources, which may dilute our stockholders, or cause our stock price to decline or restrict our operating activities. Adequate additional financing may not be available to us on acceptable terms, or at all. Market volatility, including as a result of geopolitical and macroeconomic events discussed above, could adversely increase our need to access ~~capital~~ and ~~likewise,~~reimbursement ~~adversely~~by impact our ability to access capital as and when needed. For example, inflation rates, particularly in the United States, recently increased to levels not seen in years, and increased inflation may result in increases in our operating costs (including our labor costs), reduced liquidity and limits on our ability to access credit or otherwise raise capital on acceptable terms, if at all. In addition, the U.S. Federal Reserve has raised, and may again raise, interest rates in response to concerns about inflation, which, coupled with reduced government ~~spending~~ and ~~volatility~~third-party inpayors ~~financial~~for ~~markets~~product ~~may~~candidates ~~have~~that ~~the~~we ~~effect of heightening these risks and further increasing economic uncertainty.~~ develop;

•

~~Our~~establishing ~~failure~~and tomaintaining ~~raise~~supply ~~capital as~~ and ~~when~~manufacturing ~~needed~~relationships orwith onthird ~~acceptable~~parties ~~terms~~that ~~would~~can ~~have~~provide aadequate, ~~negative~~in ~~impact~~both onamount ~~our~~and ~~financial~~quality, ~~condition~~products and ~~our~~services ~~ability~~ to ~~pursue~~support ~~our~~clinical ~~business~~development ~~strategy,~~ and ~~we may have to delay, reduce~~ the ~~scope~~market ~~of,~~demand ~~suspend or eliminate one or more of our research-stage programs, clinical trials or future commercialization efforts. We also could be required to seek collaborators~~ for ~~palazestrant, OP-3136 or any future~~ product ~~candidate~~candidates ~~at an earlier stage than otherwise would be desirable or on terms~~ that ~~are less favorable than might otherwise be available or relinquish or license on unfavorable terms our rights to our product candidates in markets where~~ we ~~otherwise would seek to pursue development or commercialization ourselves. Any of the above events could significantly harm our business~~develop, ~~prospects,~~if ~~financial condition and results of operations and cause the price of our common stock to decline.~~approved;

•

Weobtaining ~~have~~market ~~incurred~~acceptance ~~net~~of ~~losses~~product ~~since~~candidates ~~inception,~~that ~~and~~ we ~~expect~~develop ~~to continue to incur net losses for the foreseeable future. In addition, we may be unable to continue~~ as aviable ~~going~~treatment ~~concern over the long term.~~options;

•

Weaddressing ~~have incurred net losses in each reporting period since our inception, have not generated~~ any ~~revenue~~competing ~~from~~technological ~~product sales to date~~ and ~~have~~market ~~financed our operations principally through sales of shares of our common stock~~ developments;

•

49negotiating favorable terms in any collaboration, licensing or other arrangements into which we may enter and performing our obligations in such collaborations;

•

~~Table~~maintaining, protecting, enforcing and expanding our portfolio of ~~Contents~~intellectual property rights, including patents, trade secrets and know-how;

•

~~pursuant~~defending toagainst ~~sales of our common stock and pre~~third-~~funded~~party ~~warrants to purchase our common stock to selected institutional and accredited investors in private placement transactions~~interference, ~~at-the-market~~infringement ~~offerings,~~or ~~our~~other ~~initial~~intellectual public offering and private financings. We have incurred net losses of $129.5 million and $96.7 million for the years ended December 31, 2024 and 2023, respectively. We had an accumulated deficit of $435.1 million as of December 31, 2024. Our losses have resulted principally from expenses incurred in research and development of palazestrant, OPproperty-~~3136~~related ~~and from management and administrative costs and other expenses that we have incurred while building our business infrastructure. Our lead product candidate~~claims, ~~palazestrant, is in clinical trials. As a result, we expect that it will be several years,~~ if ~~ever,~~any; ~~before we have a commercialized product~~ and generate revenue from product sales. Even if we succeed in receiving marketing approval for and commercializing palazestrant in one of our lead indications, we expect that we will continue to incur substantial research and development and other expenses as we continue the clinical development programs for palazestrant in other indications or for OP-3136.

•

~~While our expenses may fluctuate from period to period~~attracting, wehiring ~~generally expect to continue to incur increased expenses~~ and ~~operating~~retaining ~~losses~~qualified ~~for the foreseeable future as we continue our research and development efforts and seek to obtain regulatory approval for palazestrant or OP-3136~~personnel. The net losses we incur may fluctuate significantly from quarter to quarter such that a period-to-period comparison of our results of operations may not be a good indication of our future performance. The size of our future net losses will depend, in part, on the rate of future growth of our expenses and our ability to generate revenue. Our prior losses and expected future losses have had, and will continue to have, an adverse effect on our working capital. In any particular period, our operating results could be below the expectations of securities analysts or investors, which could cause our stock price to decline.

In addition, our consolidated financial statements for the years ended December 31, 2024 and 2023 included elsewhere in this Annual Report on Form 10-K have been prepared assuming we will continue as a going concern. However, we have incurred losses and negative cash flows from operations. As a development stage company, we expect to incur significant and increasing losses until regulatory approval is granted for palazestrant or OP-3136. Regulatory approval is not guaranteed and may never be obtained. As a result, these conditions raise substantial doubt about our ability to continue as a going concern over the long term.56

WeTable ~~have~~of ~~never generated revenue from product sales and may never be profitable.~~Contents

~~Our~~Even ~~ability~~if topalazestrant, ~~generate~~OP-3136, ~~revenue~~or ~~from~~any future product ~~sales~~candidates ~~and~~that ~~achieve~~we ~~profitability~~may ~~depends~~develop onare ~~our~~approved ~~ability~~for commercial sale, ~~alone~~we oranticipate incurring significant costs associated with ~~our~~commercializing ~~collaboration~~any ~~partners,~~approved toproduct ~~successfully~~candidate. ~~complete~~Our ~~the~~expenses ~~development~~could ~~of,~~increase ~~and~~beyond ~~obtain~~expectations ~~the~~if ~~regulatory~~we ~~approvals~~are ~~necessary~~required toby ~~commercialize,~~the ~~palazestrant~~FDA, ~~OP-3136~~EMA ~~and~~or ~~any~~other ~~future~~comparable ~~product~~regulatory ~~candidates~~authorities weto ~~may~~perform ~~develop.~~clinical Wetrials door ~~not~~non-clinical ~~anticipate~~studies ~~generating~~in ~~revenue~~addition ~~from~~to ~~product~~those ~~sales~~that ~~for~~we ~~the~~currently ~~next~~anticipate. ~~several~~Even ~~years,~~ if ~~ever.~~we ~~Our~~are ~~ability~~able to generate revenue from ~~product~~the ~~sales~~sale ~~depends~~of ~~heavily~~any onapproved ~~our~~products, ~~and~~we ~~our~~may ~~current~~not become profitable and ~~potential~~may ~~future~~need ~~collaborators’~~to ~~success~~obtain ~~in:~~additional funding to continue operations.

~~completing~~The ~~clinical~~terms ~~and~~of ~~non-clinical~~the ~~development~~Loan ofAgreement ~~our~~place ~~product~~restrictions ~~candidates~~on ~~and~~our ~~programs~~operating and ~~identifying~~financial ~~and~~flexibility. ~~developing~~If we raise additional capital through debt financing, the terms of any new ~~product~~debt ~~candidates;~~could further restrict our ability to operate our business.

~~seeking~~On September 5, 2023, we entered into a loan and ~~obtaining~~security ~~marketing~~agreement ~~approvals~~(the ~~for~~Original ~~any~~Loan ~~product~~Agreement) ~~candidates~~with ~~that~~Silicon Valley Bank, a division of First Citizens Bank & Trust Company (the Bank), which provided us with an aggregate principal amount of up to $50.0 million (the Original Credit Facility), of which $25.0 million became available in September 2023 (Term Loan A) upon the closing of a private placement and the issuance of our common stock to selected institutional and accredited investors pursuant to a securities purchase agreement, and the remaining $25.0 million could have been made available upon approval of the Bank in its discretion. The Original Credit Facility was scheduled to mature on August 1, 2027. On June 28, 2024, we ~~develop;~~entered into the First Amendment to Loan and Security Agreement (the First Amendment) with the Bank, which, among other things, (i) increased the aggregate principal amount of the Original Credit Facility from up to $50.0 million to up to $100.0 million (the Credit Facility) of which the Term Loan A of $25.0 million was immediately available, an additional $25.0 million will become available upon achieving certain milestones related to the execution of a first-line pivotal Phase 3 clinical trial of palazestrant in combination with ribociclib (Term Loan B), and an additional $50.0 million which may be made available upon the approval of the Bank in its discretion (Term Loan C), and (ii) extended the maturity date to July 1, 2028. On June 27, 2025, we entered into a Second Amendment to Loan and Security Agreement (the Second Amendment) with the Bank, which, among other things, (i) decreased the interest rate to a floating rate equal to the greater of 6.0% or the prime rate, and (ii) extended the draw period of Term Loan A to January 15, 2026. As of December 31, 2025, we had an outstanding liability of $3.0 million under the Credit Facility, representing the full amount drawn to date. On January 11, 2026, we entered into the Third Amendment to Loan and Security Agreement (the Third Amendment, together with the Original Loan Agreement, as amended by the First Amendment and the Second Amendment, the Loan Agreement), which, among other things, (i) extended the draw period of Term Loan A to January 31, 2027, (ii) extended the draw period of Term Loan B to January 31, 2027, (iii) extended the draw period of Term Loan C to January 31, 2027, and (iv) extended the Maturity Date to January 1, 2029 (Maturity Date). Based on the occurrence of specified (a) development milestones related to the pivotal Phase 3 OPERA-01 clinical trial of palazestrant or (b) receipt of proceeds from capital financing, the draw period of Term Loan B and Term Loan C may be further extended to July 31, 2027, and the Maturity Date may be further extended to July 1, 2029.

~~launching~~Our overall leverage and ~~commercializing~~certain ~~product~~obligations ~~candidates~~and ~~for~~affirmative ~~which~~and wenegative ~~obtain~~covenants ~~marketing~~contained ~~approval~~in the Loan Agreement and related documentation could adversely affect our financial health and business and future operations by ~~establishing~~limiting aour ~~sales~~ability ~~force~~to, ~~marketing~~among other things, ~~medical~~satisfy ~~affairs~~our ~~and~~obligations ~~distribution~~under ~~infrastructure~~the Loan Agreement; refinance our debt on terms acceptable to us or, ~~alternatively~~at all; plan for and adjust to changing business, ~~collaborating~~industry ~~with~~and amarket ~~commercialization~~conditions; ~~partner~~use our available cash flow to fund future acquisitions; make dividend payments; and obtain additional financing for working capital, to fund growth or for general corporate purposes, even when necessary to maintain adequate liquidity.

~~achieving adequate access and reimbursement by government and third-party payors for product candidates that we develop;~~57

~~establishing~~Table ~~and~~of maintaining supply and manufacturing relationships with third parties that can provide adequate, in both amount and quality, products and services to support clinical development and the market demand for product candidates that we develop, if approved;Contents

~~obtaining~~If ~~market~~we ~~acceptance~~default under the Loan Agreement, the Bank may accelerate all of ~~product~~our ~~candidates~~repayment ~~that~~obligations and exercise all of its rights and remedies under the Loan Agreement and applicable law, potentially requiring us to renegotiate our agreement on terms less favorable to us. Further, if we ~~develop~~are asliquidated, ~~viable~~the ~~treatment~~lenders’ ~~options~~right to repayment would be senior to the rights of the holders of our common stock to receive any proceeds from the liquidation. The Bank could declare a default upon the occurrence of customary events of default, including, but not limited to, nonpayment of principal, interest, fees or other amounts; material inaccuracy of a representation or warranty; failure to perform or observe covenants; cross-defaults with certain other indebtedness; bankruptcy and insolvency events; material monetary judgment defaults; occurrence of any material adverse change; delisting; and a material impairment in the Bank’s security interest. Upon the occurrence of an event of default (subject, in certain cases, to notice and grace periods), obligations under the Loan Agreement may be accelerated, thereby requiring us to repay the loan immediately. Any declaration by the Bank of an event of default could significantly harm our business and prospects and could cause the price of our common stock to decline. Additionally, if we raise any additional debt financing, the terms of such additional debt could further restrict our operating and financial flexibility.

50Risks related to the discovery, development and commercialization of our product candidates

~~Table~~We are substantially dependent on the success of ~~Contents~~our lead product candidate, palazestrant, which is currently in clinical development. If we are unable to complete development of, obtain regulatory approval for, and commercialize palazestrant in one or more indications and in a timely manner, our business, financial condition, results of operations, and prospects will be significantly harmed.

~~addressing~~Our ~~any~~future ~~competing~~success ~~technological~~is heavily dependent on our ability to timely complete clinical trials, obtain marketing approval for, and successfully commercialize palazestrant, our lead product candidate. We expect that a substantial portion of our efforts and expenses over the next several years will be devoted to the development of palazestrant in our ongoing clinical trials in multiple indications. We are investing significant efforts and financial resources in the research and development of palazestrant. Palazestrant will require additional clinical development, evaluation of clinical, non-clinical and manufacturing activities, marketing approval from regulatory authorities, and significant marketing efforts before we can generate any revenues from product sales. We are not permitted to market ~~developments;~~or promote palazestrant before we receive marketing approval from the FDA and comparable foreign regulatory authorities, and we may never receive such marketing approvals. Should our planned clinical development of palazestrant in our lead indications fail to be completed in a timely manner or at all, we will need to rely on our ongoing and planned clinical development of palazestrant in additional indications, which will require more time and resources to obtain regulatory approval and proceed with commercialization and may ultimately be unsuccessful.

~~negotiating~~We ~~favorable~~cannot ~~terms~~assure you that our planned clinical development programs for palazestrant will be completed in ~~any~~a ~~collaboration~~timely manner, ~~licensing~~or at all, or ~~other~~that ~~arrangements~~we ~~into~~will ~~which~~be able to obtain approval for palazestrant from the FDA, European Commission (based on the positive opinion of the EMA’s Committee for Medicinal Products for Human Use), or any comparable foreign regulatory authority. If we ~~may~~are ~~enter~~unable to complete development of, obtain regulatory approval for, and ~~performing~~commercialize ~~our~~palazestrant ~~obligations~~in one or more indications and in ~~such~~a ~~collaborations;~~timely manner, our business, financial condition, results of operations, and prospects will be significantly harmed.

~~maintaining,~~Clinical ~~protecting~~development is a lengthy and expensive process with an uncertain outcome, ~~enforcing~~and results of earlier studies and ~~expanding~~trials ~~our~~may ~~portfolio~~not be predictive of ~~intellectual~~future ~~property~~trial ~~rights~~results. Failure can occur at any stage of clinical development. We have never completed a pivotal clinical trial or submitted an NDA to the FDA or similar drug approval filings to comparable foreign authorities. If we are ultimately unable to obtain regulatory approval for palazestrant, ~~including~~OP-3136, ~~patents~~or any future product candidates we may develop, ~~trade~~we ~~secrets~~will be unable to generate product revenue and ~~know-how;~~our business, financial condition, results of operations, and prospects will be significantly harmed.

~~defending~~Clinical ~~against~~testing ~~third-party~~is ~~interference~~expensive and can take many years to complete, ~~infringement~~and orits ~~other~~outcome ~~intellectual~~is ~~property~~inherently uncertain. Failure can occur at any time during the clinical trial process. The results of non-~~related~~clinical ~~claims~~studies and clinical trials of palazestrant, ifOP-3136, and any; future product candidates we may develop may not be predictive of the results of subsequent clinical trials. We have a limited operating history and to date have not demonstrated our ability to complete large-scale clinical trials.

~~attracting, hiring and retaining qualified personnel.~~58

~~Even~~Table if palazestrant, OP-3136 or any future product candidate that we may 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 the FDA, EMA or other comparable regulatory authorities to perform clinical trials or non-clinical studies in addition to those that we currently anticipate. Even if we are able to generate revenue from the sale of ~~any approved products, we may not become profitable and may need to obtain additional funding to continue operations.~~Contents

~~The~~Product ~~terms~~candidates in later stages of clinical trials may fail to show the ~~Loan~~desired ~~Agreement~~safety ~~place~~and ~~restrictions~~efficacy ontraits ~~our~~despite ~~operating~~having progressed through non-clinical studies and ~~financial~~initial ~~flexibility~~clinical trials. IfIn weaddition ~~raise~~to ~~additional~~the ~~capital~~safety ~~through~~and ~~debt~~efficacy ~~financing~~traits of any product candidate, clinical trial failures may result from a multitude of factors, including flaws in trial design, dose selection, placebo effect and patient enrollment criteria. A number of companies in the ~~terms~~biopharmaceutical industry have suffered significant setbacks in advanced clinical trials due to a lack of efficacy or adverse safety profiles, notwithstanding promising results in earlier trials. Based upon negative or inconclusive results, we or any ~~new~~potential ~~debt~~future ~~could~~collaborator ~~further~~may ~~restrict~~decide, ~~our~~or ~~ability~~regulators may require us, to ~~operate~~conduct additional clinical trials or non-clinical studies. In addition, data obtained from trials and studies are susceptible to varying interpretations, and regulators may not interpret our ~~business~~data as favorably as we do, which may delay, limit, or prevent regulatory approval.

InOur ~~September~~future ~~2023~~clinical trials may not be successful. If any of our product candidates is found to be unsafe or lacking efficacy, we ~~entered~~will ~~into~~not abe ~~loan~~able to obtain regulatory approval, and ~~security~~our ~~agreement~~business, ~~(the~~financial ~~Original~~condition, ~~Loan~~results ~~Agreement)~~of ~~with~~operations, ~~Silicon~~and ~~Valley~~prospects ~~Bank~~may be significantly harmed. In some instances, athere ~~division~~can be significant variability in safety and/or efficacy results between different trials of ~~First-Citizens~~the ~~Bank~~same &product ~~Trust~~candidate ~~Company~~due (to numerous factors, including changes in trial protocols, differences in the ~~Bank)~~composition of the patient populations, ~~providing~~adherence usto dosing regimens and other trial protocols and the dropout rate among clinical trial participants. Patients treated with anpalazestrant, ~~aggregate~~OP-3136, ~~principal~~or ~~amount~~any future product candidates we may develop may also be undergoing surgical, radiation and chemotherapy treatments and may be using other approved products or investigational new drugs, which can cause side effects or adverse events that are unrelated to palazestrant, OP-3136, or any future product candidates we may develop. As a result, assessments of upefficacy can vary widely for a particular patient, and from patient to ~~$50~~patient and site to site within a clinical trial.0 ~~million~~This (subjectivity can increase the ~~Original~~uncertainty ~~Credit~~of, ~~Facility)~~and adversely impact, our clinical trial outcomes. We do not know whether any clinical trials we may conduct will demonstrate consistent or adequate efficacy and safety sufficient to obtain marketing approval to market palazestrant, OP-3136, or any future product candidates we may develop.

InWe ~~June~~do ~~2024,~~not weknow ~~entered~~whether ~~into~~our ~~the~~current ~~first~~clinical ~~amendment~~trials toof ~~loan~~palazestrant ~~and~~or ~~security~~OP-3136 ~~agreement~~or ~~(the~~any ~~Amendment,~~future ~~and~~clinical ~~the~~trials ~~Original~~we ~~Loan~~may ~~Agreement~~conduct ~~(as~~will ~~amended~~demonstrate byconsistent ~~the~~or ~~Amendment,~~adequate ~~the~~efficacy ~~Loan~~and ~~Agreement),~~safety ~~with~~to ~~the~~obtain ~~Bank.~~regulatory ~~The~~approval ~~Amendment~~to ~~amends~~market ~~the Original Loan Agreement in order to~~palazestrant, ~~among other things~~OP-3136, ~~increase~~or ~~the~~any ~~aggregate~~future ~~principal~~product ~~amount~~candidates ofwe ~~the~~may ~~Original Credit Facility from up to $50~~develop.0 ~~million~~Most toproduct upcandidates tothat ~~$100.0~~begin ~~million~~clinical ~~(the~~trials ~~Credit~~are ~~Facility),~~never ofapproved ~~which~~by ~~$25.0~~regulatory ~~million~~authorities ~~was~~for ~~available as of December 31, 2024, an additional $25~~commercialization.0 ~~million~~If ~~which~~we ~~will~~are ~~become~~unable ~~available upon achievement of certain milestones related~~ to ~~execution~~bring ~~of a first-line pivotal Phase 3 clinical trial of~~ palazestrant, ~~in combination with ribociclib~~OP-3136, ~~and~~or anany ~~additional~~future ~~$50.0~~product ~~million~~candidates ~~which~~we may bedevelop ~~made~~to ~~available~~market, ~~upon~~our ~~approval~~ability ofto ~~the~~create ~~Bank~~long-term instockholder ~~its~~value ~~discretion. The Credit Facility~~ will ~~mature~~be ~~on July 1, 2028~~limited.

~~Our~~In ~~overall~~addition, ~~leverage~~we ~~and~~may ~~certain~~rely ~~obligations~~in ~~and~~part ~~affirmative~~on ~~and~~non-clinical, ~~negative~~clinical ~~covenants~~and ~~contained~~quality indata ~~the~~generated ~~Loan~~by ~~Agreement~~CROs and ~~related~~other ~~documentation~~third ~~could~~parties ~~adversely~~for ~~affect~~regulatory ~~our~~submissions ~~financial~~for ~~health~~palazestrant ~~and~~or ~~business~~OP-3136. ~~and~~While ~~future~~we ~~operations~~have byor ~~limiting~~will ~~our~~have ~~ability~~agreements ~~to,~~governing ~~among~~these ~~other~~third ~~things~~parties’ services, ~~satisfy~~we ~~our~~have ~~obligations~~limited ~~under~~influence ~~the~~over ~~Loan~~their ~~Agreement,~~actual ~~refinance~~performance. ~~our~~If ~~debt~~these onthird ~~terms~~parties ~~acceptable~~do not make data available to us, or, atif ~~all~~applicable, ~~plan~~make ~~for~~regulatory ~~and~~submissions ~~adjust~~in toa ~~changing~~timely ~~business~~manner, ~~industry and market conditions, use~~ our ~~available~~development ~~cash~~programs ~~flow~~may tobe ~~fund~~significantly ~~future~~delayed, ~~acquisitions~~ and ~~make~~we ~~dividend~~may ~~payments,~~need ~~and~~to ~~obtain~~conduct additional ~~financing~~studies ~~for~~or ~~working~~collect ~~capital,~~additional todata ~~fund~~independently. ~~growth~~In oreither ~~for general corporate purposes~~case, ~~even~~our ~~when~~development ~~necessary~~costs towould ~~maintain adequate liquidity~~increase.

If we default under the Loan Agreement, the Bank may accelerate all of our repayment obligations and exercise all of its rights and remedies under the Loan Agreement and applicable law, potentially requiring us to renegotiate our agreement on terms less favorable to us. Further, if we are liquidated, the lenders’ right to repayment would be senior to the rights of the holders of our common stock to receive any proceeds from the liquidation. The Bank could declare a default upon the occurrence of customary events of default, including, but not limited to, nonpayment of principal, interest, fees or other amounts; material inaccuracy of a representation or warranty; failure to perform or observe covenants; cross-defaults with certain other indebtedness; bankruptcy and insolvency events; material monetary judgment defaults; material adverse change occurs; delisting; and a material impairment in the Bank’s security interest. Upon the occurrence of an event of default (subject, in certain cases, to notice and grace periods), obligations under the Loan Agreement may be accelerated thereby requiring us to repay the loan immediately. Any declaration by the lender of an event of default could significantly harm our business and prospects and could cause the price of our common stock to decline. Additionally, if we raise any additional debt financing, the terms of such additional debt could further restrict our operating and financial flexibility.59

51Table of Contents

~~Table~~Moreover, non-clinical and clinical data are often susceptible to varying interpretations and analyses and many companies that believed their product candidates performed satisfactorily in non-clinical studies and clinical trials nonetheless failed to obtain FDA, European Commission, or comparable foreign regulatory authority approval. We cannot guarantee that the FDA or foreign regulatory authorities will interpret trial results as we do, and more trials could be required before we are able to submit an application seeking approval of ~~Contents~~palazestrant, OP-3136, or any future product candidates we may develop. To the extent that the results of the trials are not satisfactory to the FDA or foreign regulatory authorities to support marketing approval, we may be required to expend significant resources, which may not be available to us, to conduct additional trials in support of potential approval of palazestrant, OP-3136, or any future product candidates we may develop. Even if regulatory approval is secured for palazestrant or OP-3136, the terms of such approval may limit the scope and use of palazestrant or OP-3136, which may also limit its commercial potential. Furthermore, the approval policies or regulations of the FDA, European Commission, or comparable foreign regulatory authorities may significantly change in a manner that results in adverse consequences to us, including by rendering our clinical data insufficient for approval, which may lead to the FDA, European Commission, or comparable foreign regulatory authorities delaying, limiting or denying approval of palazestrant or OP-3136, including any other indication we are seeking for approval under palazestrant or OP-3136.

~~Risks~~The ~~related~~regulatory toapproval processes of the ~~discovery~~FDA, ~~development~~European Commission, and ~~commercialization~~comparable offoreign ~~our~~authorities are lengthy, time consuming and inherently unpredictable, and if we are ultimately unable to obtain regulatory approval for palazestrant, OP-3136, or any future product candidates we may develop, our business, financial condition, results of operations, and prospects will be significantly harmed.

WeThe ~~are~~time ~~substantially~~required ~~dependent~~to onobtain ~~the~~approval ~~success~~by ofthe ~~our~~FDA, ~~lead~~European ~~product~~Commission ~~candidate,~~and ~~palazestrant,~~comparable ~~which~~foreign authorities is ~~currently~~unpredictable inand typically takes many years following the commencement of clinical ~~development.~~trials Ifand wedepends ~~are~~upon ~~unable~~numerous tofactors, ~~complete~~including ~~development~~the substantial discretion of, ~~obtain~~the regulatory ~~approval~~authorities. ~~for~~In ~~and~~addition, ~~commercialize~~approval ~~palazestrant~~policies, inregulations, ~~one~~ or ~~more~~the ~~indications~~type and inamount aof ~~timely~~clinical ~~manner,~~data ~~our~~necessary ~~business,~~to ~~financial~~gain ~~condition,~~approval ~~results~~may change during the course of ~~operations~~a ~~and~~product ~~prospects~~candidate’s ~~will~~clinical bedevelopment ~~significantly~~and ~~harmed~~may vary among jurisdictions.

~~Our~~Applications ~~future success is heavily dependent on our ability to timely complete clinical trials, obtain marketing approval~~ for ~~and successfully commercialize~~ palazestrant, ~~our~~or lead product candidate. We expect that a substantial portion of our efforts and expenses over the next several years will be devoted to the development of palazestrant in our ongoing clinical trials in multiple indications. We are investing significant efforts and financial resources in the research and development of palazestrant. Palazestrant will require additional clinical development, evaluation of clinical, nonOP-~~clinical~~3136 ~~and~~could ~~manufacturing~~fail ~~activities, marketing approval from regulatory authorities, and significant marketing efforts before we can generate any revenues from product sales. We are not permitted~~ to ~~market or promote palazestrant before we~~ receive ~~marketing~~regulatory approval ~~from~~for ~~the~~many ~~FDA and comparable foreign regulatory authorities~~reasons, ~~and~~including wethe may never receive such marketing approvals. Should our planned clinical development of palazestrant in our lead indications fail to be completed in a timely manner or at all, we will need to rely on our ongoing and planned clinical development of palazestrant in additional indications, which will require more time and resources to obtain regulatory approval and proceed with commercialization and may ultimately be unsuccessful.following:

•

~~We cannot assure you that our planned clinical development programs for palazestrant will be completed in a timely manner, or at all, or that we will be able to obtain approval for palazestrant from~~ the FDA, European Commission ~~(based on the positive opinion of the EMA’s Committee for Medicinal Products for Human Use)~~, or ~~any~~other comparable foreign regulatory ~~authority.~~authorities Ifmay wedisagree ~~are~~with ~~unable~~the ~~to complete development of~~design, ~~obtain~~implementation ~~regulatory approval for and commercialize palazestrant in one~~ or ~~more indications and in a timely manner, our business, financial condition,~~ results of ~~operations~~our ~~and~~clinical ~~prospects will be significantly harmed.~~trials;

•

~~Clinical~~the ~~development~~FDA, isEuropean ~~a lengthy and expensive process with an uncertain outcome~~Commission, ~~and~~or ~~results~~other ofcomparable ~~earlier~~foreign ~~studies~~regulatory ~~and~~authorities ~~trials~~ may ~~not~~determine bethat ~~predictive~~palazestrant ofor ~~future~~OP-3136 ~~trial~~is ~~results.~~not ~~Failure~~safe ~~can~~and ~~occur~~effective, atonly ~~any~~moderately ~~stage~~effective ofor ~~clinical development. We~~ have ~~never~~undesirable ~~completed a pivotal clinical trial~~ or ~~submitted~~unintended aside ~~New~~effects, ~~Drug~~toxicities ~~Application (NDA) to the FDA~~ or ~~similar~~other ~~drug~~characteristics ~~approval~~that ~~filings~~preclude toour ~~comparable~~obtaining ~~foreign~~marketing ~~authorities. If we are ultimately unable to obtain regulatory~~ approval ~~for~~or ~~palazestrant,~~prevent ~~OP-3136~~ or ~~any~~limit ~~future~~commercial ~~product candidates we may develop, we will be unable to generate product revenue and our business, financial condition, results of operations and prospects will be significantly harmed.~~use;

•

~~Clinical~~the ~~testing~~population isstudied ~~expensive~~in ~~and can take many years to complete, and its outcome is inherently uncertain. Failure can occur at any time during~~ the clinical trial ~~process. The results of non-clinical studies and clinical trials of palazestrant, OP-3136 and any future product candidates we~~ may ~~develop may~~ not be ~~predictive~~sufficiently ofbroad ~~the~~or ~~results~~representative ofto ~~subsequent~~assure ~~clinical~~efficacy ~~trials. We have a limited operating history~~ and tosafety ~~date~~in ~~have~~the ~~not~~full ~~demonstrated~~population ~~our~~for ~~ability~~which towe ~~complete~~seek ~~large-scale clinical trials.~~approval;

•

~~Product candidates in later stages of clinical trials may fail to show~~ the ~~desired safety and efficacy traits despite having progressed through non-clinical studies and initial clinical trials. In addition to the safety and efficacy traits of any product candidate~~FDA, ~~clinical~~European ~~trial failures may result from a multitude of factors including flaws in trial design~~Commission, dose selection, placebo effect and patient enrollment criteria. A number of companies in the biopharmaceutical industry have suffered significant setbacks in advanced clinical trials due to lack of efficacy or ~~adverse~~other ~~safety~~comparable ~~profiles,~~foreign ~~notwithstanding~~regulatory ~~promising~~authorities ~~results in earlier trials. Based upon negative or inconclusive results, we or any potential future collaborator~~ may ~~decide,~~disagree orwith ~~regulators~~our ~~may~~interpretation ~~require~~of ~~us,~~data tofrom ~~conduct additional clinical trials or~~ non-clinical studies. ~~In addition, data obtained from trials and studies are susceptible to varying interpretations, and regulators may not interpret our data as favorably as we do, which may delay, limit~~ or ~~prevent~~clinical ~~regulatory approval.~~trials;

•

~~Our~~the ~~future~~data collected from clinical trials ~~may~~of ~~not~~palazestrant beor ~~successful.~~OP-3136 Ifmay ~~any~~not ~~product~~be ~~candidate~~sufficient ~~is found~~ to besupport ~~unsafe~~the orsubmission ~~lack~~of ~~efficacy~~an NDA, weor ~~will~~other ~~not~~submission beor ~~able~~ to obtain regulatory approval ~~for~~in itthe ~~and~~United ~~our~~States ~~business,~~or ~~financial condition, results of operations and prospects may be significantly harmed. In some instances, there can be significant variability in safety~~ elsewhere;

•

52we may be unable to demonstrate to the FDA, European Commission, or other comparable foreign regulatory authorities that palazestrant's or OP-3136’s risk-benefit ratio for its proposed indication is acceptable;

Filing Compare · Olema Pharmaceuticals, Inc.