UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

FORM 10-K

(Mark One)
☒						ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended December 31, 2021
For the fiscal year ended December 31, 2022
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 001-36080

IVERIC bio, Inc.

(Exact name of registrant as specified in its charter)



Delaware		20-8185347
(State or other jurisdiction of incorporation or organization)		(I.R.S. Employer Identification No.)

8 Sylvan Way
Parsippany	NJ	07054
(Address of principal executive offices)		(Zip Code)

(609) 474-6455

(Registrant's telephone number, including area code)

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


Title of each class	Trading Symbol(s)	Name of each exchange on which registered
Common Stock, $0.001 par value	ISEE	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. ☒ Yes ☐ No

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

AsIf ofsecurities ~~June 30,~~are ~~2021,~~registered ~~the~~pursuant ~~aggregate~~to ~~market~~Section ~~value~~12(b) of the ~~voting~~Act, ~~and~~indicate ~~non-voting~~by ~~common~~check ~~equity~~mark ~~held~~whether bythe ~~non-affiliates~~financial statements of the registrant ~~was~~included ~~approximately~~in ~~$546.1 million,~~the ~~based~~filing onreflect the ~~closing~~correction ~~price~~ of ~~the~~an ~~registrant's~~error ~~common~~to ~~stock~~previously onissued ~~June 30,~~financial ~~2021~~statements. ☐

~~The~~Indicate ~~number~~by check mark whether any of ~~shares~~those ~~outstanding~~error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant'’s ~~class~~executive ofofficers ~~common~~during ~~stock,~~the asrelevant ofrecovery ~~February 21,~~period ~~2022:~~pursuant ~~115,680,118~~to § 240.10D-1(b) ☐

As of June 30, 2022, the aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant was approximately $1,093.4 million, based on the closing price of the registrant's common stock on June 30, 2022.

The number of shares outstanding of the registrant's class of common stock, as of February 27, 2023: 137,122,338

DOCUMENTS INCORPORATED BY REFERENCE

Part III of this Annual Report incorporates by reference information from the definitive Proxy Statement for the registrant's ~~2022~~2023 Annual Meeting of Shareholders, which is expected to be filed with the Securities and Exchange Commission not later than 120 days after the registrant's fiscal year ended December 31, ~~2021~~2022.

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TABLE OF CONTENTS

PART I
Item 1.	Business	2
Item 1A.	Risk Factors	7068
Item 1B.	Unresolved Staff Comments	~~127~~122
Item 2.	Properties	~~128~~122
Item 3.	Legal Proceedings	~~128~~122
Item 4.	Mine Safety Disclosures	~~128~~122
PART II
Item 5.	Market for Registrant's Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities	~~129~~123
Item 6.	Selected Financial Data	~~130~~124
Item 7.	Management's Discussion and Analysis of Financial Condition and Results of Operations	~~131~~125
Item 7A.	Quantitative and Qualitative Disclosures About Market Risk	~~151~~139
Item 8.	Financial Statements and Supplementary Data	~~151~~139
Item 9.	Changes in and Disagreements With Accountants on Accounting and Financial Disclosure	~~151~~139
Item 9A.	Controls and Procedures	~~151~~139
Item 9B.	Other Information	~~154~~142
PART III
Item 10.	Directors, Executive Officers and Corporate Governance	~~154~~142
Item 11.	Executive Compensation	~~155~~142
Item 12.	Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters	~~155~~142
Item 13.	Certain Relationships and Related Transactions, and Director Independence	~~155~~142
Item 14.	Principal Accountant Fees and Services	~~155~~143
PART IV
Item 15.	Exhibits and Financial Statement Schedules	~~156~~144
Item 16.	Form 10-K Summary	~~158~~147

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FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this Annual Report on Form 10-K, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words "anticipate," "believe," "goals," "estimate," "expect," "intend," "may," "might," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.

The forward-looking statements in this Annual Report on Form 10-K include, among other things, statements about:

•the potential benefits of our business plan and strategy, including our goal to deliver treatment options for ~~all~~various stages of age-related macular degeneration (AMD);

•our expectations regarding the impact of results from GATHER1, our completed Phase 3 clinical trial evaluating ~~Zimura~~avacincaptad pegol (ACP) for the treatment of Geographic Atrophy (GA) secondary to AMD, and from GATHER2, our ongoing Phase 3 clinical trial evaluating ACP for the treatment of GA secondary to AMD, on our business and regulatory strategy, including, the timing and response to our new drug application (NDA) submitted to the U.S. Food and Drug Administration (FDA), our plans to ~~pursue~~submit ~~development~~marketing ofauthorization ~~Zimura~~applications into the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), and our expectations for using ACP for the treatment of intermediate AMD;

•the timing, costs, conduct and outcome of GATHER2, ~~our~~including ~~ongoing~~expectations ~~Phase~~regarding 3patient ~~clinical~~retention ~~trial~~and ~~evaluating Zimura for~~ the ~~treatment~~safety profile of ~~GA secondary to AMD~~ACP, including ~~expectations~~from ~~regarding~~our ~~receipt~~open-label ofextension ~~topline~~study ~~data~~for ~~from~~patients ~~the~~who ~~trial~~completed ~~and~~the ~~regarding~~GATHER2 ~~patient retention~~trial, and expectations regarding the potential for ~~Zimura~~ACP to receive regulatory approval for the treatment of GA based on the clinical trial results we have received to date ~~and the future results from the GATHER2 clinical trial and any other trials we or a potential collaborator may conduct~~;

•our plans and ~~expectations~~strategy for ~~initiating~~the apotential ~~clinical~~commercialization ~~trial~~of ~~evaluating~~ACP, ~~Zimura~~including ~~for~~hiring ~~the~~of ~~treatment~~medical ofaffairs ~~intermediate~~and ~~AMD~~commercialization personnel, ~~and~~building ~~for~~a ~~evaluating~~commercialization infrastructure, ~~obtaining~~including ~~rights~~sales, tomarketing and ~~developing~~distribution ~~sustained~~capabilities, ~~release~~and ~~delivery~~our ~~technologies~~expectations regarding the market dynamics for ~~Zimura~~treatments for GA and other commercial matters;

•our ~~plans~~ability to establish and ~~strategy~~maintain capabilities and capacity for the ~~potential~~manufacture ~~commercialization~~ of ~~Zimura~~ACP and our other product candidates, including ~~hiring~~scale up and validation of ~~medical~~the ~~affairs~~manufacturing process for ACP drug substance and ~~commercialization~~drug ~~personnel~~product, ~~building~~and asecuring ~~commercialization~~the ~~infrastructure,~~supply ~~including~~of ~~sales,~~the ~~marketing~~polyethylene ~~and~~glycol ~~distribution~~(PEG) ~~capabilities,~~starting material and other materials for our ~~expectations~~expected ~~regarding~~manufacturing needs and securing the ~~market~~supply ~~dynamics~~of ~~for~~ACP ~~treatments~~drug ~~for~~substance, GAdrug product and ~~other~~finished ~~commercial~~goods ~~matters~~for our expected needs;

•our ~~ability~~plans ~~to establish and maintain arrangements and capabilities~~ for ~~the~~evaluating, ~~manufacture~~obtaining ofrights ~~Zimura and our other product candidates~~to, ~~including~~developing ~~scale up~~ and ~~validation~~potentially ofcommercializing ~~the~~new ~~manufacturing~~formulations ~~process~~of ~~for~~ACP ~~Zimura~~with ~~drug~~the ~~substance~~silica-based ~~and~~sustained ~~drug~~release ~~product,~~technology ~~and~~we ~~securing~~in-licensed ~~the~~from ~~supply~~DelSiTech ofLtd. ~~Zimura~~(DelSiTech) ~~drug product~~ and ~~the~~other ~~polyethylene~~sustained ~~glycol~~release ~~(PEG)~~delivery ~~starting~~technologies ~~material~~ for ~~our expected needs~~ACP;

•the timing, costs, conduct and outcome of STAR, our ongoing Phase 2b screening trial evaluating ~~Zimura~~ACP for the treatment of autosomal recessive Stargardt disease, including expectations regarding the recruitment of additional patients for this trial;

•our plans and ability to consummate business development transactions, including potential collaboration opportunities for further development and potential commercialization of ~~Zimura~~ACP outside the United States ~~and potential collaboration opportunities for further development of IC-100 and IC-200~~; and in-licenses or other opportunities to acquire rights to additional product candidates or technologies to treat retinal diseases, including additional sustained release delivery technologies for ~~Zimura~~ACP;

•~~the actual and expected effects of the COVID-19 pandemic and related response measures on~~ our ~~business~~estimates ~~and~~regarding ~~operations~~expenses, ~~including~~future ~~the~~revenues ~~timing, costs, conduct~~ and ~~outcome~~debt ofservice ~~our research and development programs~~obligations, ~~our supply chain,~~ the ~~work~~sufficiency of our ~~third-party~~cash ~~vendors~~resources and ~~collaborators,~~our ~~the~~capital ~~work~~requirements and ~~well-being~~need ~~of our employees~~for, and ~~our~~ability ~~financial~~to ~~position~~obtain, additional financing;

•our ~~estimates~~plans ~~regarding~~to ~~expenses,~~raise ~~future~~additional ~~revenues~~capital, ~~capital~~including ~~requirements~~through ~~and~~equity ~~needs~~offerings, ~~for~~debt financings, ~~and~~collaborations, ~~ability~~strategic toalliances, ~~obtain~~licensing arrangements, ~~additional~~royalty ~~financing~~agreements and marketing and distribution arrangements;

•the timing, costs, conduct and outcome of our ongoing and planned clinical trials, including statements regarding the timing of the initiation and completion of, and the receipt of results from, such clinical trials, the costs to conduct such clinical trials, and the impact of the results of such clinical trials on our business strategy;

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•the timing, costs, conduct and outcome of our ongoing clinical trials, including statements regarding the timing of the initiation and completion of, and the receipt of results from, such clinical trials, the costs to conduct such clinical trials, and the impact of the results of such clinical trials on our business strategy;

•the timing, costs, conduct and outcome of our ongoing and planned research and preclinical development activities, including statements regarding the timing of the initiation and completion of, and the receipt of results from, such activities, the costs to conduct such activities, and the impact of the results of such activities on our business strategy;

•the timing of and our ability to submit investigational new drug applications for, and to submit new drug applications or marketing authorization applications for and to obtain marketing approval of our product candidates, and the ability of our product candidates to meet existing or future regulatory standards;

•the potential advantages of our product candidates and other technologies that we are pursuing, including our hypotheses regarding complement factor C5 inhibition and HtrA1 inhibition as potentially relevant mechanisms of action to treat GA and other stages of AMD, and of gene therapy, including the use of minigenes;

•our estimates regarding the number of patients affected by the diseases our product candidates and development programs are intended to treat;

•our estimates regarding the potential market opportunity for our product candidates, including our ability to obtain coverage and reimbursement for those product candidates, if approved;

•the rate and degree of potential market acceptance and clinical utility of our product candidates, if approved;

•the potential receipt of revenues from future sales of our product candidates, if approved;

•the actual and expected effects of the COVID-19 pandemic, other macro-economic events and related response measures on our business and operations, including the timing, costs, conduct and outcome of our research and development programs, our supply chain, the work of our third-party vendors and collaborators, the work and well-being of our employees, and our financial position;

•our personnel and human capital resources;

•our intellectual property position;

•the impact of existing and new governmental laws and regulations; and

•our competitive position.

We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and our stockholders should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. We have included important factors in the cautionary statements included in this Annual Report on Form 10-K, particularly under the section "Summary of Principal Risk Factors" below and the risk factors detailed further in Item 1A, "Risk Factors" of Part I of this report and in our Securities and Exchange Commission reports filed after this report, that could cause actual results or events to differ materially from the forward-looking statements that we make. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments we may make.

You should read this Annual Report on Form 10-K and the documents that we have filed as exhibits to this Annual Report on Form 10-K completely and with the understanding that our actual future results may be materially different from what we expect. The forward-looking statements contained in this Annual Report on Form 10-K are made as of the date of this Annual Report on Form 10-K, and we do not assume any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by applicable law.

This Annual Report on Form 10-K includes statistical and other industry and market data that we obtained from industry publications and research, surveys and studies conducted by third parties. Industry publications and third-party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information.

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Summary of Principal Risk Factors

The following is a summary of the principal factors that make an investment in our company speculative or risky. This summary does not address all of the risks and uncertainties that we face. Additional risk and uncertainties not presently known to us or that we presently deem less significant may also impair our business operations. Additional discussion of the risks summarized in this summary, and other risks that we face, can be found in Item 1A. Risk Factors section of this Annual Report on

Form 10-K, and should be carefully considered, together with other information in this Annual Report on Form 10-K and

our other filings with the Securities Exchange Commission, before making an investment decision regarding our common

stock. The forward-looking statements discussed above are qualified by these risk factors. If any of the following risks occur,

our business, financial condition, results of operations and future growth prospects could be materially and adversely affected.

21.The value of your investment is highly dependent on the success and potential commercialization of ACP. We are working to transition to being a company capable of commercializing a pharmaceutical product, if approved, and may not be successful in this transition.

~~Table~~2.We have a history of ~~Contents~~ significant operating losses and expect to continue to incur losses until we can successfully commercialize one or more of our product candidates, if ever. We may never achieve or maintain profitability.

13.We ~~are~~may aneed ~~development-stage~~additional ~~company~~financing ~~without~~in ~~any~~order ~~approved~~to ~~products.~~commence, ~~The~~if ~~value~~approved, ofand ~~your~~continue ~~investment~~commercializing isACP, ~~highly~~or ~~dependent~~continue ondeveloping ~~the~~our ~~success~~other ofproduct ~~Zimura~~candidates. ~~and~~Securing ~~our~~financing ~~other~~may ~~research~~be challenging and/or ~~development~~dilutive ~~programs,~~to ~~which~~our ~~carry~~shareholders, ~~numerous~~and ~~risks.~~if Wewe are ~~working~~unable to ~~transition~~secure tofinancing ~~being~~when aneeded, ~~company~~we ~~capable~~may ofneed ~~commercializing~~to acurtail ~~pharmaceutical~~our ~~product,~~development ifprograms ~~approved,~~or ~~and~~planned ~~may~~commercialization ~~not be successful in this transition~~activities.

24.WeThe ~~have~~covenants ~~had~~in aour ~~history~~Loan ofand ~~operating~~Security atAgreement ~~significant~~with ~~losses~~Hercules Capital, Inc. and ~~expect~~Silicon toValley ~~continue~~Bank tomay dolimit soand ~~until~~restrict wefrom ~~can~~us ~~successfully~~from ~~commercialize~~pursuing ~~one~~certain oroperating ~~more~~activities. ofIf ~~our~~we ~~product~~are ~~candidates,~~in ifdefault ~~ever.~~under Wethat agreement, we may ~~never~~need ~~achieve~~to ~~profitability.~~repay all existing indebtedness under that term loan facility.

35.We ~~may~~ need ~~additional~~to ~~financing~~satisfy numerous regulatory requirements in order to ~~finish~~secure ~~developing~~marketing approval and ~~start~~reimbursement ~~commercializing~~approval, ~~one~~if orapplicable, ~~more~~for ofACP ~~our~~and other product candidates~~, if approved~~. ~~Securing~~These ~~financing~~requirements ~~may~~differ beacross ~~challenging~~jurisdictions. ~~and/or~~Failure ~~dilutive~~ to ~~our~~satisfy ~~shareholders,~~ and ifmaintain wethose ~~are~~requirements ~~unable~~can topreclude ~~secure~~us ~~financing~~from ~~when~~commercializing ~~needed, we may need to curtail~~ our ~~development programs or planned commercialization activities~~products.

46.~~The~~Regulatory ~~COVID-19~~authorities, ~~pandemic~~including ~~has~~the ~~adversely~~FDA ~~affected~~and ~~our business~~EMA, ~~for~~may ~~example,~~disagree bywith ~~impacting~~our ~~the~~analyses ~~initiation~~or ~~and~~conclusions ~~conduct~~from of our clinical trials, ~~the~~of ~~work~~ACP in GA secondary to AMD. Since receipt of ~~our~~the ~~contract~~12-month ~~manufacturing~~results ~~organizations~~from GATHER1, ~~contract~~we ~~research~~have ~~organizations~~not ~~and~~had ~~other~~any ~~vendors,~~formal ~~and~~interactions ~~aspects~~with ofthe EMA regarding our ~~supply~~planned ~~chain.~~regulatory ~~Because~~pathway offor ACP in GA and the ~~ongoing~~EMA and ~~fluid~~other ~~nature~~regulatory authorities may disagree with the requirements of the ~~pandemic,~~FDA. itWe ~~will~~may ~~continue~~need to ~~affect~~conduct ~~our~~additional ~~business.~~clinical trials or nonclinical studies for ACP in order to obtain marketing approval or reimbursement approval.

57.Manufacturing our product candidates is technically complex, expensive and time consuming. We may face issues with scaling up and validating the manufacturing process for ACP. We may not be ~~successful~~able into ~~obtaining~~secure ~~rights~~adequate tosupply ~~and~~of ~~developing~~PEG astarting ~~sustained~~material, ~~release~~ACP ~~delivery~~drug ~~technology~~substance, ACP drug product or ACP finished goods for ~~Zimura~~our future needs, including potential commercial launch. Issues with manufacturing can derail the further development or commercialization of our product candidates.

68.~~Drug~~To ~~development~~commercialize isany ~~inherently~~of ~~risky~~our ~~with~~product ~~numerous scientific~~candidates, ~~technical~~if approved, ~~regulatory~~we will need to set up a sales and ~~other~~marketing ~~challenges~~infrastructure. AWe ~~promising~~are ~~drug~~continuing ~~candidate~~to ~~can~~hire ~~fail~~commercialization atpersonnel ~~any~~and ~~time~~will ~~and~~need ~~for~~to ~~any~~continue ~~number~~building our commercial infrastructure. The success of ~~reasons~~our commercialization efforts will depend in part on the degree of acceptance of our product candidates by patients, the medical community and payors.

79.We ~~are~~face ~~pursuing~~substantial ~~the~~competition ~~development~~from oflarge ~~our~~pharmaceutical ~~product candidates using novel mechanisms of action targeting indications for which there are no approved products. These include~~companies, ~~for~~smaller ~~example,~~biotech ~~complement~~companies ~~inhibition~~ and ~~inhibition of High temperature requirement A serine peptidase 1 protein for GA, and complement inhibition for intermediate AMD and autosomal recessive Stargardt disease~~others. ~~These approaches carry numerous scientific, regulatory and other risks.~~

810.~~Regulatory authorities, including the U.S. Food and~~ Drug ~~Administration,~~development oris ~~FDA,~~inherently ~~and~~risky ~~the~~with ~~European~~numerous ~~Medicines Agency~~scientific, ~~or EMA~~technical, may disagree with the design of or our analyses or conclusions from our clinical trials of Zimura in GA or our planned development pathway for Zimura in intermediate AMD. Since receipt of the 12-month results from GATHER1, we have not had any formal interactions with the EMA regarding our planned regulatory ~~pathway for Zimura in GA~~ and ~~the EMA and~~ other ~~regulatory authorities may disagree with the requirements of the FDA~~challenges. WeA ~~may~~promising ~~need~~drug tocandidate ~~conduct~~can ~~additional~~fail ~~clinical~~at ~~trials~~any ortime ~~nonclinical~~and ~~studies~~ for ~~Zimura~~any innumber ~~order~~of ~~to obtain marketing approval or reimbursement approval~~reasons.

911.~~The~~We ~~results~~are ofpursuing the ~~GATHER2~~development ~~trial~~of ~~may~~our ~~not~~product ~~replicate~~candidates ~~the~~using ~~results~~novel mechanisms of ~~the~~action ~~GATHER1~~targeting ~~trial.~~indications Wefor ~~may~~which ~~discover~~there ~~safety~~are ~~issues~~few ~~with~~or ~~our~~no ~~product~~approved ~~candidates~~products. ~~due~~These toinclude, ~~known~~for example, complement inhibition and ~~currently~~inhibition ~~unknown~~of ~~factors~~High temperature requirement A serine peptidase 1 protein for GA, ~~which~~and ~~could~~complement ~~hamper~~inhibition ~~their~~for ~~further~~intermediate ~~development~~AMD and autosomal recessive Stargardt disease. These approaches carry numerous scientific, regulatory and other risks.

10.Manufacturing our product candidates is technically complex, expensive and time consuming. We may face issues with scaling up and validating the manufacturing process for Zimura. We may not be able to secure adequate manufacturing capacity of Zimura drug product or adequate supply of the PEG starting material for our future needs, including potential commercial launch. Issues with manufacturing can derail the further development or commercialization of our product candidates.

11.We face substantial competition from large pharmaceutical companies, smaller biotech companies and others.

12.To commercialize any of our product candidates, if approved, we will need to set up a sales and marketing infrastructure. We have only recently hired commercialization personnel and will need to continue building our commercial infrastructure. The success of our commercialization efforts will depend in part on the degree of acceptance of our product candidates by regulatory authorities, patients, the medical community and payors.

13.We do not have any internal manufacturing facilities and rely heavily on our third-party contract manufacturers. They may have different business priorities than we do and may fail to meet our expectations or follow regulatory requirements, including current good manufacturing practices requirements. We may need to engage alternative manufacturers or suppliers sooner than we currently expect.

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1412.WeThe ~~rely~~12-month ~~heavily~~results onof ~~our~~GATHER2 ~~third-party~~may ~~contract~~not ~~research~~be ~~organizations~~replicated asby ~~well~~the as24-month ~~our~~results ~~clinical~~from the trial, ~~sites.~~which ~~They~~ may ~~have~~not ~~different~~replicate ~~priorities~~the ~~than~~results weof dothe ~~and~~GATHER1 trial. We may ~~fail~~discover tosafety ~~follow~~issues ~~regulatory~~with ~~requirements,~~our ~~including~~product ~~good~~candidates ~~laboratory~~due ~~practice~~to known and currently unknown factors, ~~good~~which ~~clinical~~could ~~practice~~hamper ~~and~~their ~~other~~further ~~data~~development ~~integrity~~or ~~requirements~~commercialization.

1513.We may ~~pursue~~not abe ~~collaboration~~successful ~~for the further development and potential commercialization of Zimura~~ in ~~one~~developing ~~or more territories outside the United States, and plan to pursue~~ a ~~collaboration~~formulation ~~for the further development and potential commercialization~~ of ~~IC-100~~ACP ~~and~~with ~~IC-200. We may also pursue a collaboration for~~ the ~~further development of any promising~~ sustained release delivery ~~technologies~~technology ~~for Zimura. For any of these,~~ we ~~may~~in-licensed ~~not~~from beDelSiTech ~~able to enter into a collaboration agreement on favorable terms,~~ or atobtaining ~~all.~~rights ~~Even if we are able~~ to doand ~~so,~~developing ~~the~~other ~~collaboration~~sustained ~~may~~release ~~not~~delivery betechnologies ~~successful~~for ACP.

1614.We ~~rely~~do onnot ~~patents~~have toany ~~protect~~internal manufacturing facilities and rely heavily on our ~~proprietary~~third-party ~~position~~contract manufacturers. WeThey may ~~not~~have ~~obtain~~different ~~the~~business ~~patent~~priorities ~~rights~~than ~~that~~ we ~~seek~~do and/ may fail to meet our expectations or wefollow ~~may~~regulatory ~~not~~requirements, beincluding ~~able~~current togood ~~exclude~~manufacturing ~~our~~practices ~~competitors~~and ~~from~~data ~~relevant~~integrity ~~markets~~requirements. We may beneed ~~subject~~ to ~~litigation~~engage ~~involving~~alternative ~~our~~manufacturers ~~patents~~ or ~~those~~suppliers ofsooner ~~third~~than ~~parties~~we currently expect.

1715.We ~~are~~plan ~~highly~~to ~~dependent~~rely on ~~our~~third-party ~~information~~distribution ~~security systems~~ and ~~those~~other ofcommercial ~~third~~services ~~parties~~vendors weto ~~work~~assist us with. ~~A cybersecurity incident may cause interruptions to~~ the ~~progress~~commercialization of ~~our~~ACP, ~~development~~if ~~programs~~approved, and ~~operations,~~those ~~financial~~third orparties ~~regulatory~~may ~~penalties~~not ~~and/or~~perform ~~harm~~satisfactorily tofor ~~our~~any ~~reputation~~number of reasons.

1816.We rely heavily on aour ~~limited~~third-party ~~number~~contract ofresearch ~~employees~~organizations toas ~~conduct~~well ~~our~~as ~~operations, including supervising~~ our ~~outside~~clinical ~~vendors~~trial sites. ~~The~~They ~~skills~~may ~~needed~~have todifferent ~~advance~~priorities ~~our~~than ~~research~~we ~~and~~do ~~development programs~~ and ~~plan~~may ~~for~~fail ~~commercialization of our product candidates are highly specialized. We plan~~ to ~~hire~~follow ~~additional~~regulatory ~~qualified personnel~~requirements, including ~~commercialization~~good ~~and~~laboratory ~~medical affairs personnel~~practice, togood ~~support~~clinical ~~the~~practice ~~growth of our business. Hiring these personnel~~ and ~~retaining~~other ~~existing~~data ~~employees~~integrity ~~may be challenging~~requirements.

1917.We ~~need~~plan to ~~satisfy~~explore ~~numerous~~collaboration ~~regulatory~~opportunities ~~requirements~~for inthe ~~order~~further todevelopment ~~secure~~and ~~marketing~~potential ~~approval~~commercialization ~~and~~of ~~reimbursement~~ACP ~~approval,~~in ifone ~~applicable,~~or ~~for~~more ~~any~~territories ofoutside ~~our~~the ~~product~~United ~~candidates~~States. ~~These~~We ~~requirements~~may ~~differ~~not ~~across~~be ~~jurisdictions~~able to enter into a collaboration on favorable terms, or at all. ~~Failure~~Even toif ~~satisfy~~we ~~and~~are ~~maintain~~able ~~those~~to ~~requirements~~do ~~can~~so, ~~preclude~~the uscollaboration ~~from~~may ~~commercializing~~not ~~our~~be ~~products~~successful.

2018.We ~~and~~rely ~~any~~on ~~commercialization~~patents ~~partners~~to ~~are~~protect ~~subject~~our toproprietary ~~numerous~~position. ~~healthcare~~We ~~laws~~may ~~and~~not ~~regulations~~obtain ~~governing~~the ~~our~~patent ~~relationships~~rights ~~with~~that ~~patients,~~we ~~healthcare~~seek ~~professionals~~ and/or ~~third-party~~we ~~payors.~~may ~~Failure~~not be able to ~~comply~~exclude ~~with~~our ~~these~~competitors ~~requirements~~from ~~may~~relevant ~~adversely~~markets. ~~affect~~We ~~our~~may ~~business,~~be ~~including~~subject asto welitigation ~~prepare~~involving ~~for~~our ~~potential~~patents ~~commercialization~~or those of ~~Zimura.~~third parties.

2119.~~The~~We ~~reimbursement~~are ~~and~~highly ~~payment~~dependent ~~regime~~on ~~for~~our ~~pharmaceutical~~information ~~products~~security insystems ~~the~~and ~~United~~those ~~States~~of ~~remains~~third inparties ~~flux,~~we ~~including~~work aswith. aA ~~result~~cybersecurity ofincident ~~the~~may ~~implementation~~cause ofinterruptions ~~and~~to ~~litigation~~the ~~involving~~progress ~~the~~of ~~Affordable~~our ~~Care~~operations, ~~Act.~~financial ~~There~~or ~~are~~regulatory ~~ongoing,~~penalties and/or ~~often~~harm ~~bipartisan, efforts~~ to ~~reduce~~our ~~the prices of pharmaceutical products~~reputation.

20.We rely on a limited number of employees to conduct our operations, including supervising our outside vendors. The skills needed to advance our research and development programs and plan for commercialization of our product candidates are highly specialized. We are hiring additional qualified personnel, including sales force personnel, to support the growth of our business. Hiring these personnel and retaining existing employees may be challenging.

21.We and any potential commercialization partners are subject to numerous healthcare laws and regulations governing our relationships with patients, healthcare professionals and third-party payors. Failure to comply with these requirements may adversely affect our business.

22.The reimbursement and payment regime for pharmaceutical products in the United States remains in flux. There are ongoing, and often bipartisan, efforts to reduce the prices of pharmaceutical products.

USE OF TRADEMARKS

The trademarks, trade names and service marks appearing in this Annual Report on Form 10-K are the property of their respective owners. We have omitted the ® and ™ designations, as applicable, for the trademarks named in this Annual Report on Form 10-K after their first reference in this Annual Report on Form 10-K.

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PART I

Item 1. Business

Overview and Our Strategy

We are a science-driven biopharmaceutical company focused on the discovery and development of novel treatments for retinal diseases with significant unmet medical needs. We are committed to having a positive impact on patients’ lives by delivering high-quality, safe and effective treatments designed to address debilitating retinal diseases, including earlier stages of age-related macular degeneration, or AMD.

Our lead asset is our clinical stage product candidate ~~Zimura® (~~avacincaptad pegol), which is also referred to as ACP or Zimura®, a complement C5 inhibitor. We are currently targeting the following diseases with ~~Zimura~~ACP:

•Geographic Atrophy, or GA, which is the advanced stage of AMD and is characterized by marked thinning or atrophy of retinal tissue, leading to irreversible loss of vision;

•intermediate AMD, which is an earlier stage of AMD ~~that precedes GA~~; and

•autosomal recessive Stargardt disease, or STGD1, which is an orphan inherited condition characterized by progressive damage to the central portion of the retina, or the macula, and other retinal tissue, leading to loss of vision.

In ~~July~~October ~~2021~~2019, we ~~completed~~announced ~~patient~~positive ~~enrollment~~12-month data for ~~GATHER2~~GATHER1, our first Phase 3 clinical trial evaluating ~~the~~ACP ~~safety and efficacy of Zimura~~ for the treatment of GA secondary to AMD. In GATHER1, 286 patients were randomized to receive various doses of ACP, including ACP 2 mg, or sham control. We ~~also~~observed ~~received~~a 27.7% (p-value = 0.0063) reduction in the mean rate of growth (slope) estimated based on GA area between the ACP 2 mg group and the corresponding sham control group over 12 months, when performing the primary analysis, and a ~~written~~35.4% ~~agreement~~(p-value ~~from~~= 0.0050) reduction in the mean rate of growth (slope) estimated based on GA area between the two groups over 12 months, when performing the supportive analysis. These results are based on an analysis of the primary efficacy endpoint required by the U.S. Food and Drug Administration, or ~~the~~ FDA, ~~under~~in aaccordance with our Special Protocol Assessment, or the SPA, ~~for~~which ~~the~~we ~~overall~~describe ~~design~~further ~~of GATHER2~~below. We ~~expect~~analyzed ~~topline~~the ~~data~~endpoint ~~from~~by using the ~~GATHER2~~square ~~trial~~root transformation of the GA area, which we refer to ~~become~~as ~~available~~the ~~during~~primary analysis, and we analyzed the ~~second~~endpoint ~~half~~by ofusing ~~2022~~the observed GA area (without square root transformation), ~~approximately~~which ~~one~~we ~~year~~refer ~~after~~to as the ~~enrollment~~supportive analysis. In GATHER1, through month 12, we did not observe any events of ~~the~~endophthalmitis ~~last~~or ~~patient~~ischemic ~~plus~~optic ~~the~~neuropathy ~~time~~events, ~~needed~~and ~~for~~only ~~database~~one ~~lock~~case of intraocular inflammation, which was mild and ~~analysis.~~transient Weand ~~also~~reported ~~plan~~as related to ~~initiate~~the ainjection ~~Phase~~procedure. 3The ~~clinical~~incidence ~~trial~~of ~~evaluating~~choroidal ~~Zimura~~neovascularization, ~~for~~or CNV, in the study eye through month 12 was 6 patients ~~with~~(9.0%) ~~intermediate~~in ~~AMD~~the ~~during~~ACP 2 mg group and 3 patients (2.7%) in the ~~second~~corresponding ~~half~~sham ofcontrol ~~2022~~group.

In ~~addition~~June ~~to Zimura~~2020, we ~~are~~started ~~developing~~enrolling patients in GATHER2, our ~~preclinical~~second ~~product~~Phase ~~candidate~~3 ~~IC-500,~~clinical atrial ~~High~~evaluating ~~temperature~~ACP ~~requirement~~for Athe ~~serine~~treatment ~~peptidase~~of 1GA ~~protein,~~secondary orto ~~HtrA1,~~AMD. ~~inhibitor~~In July 2021, ~~for~~we GAreceived ~~and~~a ~~potentially~~written ~~other~~agreement ~~age-related~~from ~~retinal~~the ~~diseases~~FDA under the SPA for the overall design of GATHER2. ~~Based~~The SPA is a procedure by which the FDA provides a clinical trial sponsor with an official evaluation and written guidance on ~~current~~the ~~timelines,~~design weof ~~expect~~a proposed protocol intended to ~~submit~~form anthe ~~investigational~~basis for a new drug application, or ~~IND,~~NDA. toIn connection with our SPA, the FDA recommended, and we accepted, modifying the primary efficacy endpoint for ~~IC-500~~the GATHER2 trial from the mean rate of change in ~~mid-2023~~GA area over 12 months measured by fundus autofluorescence, or FAF, at three timepoints: baseline, month 6 and month 12, to the mean rate of growth (slope) estimated based on GA area measured by FAF in at least three timepoints: baseline, month 6 and month 12.

~~Our~~In ~~portfolio~~September ~~also~~2022, ~~includes~~we ~~two~~announced ~~preclinical~~positive ~~stage~~12-month ~~gene~~top-line ~~therapy~~data ~~product~~for ~~candidates~~GATHER2. In GATHER2, 448 patients were randomized on a 1:1 basis to receive ACP 2 mg or sham control over the first 12 months of the trial. At 12 months, we measured the primary efficacy endpoint in accordance with the SPA. In GATHER2, we observed a 14.3% (ICp-~~100~~value = 0.0064) reduction in the mean rate of growth (slope) in GA area between the two groups at 12 months with the primary analysis, and ICa 17.7% (p-~~200~~value = 0.0039) ~~and~~reduction ~~several~~in ~~ongoing~~the ~~gene~~mean ~~therapy~~rate ~~research~~of ~~programs,~~growth ~~each~~(slope) in GA area between the two groups at 12 months with the supportive analysis. We did not observe any events of ~~which~~endophthalmitis, ~~uses~~intraocular ~~adeno-associated~~inflammation ~~virus~~events, events of vasculitis or ~~AAV~~ischemic optic neuropathy events through month 12, ~~for~~and ~~gene~~the ~~delivery.~~incidence ~~These~~of ~~AAV~~CNV ~~mediated~~in ~~gene~~the ~~therapy~~study ~~programs~~eye ~~are~~through ~~targeting~~month 12 was 15 patients (6.7%) in the ~~following~~ACP ~~orphan~~2 ~~inherited~~mg ~~retinal~~group ~~diseases,~~and or9 ~~IRDs:~~patients (4.1%) in the sham control group.

~~•rhodopsin-mediated~~We ~~autosomal~~believe ~~dominant~~that ~~retinitis~~with ~~pigmentosa~~the statistically significant results from our GATHER1 and GATHER2 trials and the safety profile of ACP to date, orwe ~~RHO~~have sufficient data from two independent, adequate and well-~~adRP~~controlled pivotal clinical trials of ACP in GA secondary to AMD to support an application for marketing approval. In November 2022, ~~which~~the isFDA ~~characterized~~granted bybreakthrough ~~progressive~~therapy ~~and~~designation ~~severe~~to ~~bilateral~~ACP ~~loss~~for the treatment of ~~vision~~GA ~~leading~~secondary to ~~blindness;~~AMD. In December 2022, we completed the rolling submission of our NDA to the FDA for marketing approval of ACP for the treatment of GA secondary to AMD. In February 2023, the FDA accepted our NDA for filing and granted priority review with a Prescription Drug User Fee Act, or PDUFA, target action date of August 19, 2023.

~~•IRDs associated with mutations in the BEST1 gene, including Best vitelliform macular dystrophy, or Best disease;~~5

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In addition to ACP, we are developing our preclinical product candidate IC-500, a High temperature requirement A serine peptidase 1 protein, or HtrA1, inhibitor, for GA secondary to AMD and potentially other age-related retinal diseases. Based on current timelines and subject to successful preclinical development and current good manufacturing practices, or cGMP, manufacturing, we expect to submit an investigational new drug application, or IND, to the FDA for IC-500 during the first half of 2024.

Our portfolio also includes several ongoing gene therapy research programs, each of which uses adeno-associated virus, or AAV, for gene delivery. These AAV mediated gene therapy programs are targeting the following orphan inherited retinal diseases, or IRDs:

•Leber Congenital Amaurosis type 10, or LCA10, which is characterized by severe bilateral loss of vision at or soon after birth;

•STGD1; and

•IRDs associated with mutations in the USH2A gene, which include Usher syndrome type 2A, or Usher 2A, and USH2A-associated non-syndromic autosomal recessive retinitis pigmentosa.

As we focus our efforts on and prioritize the development and potential commercialization of Zimura, we have been considering our development options for IC-100 and IC-200, which we have been developing for RHO-adRP and BEST1-related IRDs, respectively. We currently plan to seek a collaborator for the future development and potential commercialization of these product candidates.

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Research and Development Pipeline

We have summarized the current status of our ongoing research and development programs in the table below.

† In December 2022, we assigned the rights to our licenses to IC-100 (RHO-adRP) and IC-200 (BEST1-related IRDs) to Opus Genetics.*We have an option to exclusively in-license intellectual property resulting from these programs.

~~2021~~2022 Highlights

•In ~~2021~~2022, we achieved a number of significant company milestones, including the following:

•In ~~July~~September ~~2021~~2022, we ~~completed~~announced ~~patient~~positive ~~enrollment in GATHER2, four months ahead of our original schedule. We expect~~ 12-month ~~top-line~~ data from ~~this trial to become available during~~ the ~~second~~GATHER2 ~~half~~trial. ofWe ~~2022,~~achieved ~~approximately~~a ~~one~~12-month ~~year~~injection ~~after~~fidelity ~~the~~rate ~~enrollment~~ of ~~the~~92.5% ~~last~~for ~~patient plus~~ the ~~time~~GATHER2 ~~needed for database lock and analysis~~trial.

•In ~~July~~November ~~2021~~2022, ~~we received a written agreement from~~ the FDA ~~under~~granted abreakthrough ~~SPA~~therapy ~~for~~designation ~~the overall design of GATHER2. We also had a number of other interactions with the FDA throughout 2021, which we believe clarified our regulatory pathway and plans~~ for ~~submitting~~ACP ~~a new drug application, or NDA, to the FDA~~ for ~~marketing approval of Zimura for~~ the treatment of GA, ifsecondary ~~the~~to ~~GATHER2 data are positive~~AMD.

•In ~~June~~December ~~2021~~2022, we ~~announced~~completed ~~data from post-hoc analyses on~~ the ~~GATHER1~~rolling ~~data,~~submission ~~in which we evaluated the progression~~ of ~~incomplete~~our ~~Retinal~~NDA ~~Pigment Epithelial and Outer Retinal Atrophy, or iRORA,~~ to ~~complete Retinal Pigment Epithelial and Outer Retinal Atrophy, or cRORA, and~~ the ~~progression~~FDA of drusen to iRORA or cRORA, in patients receiving Zimura 2 mg as compared to patients in the corresponding sham group. The post-hoc analysis data show a 19.6% absolute reduction in the rate of progression from drusen to iRORA or cRORA, for ~~the~~marketing ~~Zimura~~approval ~~2 mg group as compared to sham at 18 months, representing a relative reduction~~ of ~~72%.~~ACP ~~The data also show a 21.8% absolute reduction in the rate of progression from iRORA to cRORA~~ for the ~~Zimura~~treatment ~~2 mg group as compared to sham at 18 months, representing a relative reduction~~ of ~~52%.~~GA Wesecondary ~~have been encouraged by the post-hoc analyses data and are planning a Phase 3 clinical trial studying Zimura in patients with intermediate AMD, which we plan~~ to ~~initiate during the second half of 2022~~AMD.

•In ~~July~~June ~~2021 and October 2021~~2022, we ~~closed~~entered ~~two~~into ~~underwritten~~an ~~public~~exclusive ~~offerings~~license inagreement ~~which~~with weDelSiTech ~~sold 13~~Ltd.,~~397,500~~ ~~shares~~or ~~of our common stock and 10~~DelSiTech,~~350,000~~ ~~shares~~for ofworldwide ~~our~~development ~~common stock, respectively. The net proceeds from the public offerings, after deducting underwriting discounts~~ and ~~commissions~~commercialization ~~and~~rights ~~other~~to ~~offering~~its ~~expenses~~silica ~~payable~~based bysustained ~~us,~~release ~~were~~delivery ~~approximately~~technology ~~$107.8~~for ~~million~~use ~~and~~with ~~$162~~ACP.~~6 million, respectively.~~

•WeIn ~~continued~~July to2022, ~~hire~~we ~~strategically~~entered tointo ~~support~~a ~~key~~Loan ~~areas~~and ofSecurity ~~our~~Agreement ~~business,~~with ~~such~~Hercules asCapital ~~commercial~~Inc. ~~planning, medical affairs~~ and ~~clinical~~Silicon ~~development,~~Valley ~~manufacturing~~Bank, ~~preclinical~~or ~~research,~~the ~~and~~Loan ~~regulatory affairs and pharmacovigilance~~Agreement, ~~with~~providing aup ~~total~~to of$250.0 37million ~~full-time~~in ~~employees~~term ~~joining~~loans, ~~our~~or ~~team over~~ the ~~course~~2022 ofTerm ~~2021~~Loan Facility.

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•In December 2022, we closed an underwritten public offering in which we sold 15,352,500 shares of our common stock and raised approximately $324.3 million in net proceeds, after deducting underwriting discounts and commissions and other offering expenses.

•We continued to hire strategically to support key areas of our business, with a total of 74 full-time employees joining our team over the course of 2022.

Business Development and Financing Activities

~~Beginning~~As inwe ~~2017~~prepare for the potential marketing approval and potential commercial launch of ACP, weprogress ~~pursued~~our aresearch ~~business~~and development ~~strategy~~programs ~~focused~~and onevaluate ~~evaluating~~our ~~various~~overall ~~available~~strategic ~~technologies~~priorities, we continue to ~~treat~~pursue ~~ophthalmic~~selective ~~diseases,~~business ~~particularly~~development ~~those~~and infinancing ~~the~~opportunities ~~back~~that ofadvance ~~the~~us ~~eye~~toward our strategic goals. We plan to continue to evaluate, on a selective and ~~exploring~~targeted basis, opportunities to obtain rights to additional ~~products~~product candidates and ~~product~~technologies ~~candidates~~for ~~employing~~retinal ~~these~~diseases, ~~technologies.~~with ~~Our~~a ~~efforts~~focus ~~resulted~~on inadditional ~~the~~sustained ~~expansion~~release ofdelivery ~~our~~technologies ~~research~~for ~~and~~ACP. ~~development~~In ~~pipeline~~addition, ~~including~~we ~~the~~plan ~~addition~~to ofexplore ~~IC-500,~~potential ~~IC-100,~~collaboration ~~IC-200~~opportunities for the future development and apotential ~~number~~commercialization of ~~collaborative~~ACP ~~gene~~in ~~therapy~~one ~~sponsored~~or ~~research~~more ~~programs.~~territories outside the United States.

AsPlease wesee ~~continue~~later ~~the~~in ~~development~~this ofBusiness ~~our~~section ~~product candidates and programs, prepare~~ for ~~the~~information ~~potential~~about ~~commercialization of Zimura and evaluate~~ our ~~overall~~exclusive ~~strategic~~license ~~priorities,~~agreement wewith ~~will~~DelSiTech continue to pursue selective business development and financing opportunities that advance us toward our strategic goals. We plan to continue to evaluate, on a selective and targeted basis, opportunities to potentially obtain rights to additional product candidates and technologies for ~~retinal~~its ~~diseases, with a focus on~~ sustained release delivery ~~technologies~~technology for ~~Zimura.~~ACP Inand ~~addition,~~our weasset ~~continue~~purchase toagreement ~~explore~~with ~~potential~~Opus ~~collaboration~~Genetics ~~and~~Inc., ~~out-licensing~~or ~~opportunities~~Opus, for ~~the~~our ~~future~~former ~~development~~preclinical ~~and~~stage ~~potential~~gene ~~commercialization~~therapy ~~of our~~ product candidates, including potential collaboration opportunities for the future development and potential commercialization of Zimura in one or more territories outside the United States and collaboration opportunities for the future development and potential commercialization of IC-100 and IC-200.

For information about the 2022 Term Loan Facility with Hercules Capital and Silicon Valley Bank and our follow-on public ~~offerings~~offering ~~that we~~ completed in ~~July~~December ~~2021 and October 2021~~2022, please see the Liquidity and Capital Resources section of Management' s Discussion and Analysis of Financial Condition and Results of Operations set forth in Part I, Item 7 of this Annual Report on Form 10-K. We ~~expect~~believe we have sufficient financial resources to launch ACP for GA in the United States, if approved based on our expectations. We plan to continue to pursue capital raising transactions when they are available on terms favorable to us and if the opportunity advances our strategic goals.

Impact of COVID-19

Beginning in March 2020, the COVID-19 pandemic and measures taken to contain it have affected various aspects of our business and operations, including our clinical trials, our supply chain, our workforce and the work of our third-party contract manufacturers, contract research organizations, or CROs, and other vendors. For example, in March 2020, we decided to delay the initiation of patient enrollment in our GATHER2 trial. We completed patient enrollment for GATHER2 in July 2021, and we and our clinical trial sites have implemented a number of changes to our clinical trial operations to protect the health and safety of our clinical trial participants and site staff. Additionally, many of our third-party contract manufacturers and CROs limited their operations and staff and have recently been facing increased demand from clients due to the ongoing uncertainties associated with the COVID-19 pandemic, which resulted in delays to some of our manufacturing and research and development activities. For example, we anticipate that the start of the IND-enabling toxicology studies we are planning for IC-500 will be later than what we originally planned, primarily due to the limited availability of study slots at CROs attributable to rising demand for their services as well as increased absenteeism of staff at those CROs in wake of the COVID-19 pandemic and the recent Omicron variant. In addition, shortages, delays and governmental restrictions arising from the COVID-19 pandemic, including the ongoing issues with the global supply chain, have disrupted and may continue to disrupt the ability of our contract manufacturers and CROs to source needed materials.

In March 2020, as a result of the COVID-19 pandemic, we instituted company-wide remote working and we expect to continue working in a hybrid (partially remote and partially in office) working model for the foreseeable near future. We are continuing to monitor and support the health and well-being of our employees and their productivity as remote working continues. Starting in the middle of 2021, we began permitting employees to return to the office on a voluntary basis subject to compliance with our newly implemented health and safety policies.

For a more detailed discussion of the actual and potential impacts to us as a result of the COVID-19 pandemic, see the other sections of this Annual Report on Form 10-K, including Management's Discussion and Analysis of Results of Operations and Financial Position set forth in Part I, Item 7 and the Risk Factors set forth in Part I, Item 1A.

Eye Diseases

Eye diseases can be caused by many factors and can affect both the front orand back of the eye. In more severe cases, eye diseases can result in total loss of vision. In the developed world, the most common eye diseases that can result in total loss of vision are those affecting the retina and optic nerve, including AMD, diabetic retinopathy and glaucoma. These diseases deprive patients of their sight and, as a result, impair their ability to live independently and perform daily activities. Any improvement in vision, or even a slowing of the rate of progression of vision loss, has a tremendous impact on the quality of life of people with impaired vision. There are many other eye diseases that are less common but still represent an unmet medical need, particularly orphan IRDs that are associated with mutations in a single gene, referred to as monogenic, that lead to retinal degeneration and vision loss, generally in younger patients. We believe that these disease areas present several potential opportunities for ophthalmic drug development. A 2014 report from Prevent Blindness, a patient advocacy group, estimated that the total real annual costs in the United States related to eye diseases and vision problems expressed in constant 2014 dollars would increase from $145 billion in 2014 to $376 billion by 2050.

Age Related Macular Degeneration, including Geographic Atrophy and intermediate AMD

AMD is an age-related disease characterized by progressive degenerative abnormalities in the macula, a small area in the central portion of the retina responsible for central vision. AMD is characteristically a disease of the elderly and is the leading cause of visual loss in individuals over 50 years of age in developed countries. Based on a 2016 paper published in Eye and Vision and a 2014 paper published in The Lancet, we expect that by 2050 approximately 22 million individuals in the United States will have a form of AMD and that by 2040 approximately 288 million individuals worldwide will have a form of AMD. Because of increasing life expectancy in developed and developing countries, the elderly population is expected to grow significantly in coming decades. Projections based on U.S. Census Bureau data suggest that the number of Americans over the age of 65 will nearly double to approximately 88 million by the middle of this century. In the absence of adequate prevention or treatment measures, the number of cases of AMD with visual loss is expected to grow in parallel with the aging population, leading to a major public health challenge with significant socioeconomic implications.

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~~opportunities~~approximately ~~for~~80% ~~ophthalmic~~of ~~drug~~AMD ~~development~~patients have the dry form of the disease. A ~~2014~~In ~~report~~the ~~from~~dry ~~Prevent~~form ~~Blindness~~of AMD, athe ~~patient~~eventual ~~advocacy~~loss ~~group~~of photoreceptors, ~~estimated~~RPE ~~that~~cells and associated capillary blood vessels in the ~~total~~macula ~~real~~results ~~annual~~in ~~costs~~marked thinning and/or atrophy of retinal tissue. This advanced stage of dry AMD is called GA. In the wet form of AMD, abnormal new blood vessels originate beneath the retina, in a layer called the ~~United~~choroid, ~~States~~and ~~related~~invade into the overlying retinal layers, through a process called choroidal neovascularization, or CNV. The macula of patients diagnosed with the wet form of AMD, who are usually treated with currently approved standard of care anti-vascular endothelial growth factor, or anti-VEGF, therapies, can continue to ~~eye~~atrophy ~~diseases~~resulting ~~and~~in ~~vision~~GA, ~~problems~~which ~~expressed~~suggests that in ~~constant~~many ~~2014~~AMD ~~dollars~~patients, ~~would~~regardless ~~increase~~of ~~from~~whether ~~$145~~they ~~billion~~have inthe ~~2014~~dry or the wet form, the final anatomic outcome leading to ~~$376~~loss ~~billion~~of byvision ~~2050.~~is GA.

~~Age~~ GA ~~Related~~is ~~Macular~~a ~~Degeneration~~significant cause of bilateral, ~~including~~irreversible ~~Geographic~~and ~~Atrophy~~severe loss of functional vision. Many individuals with GA experience dark spots in their field of vision, referred to as scotoma, even if their central vision remains normal. As a result, GA has a major impact on the functional vision, quality of life, and ~~intermediate~~independence of affected individuals. The median time for development of central GA from the time of diagnosis is two and a half years with the condition expected to develop in the fellow eye within approximately seven years. Based on epidemiology studies published in 2004 in Archives of Ophthalmology and in 2011 JAMA Ophthalmology, we estimate that there are currently approximately 1.6 million people in the United States with GA. Furthermore, based on a study published in 2015 in the American Journal of Ophthalmology, we estimate that approximately 159,000 people in the United States develop GA each year. Although multiple anti-VEGF therapies are available for treatment of wet AMD, as of February 2023 there is only one FDA approved treatment for GA.

~~AMD~~Before ~~is an age-related disease characterized by progressive degenerative abnormalities in~~ the ~~macula,~~development aof ~~small area in the~~ central ~~portion~~GA ofor ~~the~~wet ~~retina~~AMD, ~~responsible~~many ~~for central vision.~~ AMD ispatients ~~characteristically~~experience a ~~disease~~less ofadvanced ~~the~~form ~~elderly~~of ~~and is~~ the ~~leading~~disease, ~~cause~~commonly ofreferred ~~visual~~to ~~loss~~as inintermediate ~~individuals over 50 years of age in developed countries~~AMD. ~~Based~~Intermediate onAMD ais ~~2016~~typically ~~epidemiology~~characterized ~~paper~~by ~~published~~the inpresence ~~Eye~~of ~~and~~extensive ~~Vision,~~medium-size wedrusen ~~estimate~~(between ~~that~~63 ~~currently~~µm ~~approximately 11 million individuals in the United States~~ and ~~170~~125 ~~million~~µm ~~individuals worldwide have a form of AMD. Because of increasing life expectancy~~ in ~~developed~~height) and/or ~~developing~~one ~~countries,~~or ~~the~~more ~~elderly~~large ~~population~~drusen is(larger ~~expected~~than to125 ~~grow~~µm ~~significantly~~ in ~~coming decades~~height). ~~Projections~~While ~~based~~most ~~on U.S. Census Bureau data suggest that the number~~ of ~~Americans~~these ~~over~~patients ~~the~~have ~~age~~well ofpreserved 65best ~~will~~corrected ~~more~~visual ~~than~~acuity, ~~double~~or toBCVA, ~~approximately~~and 80are ~~million~~otherwise byasymptomatic, ~~the~~many ~~middle~~experience ofother ~~this~~visual ~~century.~~disturbances Insuch ~~the~~as ~~absence~~blurred ofvision ~~adequate~~while ~~prevention~~reading or ~~treatment~~difficulty ~~measures, the number of cases of AMD~~ with ~~visual~~adapting ~~loss is expected~~ to ~~grow~~seeing in ~~parallel~~low ~~with the aging population, leading to a major public health challenge with significant socioeconomic implications~~light.

AMD, at its early stages, presents with abnormalities in the retinal pigment epithelium, or the RPE, and yellow-white deposits under the RPE known as drusen, which generally become larger and more numerous as AMD progresses. The RPE is a layer of cells within the retina on which photoreceptors, the cells in the retina that are responsible for capturing light and converting it to electrochemical signals to the brain, are dependent for nutrients, waste disposal and other needs. As the disease progresses with age to the advanced stage, it generally progresses as either the non-neovascular or dry form of AMD or the neovascular or wet form of the disease. In the dry form of AMD, the eventual loss of photoreceptors, RPE cells and associated capillary blood vessels in the macula results in marked thinning and/or atrophy of retinal tissue. This advanced stage of dry AMD is called GA. In the wet form of AMD, abnormal new blood vessels originate beneath the retina, in a layer called the choroid, and invade into the overlying retinal layers, through a process called choroidal neovascularization, or CNV. The macula of patients diagnosed with the wet form of AMD, who are usually treated with currently approved standard of care anti-vascular endothelial growth factor, or anti-VEGF, therapies, can continue to atrophy resulting in GA, which suggests that in many AMD patients, regardless of whether they have the dry or the wet form, the final anatomic outcome leading to loss of vision is GA.

GA is a significant cause of bilateral, irreversible and severe loss of functional vision. Many individuals with GA experience dark spots in their field of vision, referred to as scotoma, even if their central vision remains normal. As a result, GA has a major impact on the functional vision, quality of life, and independence of affected individuals. The median time for development of central GA from the time of diagnosis is two and a half years with the condition expected to develop in the fellow eye within approximately seven years. Based on a comprehensive epidemiology study published in 2004 in Archives of Ophthalmology, we estimate that there are currently approximately 1.5 million people in the United States with GA. Furthermore, based on a study published in 2015 in the American Journal of Ophthalmology, we estimate that approximately 159,000 people in the United States develop GA each year. Although anti-VEGF therapy is available for treatment of wet AMD, no FDA or European Medicines Agency, or EMA, approved treatment is currently available for GA.

Before the development of central GA or wet AMD, many AMD patients experience a less advanced form of the disease, commonly referred to as intermediate AMD. Intermediate AMD is typically characterized by the presence of extensive medium-size drusen (>63 µm and <125 µm in height) and/or one or more large drusen (>125 µm in height). While most of these patients have well preserved best corrected visual acuity, or BCVA, and are otherwise asymptomatic, many experience other visual disturbances such as blurred vision while reading or difficulty with adapting to seeing in low light. We estimate that by 2039, there will be approximately six million individuals with drusen in the United States and eight million individuals with drusen in France, Germany, Italy, Spain and United Kingdom, which we refer to as the EU5 countries, on a combined basis. Intermediate AMD is a subset of drusen.

The absence of treatment options for GA and many other stages of AMD, including intermediate AMD, represents an area of urgent unmet medical need and a major public health concern for the expanding elderly population.

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Inherited Retinal Diseases

IRDs are a group of eye disorders caused by one or more inherited gene mutations that result in lack of functional proteins necessary for normal vision. Generally, IRDs are severe and progressive and will result in vision loss or blindness, either at birth or in early childhood, or gradually over time. IRDs are generally orphan diseases, meaning that these diseases affect fewer than 200,000 individuals in the United States. Partially due to their orphan nature, there are no approved treatment options available for most IRDs. Recently, gene therapies have emerged as potential therapies for monogenic IRDs, where a mutation to a single gene has been identified as the cause.

Humans generally inherit a complete set of genes from each of their parents, and therefore have two copies, or alleles, for each gene, either of which may carry a mutation, and either, or both, of which may be expressed in particular cells throughout the body. An inherited condition is referred to as autosomal recessive when the subject must inherit mutated alleles from each parent for the condition to manifest. An inherited condition is referred to as autosomal dominant when the subject must only inherit one mutated allele from either parent for the condition to manifest. The predominant or standard, non-mutated form of a gene is referred to as the wildtype form, and the protein resulting from expression of the wildtype gene is referred to as wildtype protein. In autosomal recessive conditions, because both alleles for a particular gene carry a mutation, the subject cannot produce any wildtype protein, and instead the proteins that are expressed, if any, have either limited or no function. In autosomal dominant conditions, a number of factors may contribute to the condition:

•a subject may express only the mutant allele and not the wildtype allele, resulting in production of only protein with limited or no function and not the wildtype protein;

•a subject may be expressing both alleles, but because of the mutation on one of the alleles, the amount of functional protein may not be sufficient; or

•the protein expressed by the mutant allele may be toxic to the cells in which it is produced.

Stargardt Disease

Stargardt disease is an IRD that causes progressive damage to the macula and retina, leading to loss of vision in children and adolescents. The most common form of Stargardt disease is STGD1, the autosomal recessive form. STGD1 is caused by mutations in the ABCA4 gene, which is responsible for making a protein that helps to clear byproducts resulting from the visual cycle from inside photoreceptor cells in the eye.

Multiple sources, including the National Eye Institute and Genetics Home Reference, both of which are affiliated with the U.S. National Institutes of Health, or NIH, estimate the prevalence of Stargardt disease to be between 1 in 8,000 and 1 in 10,000, implying that in the United States and the EU5 on a combined basis there are currently a total of 62,000 to 77,000 affected persons. There are currently no therapies approved by the FDA or EMA to treat Stargardt disease. The FDA has recognized Stargardt disease as an orphan disease, with several treatments in development having received orphan drug designation from the FDA.

Rhodopsin-Mediated Autosomal Dominant Retinitis Pigmentosa

RHO-adRP is a form of retinitis pigmentosa, or RP. RP is the most prevalent IRD and is typically characterized by the initial degeneration of the rod photoreceptors, which are responsible for low light vision and peripheral vision. The degeneration of the rod photoreceptors over time leads to the degeneration of the cone photoreceptors, which are the photoreceptors in the central part of the retina that are responsible for color and sharp vision. This degeneration causes night blindness and severe and progressive visual impairment. Although often diagnosed during adolescence or young adulthood, most RP patients become legally blind by age 40.

Rhodopsin is a biological pigment found in the rod photoreceptors that is extremely sensitive to light and thus is crucial for low light vision. There are more than 150 identified mutations in RHO, the gene that encodes for rhodopsin. The presence of a mutated RHO gene is linked to the occurrence of RHO-adRP.

Based on disease prevalence rates contained in a study published in the Archives of Ophthalmology in 2007, we estimate that in the United States and EU5 on a combined basis, there are a total of approximately 11,000 affected persons with RHO-adRP. There is currently no FDA or EMA approved therapy to treat RHO-adRP.

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~~BEST1-Related~~Multiple ~~IRDs~~sources, including the National Eye Institute and Genetics Home Reference, both of which are affiliated with the U.S. National Institutes of Health, or NIH, estimate the prevalence of Stargardt disease to be between 1 in 8,000 and 1 in 10,000, implying that in the United States and the EU5 on a combined basis there are currently a total of 62,000 to 77,000 affected persons. There are currently no therapies approved by the FDA or EMA to treat Stargardt disease. The FDA has recognized Stargardt disease as an orphan disease, with several treatments in development having received orphan drug designation from the FDA.

The BEST1 gene encodes for a multifunctional protein known as bestrophin-1, or BEST1, which regulates chemical transport and signaling in RPE cells and helps maintain homeostasis in the subretinal space, the space between the photoreceptors and the RPE. The most common BEST1-related IRD is Best disease, which is generally autosomal dominant and generally affects individuals in both eyes. In Best disease, the lack of functional BEST1 protein results in the formation of egg yolk-like lesions in the macula that, over time, progress to macular atrophy and permanent loss of vision. In addition, because there are over 200 known mutations in the BEST1 gene, there are other BEST1-related IRDs being studied, including autosomal dominant and autosomal recessive forms.

Based on disease prevalence rates contained in a study published in Ophthalmic Genetics in 2017, we estimate that in the United States and EU5 on a combined basis, there are a total of approximately 10,000 to 40,000 affected persons with BEST1-related IRDs, the substantial majority of whom we believe have the autosomal dominant form of Best disease. There are currently no FDA or EMA approved therapies to treat any BEST1-related IRD.

Leber Congenital Amaurosis Type 10

Leber Congenital Amaurosis, or LCA, is an IRD that manifests at birth or early in childhood. It is characterized by early onset of vision loss in children leading to blindness. Affected individuals often manifest symptoms such as roving eye movements, deep-set eyes and sensitivity to bright light. There are multiple types of LCA, which are associated with mutations in different genes. The most common type is LCA10, which is caused by mutations in the CEP290 gene. Mutations in the CEP290 gene are believed to lead to the abnormal function and potentially loss of photoreceptor cells.

Based on disease prevalence rates contained in a study published in the American Journal of Human Genetics in 2006, we estimate that in the United States and EU5 on a combined basis, there are a total of approximately 2,700 to 4,100 affected persons with LCA10. There is currently no FDA or EMA approved therapy to treat LCA10.

USH2A-Related IRDs

The USH2A gene encodes for a protein called usherin. Usherin is believed to be important in the development and maintenance of cells in the retina and the inner ear. There are two principal IRDs associated with mutations in the USH2A gene: Usher 2A and USH2A-associated ~~nonsyndromatic~~nonsyndromic autosomal recessive retinitis pigmentosa. Usher 2A is an autosomal recessive syndrome characterized by hearing loss from birth and progressive vision loss, due to RP, ~~that~~which begins in adolescence or adulthood. USH2A-associated ~~nonsyndromatic~~nonsyndromic autosomal recessive retinitis pigmentosa is a genetic condition that manifests as vision loss without associated hearing loss.

Based on a study published in Experimental Eye Research in 2004, we estimate that in the United States and EU5 on a combined basis, there are a total of approximately 20,000 to 62,000 affected persons with USH2A-related IRDs. There are currently no FDA or EMA approved therapies to treat Usher 2A or USH2A-associated ~~nonsyndromatic~~nonsyndromic autosomal recessive retinitis pigmentosa.

~~Zimura~~Avacincaptad pegol (ACP)

We are currently developing our product candidate ~~Zimura~~ACP, a C5 complement inhibitor, for the treatment of GA and ~~intermediate AMD, both of which are different stages of AMD, and~~ STGD1. ~~Zimura~~ACP is a chemically-synthesized, pegylated RNA aptamer. Aptamers are short molecules made up of a single stranded nucleic acid sequence or an amino acid sequence. The specific three-dimensional structure of an aptamer, which results from its specific sequence, allows it to bind molecular targets with high selectivity and specificity. ~~Zimura~~ACP is a pegylated aptamer, which means that polyethylene glycol, or PEG, a common biochemical compound attached to drugs to increase their duration of action in the human body and to decrease immune response, is linked to the chemically-synthesized strand of RNA.

The Complement System and Its Potential Role in AMD and STGD1

The complement system consists of a series of proteins that are involved in the defense of the body against infectious agents, or pathogens, and other foreign proteins. The complement system modulates a variety of immune and inflammatory responses to these pathogens and foreign proteins. Under normal circumstances, complement proteins, together with antibodies and white blood cells, act beneficially to protect the body by removing the pathogens and foreign proteins, along with other cellular debris. The complement system is generally tightly regulated, achieving the proper balance of activation and inhibition depending on the body’s requirements. Poorly regulated or aberrant activation of the complement system, without a balanced or proportional inhibition of complement proteins, may result in a variety of pathological conditions. For example, in a study published in Histology and Histopathology in 2012, researchers found that human retinal drusen deposits, which are the hallmark of AMD, contained components of complement proteins.

10 The complement system is generally activated via one of three biological pathways commonly referred to as the classical pathway, the alternative pathway and the lectin pathway. These pathways eventually converge with the generation of an enzyme known as C3 convertase. C3 convertase cleaves, or separates, a serum protein called C3, into C3a and C3b. C3b is an important element of the body’s immune system, as it binds to pathogens and makes them susceptible to destruction by

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~~proportional~~white ~~inhibition~~blood cells. C3b also cleaves complement protein C5. The cleavage of C5 results in the formation of the terminal complement ~~proteins,~~fragments ~~may~~C5a ~~result~~and C5b. A study published in athe ~~variety~~Journal of ~~pathological~~Biological ~~conditions~~Chemistry in 2015 concluded that C5a primes RPE cells for inflammasome activation in the presence of waste products from the visual cycle. ~~For~~Inflammasomes ~~example~~are intracellular protein structures that lead to cell death. Other studies have shown the presence of inflammasomes inside the RPE cells of post-mortem eyes of patients with GA. Formation of C5b, in acombination ~~study~~with ~~published~~serum inproteins ~~Histology~~C6, C7, C8 and ~~Histopathology~~C9, inleads ~~2012~~to the generation of C5b-9, ~~researchers~~referred ~~found~~to ~~that~~as ~~human~~membrane ~~retinal~~attack ~~drusen~~complex, ~~deposits~~or MAC, which ~~are~~has been shown to cause cell death. In particular, various studies have shown that MAC, together with the ~~hallmark~~presence of lipofuscin, a yellow-brown waste byproduct from the visual cycle that is commonly found in the RPE cells of AMD patients, ~~contained~~interferes ~~components~~with the proper functioning of ~~complement~~RPE ~~proteins~~cells, leading to their dysfunction and death.

The complement system is generally activated via one of three biological pathways commonly referred to as the classical pathway, the alternative pathway and the lectin pathway. These pathways eventually converge with the generation of an enzyme known as C3 convertase. C3 convertase cleaves, or separates, a serum protein called C3, into C3a and C3b. C3b is an important element of the body’s immune system, as it binds to pathogens and makes them susceptible to destruction by white blood cells. C3b also cleaves complement protein C5. The cleavage of C5 results in the formation of the terminal complement fragments C5a and C5b. A study published in the Journal of Biological Chemistry in 2015 concluded that C5a primes RPE cells for inflammasome activation in the presence of waste products from the visual cycle. Inflammasomes are intracellular protein structures that lead to cell death. Other studies have shown the presence of inflammasomes inside the RPE cells of post-mortem eyes of patients with GA. Formation of C5b, in combination with serum proteins C6, C7, C8 and C9, leads to the generation of C5b-9, referred to as membrane attack complex, or MAC, which has been shown to cause cell death. In particular, various studies have shown that MAC, together with the presence of lipofuscin, a yellow-brown waste byproduct from the visual cycle that is commonly found in the RPE cells of AMD patients, interferes with the proper functioning of RPE cells, leading to their dysfunction and death.

A simplified illustration of the complement system and the relationships between the complement proteins appears below:

Although the causes of AMD are not completely understood—in addition to advanced age, there are environmental and genetic risk factors that contribute to the development of AMD including ocular pigmentation, dietary factors, a positive family history for AMD, high blood pressure and smoking—a body of recent scientific literature suggests that complement system activation may also contribute to the pathogenesis of AMD. A study published in the Journal of Immunology in 2015 concluded that MAC accumulation in RPE cells leads to mitochondrial damage and cellular dysfunction, which we believe eventually leads to RPE cell death. Additionally, a study published in the American Journal of Ophthalmology in 2002 described the presence of MAC in post-mortem human donor eyes with dry AMD and GA. A study published in Nature Communications in 2021 used patient-derived induced pluripotent stem cells to show that local activation of the complement system could induce drusen formation in RPE cells and that the inhibition of C5a could mitigate AMD-like pathology in the RPE cells. We believe these findings suggest that inhibition of the complement system, especially an inhibitor that prevents the cleavage of C5 into C5a and C5b, could prevent RPE cell death and potentially other pathological causes of AMD.

11 The pathogenesis of STGD1, which is caused by a mutation in the ABCA4 gene, also may involve activation of the complement system. With a defective copy of the ABCA4 protein, waste byproducts that a normal ABCA4 protein would otherwise help to clear accumulate in the RPE. Waste byproducts that accumulate in the RPE are referred to as bisretinoids. We believe that the accumulation of bisretinoids in RPE cells leads to activation of the complement system and the accumulation of MAC. In RPE cells, MAC is normally cleared by lysosomes, which are organelles within cells responsible for waste degradation and disposal. Bisretinoid accumulation leads to lysosomal dysfunction, potentially preventing the clearance of MAC. MAC accumulation also negatively impacts energy production by mitochondria inside RPE cells. Bisretinoid and

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The pathogenesis of STGD1, which is caused by a mutation in the ABCA4 gene, also may involve activation of the complement system. With a defective copy of the ABCA4 protein, waste byproducts that a normal ABCA4 protein would otherwise help to clear accumulate in the RPE. Waste byproducts that accumulate in the RPE are referred to as bisretinoids. We believe that the accumulation of bisretinoids in RPE cells leads to activation of the complement system and the accumulation of MAC~~. In~~ ~~RPE cells, MAC is normally cleared by lysosomes, which are organelles within cells responsible for waste degradation and disposal. Bisretinoid~~ accumulation leads to lysosomal dysfunction, potentially preventing the clearance of MAC. MAC accumulation also negatively impacts energy production by mitochondria inside RPE cells. Bisretinoid and MAC accumulation may lead to RPE cell deterioration and contribute to the subsequent loss of photoreceptor cells, leading to a decrease in vision over time.

In April 2017, Proceedings of the National Academy of Sciences, or PNAS, published a study reporting on the effects of complement system modulation in the RPE of a mouse model of Stargardt disease. The researchers injected recombinant AAV containing the coding sequence for CRRY, a protein that inhibits complement system activation, into albino ABCA4 mutant mice, which led to a two-fold reduction in the accumulation of bisretinoids and a 30% increase in the number of photoreceptor nuclei at one year. The study findings indicate that the inhibition of complement activation in the albino ABCA4 mutant mice leads to healthier RPE cells as compared to RPE cells of untreated mice. Researchers at Duke University published a 2013 paper in Investigative Ophthalmology & Visual Science, in which they found in an in vitro experiment that RPE cell damage resulting from the combination of complement system activation and visual cycle waste was more damaging than either component individually. When complement factor C5 was blocked, there was a significant improvement in RPE cell viability in vitro. Based on the data from these in vitro and in vivo experiments, we believe molecules involved in the inhibition or regulation of the complement system and MAC activation are prime targets for therapeutic intervention in STGD1.

~~Zimura~~ACP is designed to target and inhibit the cleavage of complement protein C5 and the formation of the terminal fragments, C5a and C5b. By inhibiting the formation of complement system terminal fragments, ~~Zimura~~ACP may decrease the activation of inflammasomes and decrease the formation of MAC, thereby potentially avoiding or slowing the degeneration of RPE cells and providing the rationale as a potential therapy for various stages of AMD and STGD1.

Our ~~Zimura~~ACP Clinical Programs

The following is a brief description of the completed GATHER1 trial, and the ongoing GATHER2 and STAR trials and the ~~planned~~open ~~intermediate~~label ~~AMD~~extension ~~trial~~study, and their current status:

•GATHER1 (also known as OPH2003; GA secondary to AMD - completed): an international, randomized, double-masked, sham controlled, multi-center Phase 2/3 clinical trial evaluating the safety and efficacy of ~~Zimura~~ACP for the treatment of GA secondary to AMD. We enrolled 286 patients in this trial across multiple treatment groups, including various ~~Zimura~~ACP doses and sham control groups, and patients were treated and followed for 18 months. In October 2019, we announced positive 12-month data from this trial and in June 2020, we completed this trial and announced 18-month data from this trial, which supported the 12-month data. In this trial, the treatment effect was observed as early as 6 months, with an increase in the absolute difference of the mean change in GA growth for treatment with either Zimura 2 mg or Zimura 4 mg, as compared to sham, at each subsequent time point, suggesting the progressive benefit of continuous treatment with Zimura.

•GATHER2 (also known as ISEE2008; GA secondary to AMD - ongoing): an international, randomized, double-masked, sham controlled, multi-center Phase 3 clinical trial evaluating the safety and efficacy of ~~Zimura~~ACP for the treatment of GA secondary to AMD. InWe ~~July~~enrolled ~~2021, we completed patient enrollment with a total of~~ 448 patients ~~enrolled.~~in ~~Patients~~this trial, who were randomized on a 1:1 basis into either a treatment group with monthly intravitreal injections of ~~Zimura~~ACP 2 mg or a sham control group. As agreed to with the FDA in connection with the SPA, the primary efficacy endpoint ~~will~~is be the mean rate of growth (slope) estimated based on GA area measured by ~~fundus autofluorescence, or~~ FAF, in at least three timepoints: baseline, month 6 and month 12. WeIn ~~plan~~September ~~to analyze the primary efficacy endpoint at 12 months~~2022, ~~and~~we ~~treat~~announced ~~and~~positive ~~follow patients for 24 months. We expect~~ 12-month ~~top-line~~ data tofrom bethis ~~available~~trial. ~~during~~We ~~the~~plan ~~second~~to ~~half~~treat ofand ~~2022,~~follow ~~approximately~~patients ~~one year following the enrollment of the last patient plus the time needed~~ for ~~database~~24 ~~lock~~months ~~and~~in ~~analysis~~total.

•~~Planned~~ISEE2009 ~~intermediate~~(also ~~AMD~~known ~~trial:~~as Wethe ~~expect~~OLE ~~this~~study; ~~trial~~open tolabel beextension study - ongoing): an international, ~~randomized,~~open ~~double-masked~~label, ~~sham-controlled,~~multicenter ~~multi-center~~study ~~Phase~~evaluating 3the ~~trial~~safety ~~with~~of ~~approximately~~ACP ~~200~~2 ~~patients~~mg ~~per~~for ~~treatment~~patients ~~group.~~who Wecompleted ~~expect~~their tomonth ~~follow and treat patients for~~ 24 ~~months.~~visits Wein ~~are currently evaluating other aspects of~~ the ~~design~~GATHER2 ~~of this~~ trial~~, including patient inclusion criteria and primary efficacy endpoints~~. We ~~plan~~are continuing to ~~obtain~~enroll ~~feedback from regulatory authorities on our plans for this trial and our development strategy in this indication, before initiating this trial during the second half of 2022~~patients.

12•STAR (also known as OPH2005; STGD1 - ongoing): an international, randomized, double-masked, sham controlled, multi-center Phase 2b clinical trial evaluating the safety and efficacy of ACP for the treatment of STGD1. We initially enrolled 95 patients in this trial, none of whom have remaining study visits. In July 2020, we reopened enrollment in this trial in the United States. We continue to enroll patients and plan to enroll approximately 25 additional patients, with the goal of enrolling a total of approximately 120 patients. We have been and will remain masked until results are analyzed for all the patients in this trial.

In addition to the GATHER1 trial, we have completed multiple clinical trials evaluating various doses of ACP in age-related retinal diseases, including:

•OPH2001, a Phase 1/2a clinical trial of various doses of ACP for the treatment of GA, with a total of 47 patients enrolled;

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•~~STAR (also known as OPH2005; STGD1 - ongoing)~~OPH2000: ana ~~international, randomized, double-masked, sham controlled, multi-center~~ Phase 2b1/2a clinical trial ~~evaluating the safety and efficacy~~ of ~~Zimura~~various ~~for~~doses ~~the treatment~~ of ~~STGD1.~~ACP Weadministered ~~initially~~in ~~enrolled~~combination 95with ~~patients~~Lucentis® ~~in this trial~~(ranibizumab), ~~none~~an ofanti-vascular ~~whom~~endothelial ~~have~~growth ~~remaining~~factor, ~~study~~or ~~visits.~~anti-VEGF, ~~In July 2020~~agent, wefor ~~reopened enrollment in this trial in~~ the ~~United~~treatment ~~States.~~of Wewet ~~continue to enroll patients and plan to enroll approximately 25 additional patients~~AMD, with ~~the goal of enrolling~~ a total of ~~approximately~~60 ~~120~~ patients. ~~We have been and will remain masked until results are analyzed for all the patients in this trial. We expect data from this trial to become available after the top-line data from the GATHER2 trial.~~ enrolled;

In•OPH2007, ~~addition~~a toPhase ~~the~~2a ~~GATHER1~~clinical trial, weof ~~have~~various ~~completed~~doses ~~multiple~~of ~~clinical~~ACP ~~trials~~administered ~~evaluating~~in ~~various~~combination ~~doses~~with ofLucentis ~~Zimura~~for inthe ~~age-related~~treatment ~~retinal~~of ~~diseases~~wet AMD, ~~including:~~with a total of 64 patients enrolled and treated; and

•~~OPH2001,~~OPH2002: a very small Phase 1/2a clinical trial of ~~various~~ACP ~~doses~~in ofcombination ~~Zimura~~with anti-VEGF agents for the treatment of ~~GA,~~idiopathic ~~with~~polypoidal achoroidal ~~total~~vasculopathy, ofor 47IPCV, in patients ~~enrolled;~~for whom anti-VEGF monotherapy had failed.

~~•OPH2000:~~ ACP ais ~~Phase~~administered ~~1/2a~~by ~~clinical~~intravitreal ~~trial~~injection. Patients ofreceiving ~~various~~intravitreal ~~doses~~injections typically receive topical numbing drops or injection of ~~Zimura~~a ~~administered~~numbing inagent ~~combination~~prior ~~with~~to ~~Lucentis®~~the ~~(ranibizumab),~~injection. The administering physician also typically rinses the ocular surface with an ~~anti-vascular~~antiseptic ~~endothelial~~solution. ~~growth~~By ~~factor,~~injecting orthe ~~anti-VEGF,~~active agent into the vitreous cavity, ~~for~~the physician delivers the ~~treatment~~agent ofin ~~wet~~close ~~AMD,~~vicinity ~~with~~to athe ~~total~~active ofdisease 60site ~~patients~~while ~~enrolled;~~minimizing the risk for systemic exposure to non-ocular tissues.

~~•OPH2007~~ An intravitreal injection results in elevation of intraocular pressure, aor ~~Phase~~IOP, 2awhich is usually transient. In our clinical ~~trial~~trials, ofthe ~~various~~IOP ~~doses~~is monitored before and after each intravitreal injection. Certain of ~~Zimura~~the ~~administered~~dosing regimens we are evaluating in ~~combination~~STAR ~~with~~involve ~~Lucentis~~multiple ~~for~~intravitreal injections administered on the ~~treatment~~same ofday. Based ~~wet~~on ~~AMD~~our clinical experience to date, ~~with~~we ahave ~~total~~not ofseen 64any ~~patients~~meaningful ~~enrolled~~or ~~and~~sustained ~~treated;~~increase in IOP in clinical trials involving multiple intravitreal injections on the same day, and we believe that multiple intravitreal injections likely could be delivered safely on the same day.

~~•OPH2002:~~ Our aACP ~~very small Phase 2a~~ clinical ~~trial~~experience ofto ~~Zimura~~date inis ~~combination~~described ~~with anti-VEGF agents for the treatment of idiopathic polypoidal choroidal vasculopathy, or IPCV,~~ in ~~patients~~greater ~~for~~detail ~~whom anti-VEGF monotherapy had failed~~below.

~~Over~~ACP ~~350 patients have been treated with Zimura in these completed clinical trials, with treatment durations extending up to 18 months. All doses of Zimura administered in these trials were well~~-~~tolerated,~~ ~~with~~GA ~~only a single occurrence of an adverse event, mild subcapsular cataract, assessed to be drug-related by participating investigators.~~ Trials

~~Zimura is administered by intravitreal injection.~~GATHER1: ~~Patients~~Completed ~~receiving~~Clinical ~~intravitreal~~Trial ~~injections~~Assessing ~~typically~~the ~~receive~~Safety ~~topical~~and ~~numbing~~Efficacy ~~drops~~of orVarious ~~injection~~Doses of aACP numbing agent prior to the injection. The administering physician also typically rinses the ocular surface with an antiseptic solution. By injecting the active agent into the vitreous cavity, the physician delivers the agent in close vicinity to the active disease site while minimizing the risk for ~~systemic~~GA ~~exposure~~Secondary to ~~non-ocular tissues.~~ AMD

AnIn ~~intravitreal~~October ~~injection~~2019, ~~results~~we inannounced ~~elevation~~12-month ofdata ~~intraocular~~from ~~pressure,~~the orGATHER1 ~~IOP~~trial and in June 2020, ~~which~~we iscompleted ~~usually~~and ~~transient. In~~announced ~~our~~18-month ~~clinical~~data ~~trials,~~from ~~the~~this ~~IOP~~trial. isThe ~~monitored~~primary ~~after~~efficacy ~~each~~analysis ~~intravitreal~~was ~~injection. Certain~~performed ofat the ~~dosing~~12-month ~~regimens~~time wepoint. ~~are~~Pursuant ~~evaluating~~to inthe ~~STAR~~clinical ~~involve~~trial ~~multiple~~protocol, ~~intravitreal~~patients ~~injections~~continued ~~administered~~to onbe ~~the~~treated ~~same~~and ~~day. Based~~followed onthrough ~~our~~month ~~clinical~~18. ~~experience~~We toremained ~~date,~~masked weregarding ~~have~~the ~~not~~treatment ~~seen~~group ~~any~~to ~~meaningful~~which oreach ~~sustained~~individual ~~increase~~patient inwas ~~IOP~~randomized inthroughout ~~clinical~~the ~~trials~~duration ~~involving~~of ~~multiple~~the ~~intravitreal~~trial. ~~injections~~Following on the ~~same~~conclusion ~~day,~~of ~~and~~the trial, we ~~believe~~have ~~that~~continued ~~multiple~~to ~~intravitreal~~review ~~injections~~and ~~likely~~analyze ~~could~~the beunmasked, ~~delivered~~individual ~~safely~~patient ondata ~~the~~from ~~same~~this ~~day~~trial.

Our Zimura clinical experience to date, as well as our ongoing and planned clinical trials for Zimura, are described in greater detail below.

Zimura - GA Trials

GATHER1: Completed Clinical Trial Assessing the Safety and Efficacy of Various Doses of Zimura for GA Secondary to AMD

In October 2019, we announced 12-month data from the GATHER1 trial and in June 2020, we completed and announced 18-month data from this trial. The primary efficacy analysis was performed at the 12-month time point. Pursuant to the clinical trial protocol, patients continued to be treated and followed through month 18. We remained masked regarding the treatment group to which each individual patient was randomized throughout the duration of the trial. Following the conclusion of the trial, we have continued to review and analyze the unmasked, individual patient data from this trial. In June 2021, July 2021 and February 2022, we announced data from additional post-hoc analyses that we performed.

Trial Design and Enrollment

A total of 286 patients were enrolled across two parts of the trial.

Part 1. In Part 1 of the trial, 77 patients were randomized into one of three treatment groups in a 1:1:1 ratio as follows:

Cohort

ACP 1 mg

ACP 2 mg

Sham

Patients

~~Table~~In Part 1 of ~~Contents~~ the trial, ACP was administered by monthly intravitreal injections, while patients in the sham control group received monthly sham injections. In 2017, based on the announcement of positive data from a competitor studying a different complement inhibitor in a Phase 2 clinical trial in GA and following review of additional third-party clinical trial data and further statistical analysis, we modified the trial design to change the total number of patients to be enrolled, to change the primary efficacy endpoint from a vision endpoint to an anatomic endpoint, to shorten the time point for the primary efficacy analysis to month 12 and to include a ACP 4 mg dose group. The patients who were enrolled in Part 1 remained in the trial following these modifications and we remained masked regarding the treatment group to which each patient was randomized.

Cohort

Zimura 1 mg

Zimura 2 mg

Sham

Patients

In Part 1 of the trial, Zimura was administered by monthly intravitreal injections, while patients in the sham control group received monthly sham injections. In 2017, based on the announcement of positive data from a competitor studying a different complement inhibitor in a Phase 2 clinical trial in GA and following review of additional third-party clinical trial data and further statistical analysis, we modified the trial design to change the total number of patients to be enrolled, to change the primary efficacy endpoint from a vision endpoint to an anatomic endpoint, to shorten the time point for the primary efficacy analysis to month 12 and to include a Zimura 4 mg dose group. The patients who were enrolled in Part 1 remained in the trial following these modifications and we remained masked regarding the treatment group to which each patient was randomized.

Part 2. In Part 2 of the trial, we enrolled 209 additional patients, who were randomized into one of three treatment groups in a 1:2:2 ratio as follows:

Cohort

~~Zimura~~ACP 2 mg

~~Zimura~~ACP 4 mg

Sham

Patients

In Part 2 of the trial, patients in the Zimura 2 mg group received one intravitreal injection of Zimura 2 mg and one sham injection at each monthly visit; patients in the Zimura 4 mg group received two intravitreal injections of Zimura 2 mg at each monthly visit; and patients in the sham control group received two sham injections at each monthly visit. In its current formulation, doses of Zimura above 2 mg would require more than one intravitreal injection.12

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In Part 2 of the trial, patients in the ACP 2 mg group received one intravitreal injection of ACP 2 mg and one sham injection at each monthly visit; patients in the ACP 4 mg group received two intravitreal injections of ACP 2 mg at each monthly visit; and patients in the sham control group received two sham injections at each monthly visit. In its current formulation, doses of ACP above 2 mg would require more than one intravitreal injection.

The primary efficacy endpoint was the mean rate of growth of GA over 12 months, while secondary efficacy endpoints evaluated mean changes in patients' visual acuity in different lighting conditions over the same period.

Key Inclusion and Exclusion Criteria

In order to determine eligibility to participate in the trial, the location and size of each patient’s GA was assessed using FAF images. FAF is a common imaging technique used by retina specialists for photographing and documenting the size of GA present in the back of the eye, or fundus. Autofluorescence refers to the natural emission of light by biological structures. In FAF images, areas of atrophy are characterized by lower autofluorescence. An independent masked reading center assessed FAF images throughout the trial, including at baseline to determine eligibility.

The fovea is the central portion of the macula where visual acuity is the highest. We sought to enroll patients whose GA was located, in whole or in part, within 1500 microns of the foveal center but that did not enter the foveal center. A disc area is the size of the area of the retina where a standard sized optic nerve emerges, which is generally accepted to be 2.5 mm2. We sought to enroll patients with a total GA area of between 1 and 7 disc areas (or 2.5 mm2 to 17.5 mm2) inclusive. If the GA was multifocal, meaning it was not continuous and had multiple locations, at least one focal lesion needed to measure at least 0.5 disc areas (or 1.25 mm2). Each patient's BCVA was also assessed using the Snellen equivalent scale, which equates the detail a patient can see at a distance of 20 feet with the detail an individual with 20/20 vision can see at a greater distance. For example, a patient with 20/50 vision sees at 20 feet what a person with 20/20 vision would see at 50 feet. To be eligible to participate in the trial, patients' BCVA in the study eye was initially required to be between 20/25 and 20/100 inclusive during Part 1 of the trial. As part of the modifications we made for Part 2 of the trial, we expanded the inclusion criteria to include patients whose BCVA in the study eye was between 20/25 and 20/320 inclusive. BCVA on the Snellen equivalent scale can be equated to a number of letters of vision on the Early Treatment of Diabetic Retinopathy Study, or ETDRS, chart. BCVAs of 20/25, 20/100 and 20/320 on the Snellen equivalent scale are equivalent to 80 ETDRS letters, 50 ETDRS letters and 25 ETDRS letters, respectively.

Patients were stratified across treatment groups by baseline BCVA, baseline GA area and the baseline pattern of autofluorescence at the margins of the GA lesion, referred to as the junctional zone. Stratification for baseline characteristics is a method for allocating patients to treatment groups to ensure that there ~~are~~is approximately the same ratio of patients with a given baseline characteristic in each treatment group as the overall randomization ratio. For vision, patients were stratified based on whether their vision was above or below 50 ETDRS letters. For GA area, patients were stratified based on whether their GA area was above or below 4 disc areas. For autofluorescence pattern, patients were stratified based on several well-known patterns that have been described in the scientific literature.

As part of the modifications for Part 2 of the trial, we amended the clinical trial protocol to provide that patients in any arm of the trial who developed CNV in the study eye would be removed from the trial and any future study treatments and assessments, since we did not believe, at the time of the modifications, that GA lesions for patients with CNV in the study eye could be reliably measured with FAF images.

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Additionally, patients who had a prior history of intravitreal treatment for any indication in either eye were excluded, as well as patients with any ocular condition in the study eye that could affect central vision or otherwise confound assessments.

Baseline Characteristics

We collected baseline characteristics for all patients participating in the trial. GA area was measured based on the area of GA in square millimeters (mm2). Reported scientific literature indicates that the rate of GA growth may be dependent on the baseline lesion size, with larger GA lesions generally growing faster than smaller lesions, subject to an overall plateau effect as the GA grows to consume almost the entire macula. For this reason, patients were stratified in this trial based on their baseline lesion size. To further mitigate for the impact of baseline lesion size on the growth of GA, a square root transformation was performed. It is reported in the scientific literature and accepted in the field that using the square root of the lesion size for calculating the mean change in size over time mitigates for the impact of the baseline lesion size. We used the square root transformation of GA area, measured in millimeters (mm), to perform the assessment of the primary efficacy endpoint in the GATHER1 trial.

Although GA can be associated with profound and irreversible vision loss, the vision loss that patients experience is not necessarily linearly correlated to the progression of GA. The specific location of the GA within patients' retinas can affect patients' vision differently. In general, patients whose GA expands into the fovea experience vision loss that is disproportionate to the vision loss experienced by patients whose GA does not expand into the fovea. Further, patients with GA may demonstrate good visual acuity but poor functional vision if their GA results in dark spots, referred to as scotomas, in their central visual field. Patients with scotomas may be able to read a vision chart letter-by-letter, especially if their GA has not entered the fovea, but they may have trouble reading a paragraph of text or driving, as these activities of daily living draw upon a field of vision that is broader than a single point of focus. For this reason, and based on our prior interactions with the FDA, we believe the efficacy assessment that is most likely to demonstrate clinical relevance for an investigational product across a heterogeneous GA patient population is reduced rate of growth in GA. If an investigational product can slow the growth of GA, it has the potential to preserve, or slow the loss of, functional vision for patients whose GA is expanding into critical areas of their central visual field, which would be clinically meaningful.

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to the vision loss experienced by patients whose GA does not expand into the fovea. Further, patients with GA may demonstrate good visual acuity but poor functional vision if their GA results in dark spots, referred to as scotomas, in their central visual field. Patients with scotomas may be able to read a vision chart letter-by-letter, especially if their GA has not entered the fovea, but they may have trouble reading a paragraph of text or driving, as these activities of daily living draw upon a field of vision that is broader than a single point of focus. For this reason, and based on our prior interactions with the FDA, we believe the efficacy assessment that is most likely to demonstrate clinical relevance for an investigational product across a heterogeneous GA patient population is reduced rate of growth in GA. If an investigational product can slow the growth of GA, it has the potential to preserve, or slow the loss of, functional vision for patients whose GA is expanding into critical areas of their central visual field, which would be clinically meaningful.

In addition to baseline GA area, it has been reported in the scientific literature that GA that is non-subfoveal, or that has not impacted the foveal center, is positively correlated with a higher rate of GA area progression and growth. We believe that once a GA lesion expands into the fovea, the rate of growth may be slowed. In addition, once GA expands to encompass the central fovea, additional progression can be limited in the central region of the retina, with any continued expansion occurring predominantly in the outer part of the retina.

In addition to measuring the area of GA, we followed patients for changes in their vision (BCVA), as measured both at a standard light level, or luminance, and lower light level, or low luminance (LL BCVA), measured in each case by ETDRS letters. Testing for visual acuity serves as an important safety assessment to assure that the decrease in visual acuity in the ~~Zimura~~ACP treatment groups was not different from the sham control groups. Because we believe that BCVA is not the optimal assessment to evaluate the impact of GA on patients’ functional vision, we included vision in the prespecified statistical analysis as a secondary, and not as a primary, endpoint.

For patients within each treatment group, where a numerical measurement was collected, we calculated the mean and standard deviation, or SD, for each measurement. SD is a statistical measure of the variability of a particular measurement within a patient population. Generally, two-thirds of all patients fall within approximately one SD, plus or minus, of the mean for any particular measurement.

The baseline characteristics are presented below for each treatment group in each Part of the trial. These baseline characteristics include the ITT, or intent-to-treat, population, which includes all patients who were randomized in the trial and who received at least one dose of study drug in the relevant treatment group. Based on these data, we believe that the baseline characteristics were generally balanced across the treatment groups.

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	Part 1			Part 2
Cohort	~~Zimura~~ACP 1 mg(N = 26)	~~Zimura~~ACP 2 mg(N = 25)	Sham (N = 26)	~~Zimura~~ACP 2 mg(N = 42)	~~Zimura~~ACP 4 mg(N = 83)	Sham 4 mg(N = 84)
Mean age, years (SD)	73.8 (8.0)	77.7 (9.6)	78.1 (8.4)	79.4 (10.7)	79.2 (8.3)	78.2 (9.0)
Female gender, number (%)	15 (57.7%)	18 (72.0%)	18 (69.2%)	27 (64.3%)	58 (69.9%)	61 (72.6%)
Active smokers, number (%)	6 (23.1%)	10 (40.0%)	7 (26.9%)	15 (35.7%)	26 (31.3%)	29 (34.5%)
Caucasian race, number (%)	25 (96.2%)	25 (100%)	25 (96.2%)	42 (100%)	82 (98.8%)	82 (97.6%)
Iris color:
Light	13 (50.0%)	16 (64.0%)	17 (65.4%)	29 (69.0%)	54 (65.1%)	57 (67.9%)
Medium	7 (26.9%)	6 (24.0%)	7 (26.9%)	9 (21.4%)	22 (26.5%)	21 (25.0%)
Dark	6 (23.1%)	3 (12.0%)	2 (7.7%)	4 (9.5%)	7 (8.4%)	6 (7.1%)
Mean intraocular pressure, mmHg (SD)	15.0 (1.9)	14.6 (2.6)	14.5 (2.8)	14.1 (2.4)	15.2 (2.5)	14.9 (2.5)
Non-subfoveal GA, number (%)	23 (88.5%)	20 (80.0%)	22 (84.6%)	42 (100%)	81 (97.6%)	82 (97.6%)
Mean GA area, mm2 (SD)	7.37 (4.32)	6.60 (3.35)	7.33 (3.73)	7.77 (4.01)	7.90 (4.18)	7.45 (3.89)
Mean Sq. Root of GA area, mm (SD)	2.591 (0.827)	2.471 (0.717)	2.623 (0.687)	2.705 (0.684)	2.715 (0.732)	2.636 (0.709)
Bilateral GA, number (%)	26 (100%)	25 (100%)	25 (96.2%)	42 (100%)	83 (100%)	83 (98.8%)
Mean BCVA, ETDRS letters (SD)	70.5 (8.0)	71.6 (7.5)	71.3 (7.5)	69.4 (11.3)	69.5 (9.8)	68.3 (11.0)
Mean LL BCVA, ETDRS letters (SD)	38.1 (22.7)	43.0 (19.7)	36.7 (21.2)	33.1 (21.3)	36.8 (20.9)	33.9 (18.8)
Patients with Hyperautofluorscence (%)	25 (96.2%)	25 (100%)	26 (100%)	41 (97.6%)	82 (98.8%)	83 (98.8%)
Patients with Hyperautofluorescence (%)	25 (96.2%)	25 (100%)	26 (100%)	41 (97.6%)	82 (98.8%)	83 (98.8%)
Height, cm (SD)	168.7 (12.0)	165.9 (8.6)	164.9 (12.1)	164.9 (11.0)	163.7 (10.6)	163.7 (9.3)
Weight, kg (SD)	81.9 (17.8)	75.6 (14.9)	74.7 (15.6)	80.8 (22.3)	76.2 (18.2)	78.4 (17.8)

12-Month Data

12-Month Safety Data

Based on our review of the safety data to date, ~~Zimura~~ACP was generally well tolerated after 12 months of administration. Over this 12-month time period, there were no investigator-reported ocular serious adverse events, no ~~Zimura~~ACP-related adverse events, no cases of ~~Zimura~~ACP-related intraocular inflammation, no cases of ~~Zimura~~ACP-related increased intraocular pressure, no cases of endophthalmitis, and no discontinuations attributed by investigators to ~~Zimura~~ACP in the trial. The numbers below are based on investigator-reported adverse events occurring up through the month 12 time point for all patients.

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The number of patients with one or more serious, systemic, treatment emergent adverse events, or TEAEs, organized by MedDRA system organ class, a standard method of reporting adverse events, are set forth in the table below:

Patients with One or More Serious TEAEs in Any Organ Class

	Part 1			Part 2
	Zimura 1 mg(N = 26)	Zimura 2 mg(N = 25)	Sham(N = 26)	Zimura 2 mg(N = 42)	Zimura 4 mg(N = 83)	Sham 4 mg(N = 84)
	ACP 1 mg(N = 26)	ACP 2 mg(N = 25)	Sham(N = 26)	ACP 2 mg(N = 42)	ACP 4 mg(N = 83)	Sham 4 mg(N = 84)
Cardiac disorders	1 (3.8%)	0	0	0	2 (2.4%)	3 (3.6%)
Gastrointestinal disorders	1 (3.8%)	1 (4.0%)	1 (3.8%)	0	2 (2.4%)	6 (7.1%)
General disorders and administration site conditions	0	0	0	1 (2.4%)	0	0
Hepatobiliary disorders	0	1 (4.0%)	1 (3.8%)	0	1 (1.2%)	0
Infections and infestations	0	1 (4.0%)	0	1 (2.4%)	6 (7.2%)	2 (2.4%)
Injury, poisoning and procedural complications	0	1 (4.0%)	0	1 (2.4%)	3 (3.6%)	2 (2.4%)
Metabolism and nutrition disorders	0	0	1 (3.8%)	0	0	0
Musculoskeletal and connective tissue disorders	1 (3.8%)	0	0	0	0	2 (2.4%)
Benign, malignant and unspecified neoplasms (including cysts and polyps)	0	0	0	0	1 (1.2%)	2 (2.4%)
Nervous system disorders	1 (3.8%)	1 (4.0%)	1 (3.8%)	1 (2.4%)	3 (3.6%)	1 (1.2%)
Psychiatric disorders	0	0	1 (3.8%)	0	0	1 (1.2%)
Respiratory, thoracic and mediastinal disorders	0	1 (4.0%)	0	0	2 (2.4%)	3 (3.6%)

The number of patients with one or more systemic TEAEs, including serious systemic TEAEs, identified by the investigator as related to the study drug (~~Zimura~~ACP or sham) are set forth in the table below:

Reported Systemic TEAEs Related to ~~Zimura~~ACP or Sham

Part 1

Part 2

Zimura 1 mg(N = 26)

Zimura 2 mg(N = 25)

Sham(N = 26)

Zimura 2 mg(N = 42)

Zimura 4 mg(N = 83)

Sham 4 mg(N = 84)

ACP 1 mg(N = 26)

ACP 2 mg(N = 25)

Sham(N = 26)

ACP 2 mg(N = 42)

ACP 4 mg(N = 83)

Sham 4 mg(N = 84)

Subjects with at least one TEAE

The number of patients with one or more ocular TEAEs in the study eye are set forth in the table below:

Reported Ocular TEAEs in Study Eyes

	Part 1			Part 2
	Zimura 1 mg(N = 26)	Zimura 2 mg(N = 25)	Sham(N = 26)	Zimura 2 mg(N = 42)	Zimura 4 mg(N = 83)	Sham 4 mg(N = 84)
	ACP 1 mg(N = 26)	ACP 2 mg(N = 25)	Sham(N = 26)	ACP 2 mg(N = 42)	ACP 4 mg(N = 83)	Sham 4 mg(N = 84)
Eye disorders	12 (46.2%)	8 (32.0%)	4 (15.4%)	24 (57.1%)	50 (60.2%)	33 (39.3%)
Eye disorders related to injection procedure	3 (11.5%)	4 (16.0%)	2 (7.7%)	14 (33.3%)	36 (43.4%)	23 (27.4%)

All of the above TEAEs that were not related to the injection procedure were also not related to the study drug. The number of patients with one or more ocular TEAEs in the study eye, identified by the investigator as related to the study drug (~~Zimura~~ACP or sham) is set forth in the table below:

Reported Ocular TEAEs in the Study Eye Related to ~~Zimura~~ACP or Sham

Part 1

Part 2

Zimura 1 mg(N = 26)

Zimura 2 mg(N = 25)

Sham(N = 26)

Zimura 2 mg(N = 42)

Zimura 4 mg(N = 83)

Sham 4 mg(N = 84)

ACP 1 mg(N = 26)

ACP 2 mg(N = 25)

Sham(N = 26)

ACP 2 mg(N = 42)

ACP 4 mg(N = 83)

Sham 4 mg(N = 84)

Subjects with at least one TEAE

Incidence of CNV. During the first 12 months of this trial, the incidence of investigator reported CNV in the untreated fellow eyes was 10 patients (3.5%) and in the study eyes was 3 patients (2.7%) in the sham group, 1 patient (4.0%) in the ~~Zimura~~ACP 1 mg group, 6 patients (9.0%) in the ~~Zimura~~ACP 2 mg group, and 8 patients (9.6%) in the ~~Zimura~~ACP 4 mg group.

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Statistical Analysis for Efficacy Measures

GATHER1 was designed as a Phase 2b screening trial based on the criteria described by Drs. Thomas Fleming and Barbara Richardson in their publication regarding clinical trial design in the context of microbicides for the prevention of HIV in the Journal of Infectious Disease in 2004. A screening trial uses the same primary efficacy endpoint as an anticipated Phase 3 clinical trial that would be used to support potential marketing approval. However, screening trials generally have a considerably smaller sample size than the anticipated Phase 3 clinical trial. Because it is particularly important to avoid false negative outcomes in a screening trial, screening trials may have higher false positive error rates than would typically be allowed in a Phase 3 trial.

A Phase 2b screening trial has three possible outcomes:

•If the estimated effect size indicates low levels of benefit, the experimental intervention would be judged as not plausibly more efficacious than the sham control, and should be discarded in its current dosage in the indication evaluated;

•If the estimated effect size is moderate but clinically relevant, with a relatively low likelihood of being achieved (for example, a probability of less than 10%) if there truly were no effect, the experimental intervention would be judged as plausibly more efficacious than the sham control and should be evaluated definitively in subsequent Phase 3 clinical trials; or

•If the estimated effect size is clinically relevant and reaches the traditional threshold for statistical significance, as was the case in the GATHER1 trial for both the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg dose groups as compared to the corresponding sham control groups, the trial could potentially serve as one of the two pivotal trials typically required for marketing approval.

A properly designed Phase 2b screening trial has a considerable likelihood of ruling out ineffective or harmful interventions, while providing encouraging (or even statistically significant) evidence of benefit that likely would require confirmation by one additional, independent Phase 3 trial.

For the primary and secondary efficacy analyses we evaluated the ITT population in accordance with a prespecified statistical analysis plan.

The statistical evidence from the GATHER1 trial regarding the comparison of ~~Zimura~~ACP 2 mg to sham control is provided by data from both Part 1, with a 1:1 randomization ratio of patients receiving ~~Zimura~~ACP 2 mg (25 patients) and sham (26 patients), as well as data from Part 2, with a 1:2 randomization ratio of patients receiving ~~Zimura~~ACP 2 mg (42 patients) and sham (84 patients), for a total of 67 patients receiving ~~Zimura~~ACP 2 mg and 110 patients receiving sham. While we believe it is appropriate to use the aggregate data from Parts 1 and 2 in the analysis of the relative effects of ~~Zimura~~ACP 2 mg as compared to sham, it would not be appropriate to simply pool the data from patients in both Parts 1 and 2, in particular, because the randomization fraction differs across these two parts of the trial. However, based on the randomization procedures used in each part of the trial, for purposes of statistical comparisons, within Part 1 of the trial, the 25 patients receiving ~~Zimura~~ACP 2 mg should be comparable to the 26 patients receiving sham. Similarly, for purposes of statistical comparisons, within Part 2 of the trial, the 42 patients receiving ~~Zimura~~ACP 2 mg should be comparable to the 84 patients receiving sham. The efficacy of ~~Zimura~~ACP 2 mg was therefore evaluated through an analysis which included a regression factor by trial part. The statistical analysis for the ~~Zimura~~ACP 4 mg group as compared to sham compares data for patients from Part 2 of the trial only. Data from patients receiving ~~Zimura~~ACP 1 mg in Part 1 of the trial was not part of the prespecified statistical analysis for the efficacy endpoints.

The prespecified statistical analysis plan for the primary and secondary endpoints of this trial used the mixed-effects repeated measures model, or MRM, to compare data for the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg groups to the corresponding sham groups. Repeated measures models are often used when the same outcome is measured at several time points for each patient. These models make use of all available data points to estimate the measurement of interest, the mean rate of change of GA growth, without making overly restrictive assumptions. In addition, these models are generally robust to missing data under the assumption that data are missing at random. During the course of a clinical trial, patients may withdraw from the clinical trial because their condition is asymptomatic, because patients believe that continued participation in the trial is not justified based on the time commitment or treatment burden, such as receiving monthly intravitreal injections, at the recommendation of the investigator or because the protocol requires it. Additionally, patients may not come to a scheduled visit at which key assessments are scheduled to be taken or patient data may not be evaluable because of poor image quality or data recording errors. Early withdrawal, missed visits and unevaluable data all result in data missing from the final data set for a clinical trial. Although the protocol called for collection of FAF images of GA at baseline, at month 6 and at month 12, for patients who withdrew from the trial before month 12, the study protocol required the collection of an FAF image to provide a measurement of GA at the time of withdrawal, which was included in the primary analysis so long as it was taken within the month prior to either the month 6 or month 12 time point. Because the MRM model would only need measurements from at least two different

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time points for analysis purposes, one of which must be the baseline, we were able to include in the primary analysis all patients who had GA measurements at baseline and within the month prior to either month 6 or month 12, or both.

The following table sets forth for the data in the primary statistical analysis the number of patients for whom GA measurements were missing for purposes of performing this analysis. Patients whose GA measurements were missing at baseline, or at both month 6 and month 12, could not be included in the primary analysis. All other patients were included in the primary analysis.

Cohort	~~Zimura~~ACP 2 mg(N = 67)	Sham 2 mg(N = 110)	~~Zimura~~ACP 4 mg(N = 83)	Sham 4 mg(N = 84)
Missing GA measurement at BL, M6 and M12	0 (0%)	0 (0%)	0 (0%)	0 (0%)
Missing GA measurement at M6 and M12 only	8 (11.9%)	11 (10.0%)	17 (20.5%)	5 (6.0%)
Missing GA measurement at BL only	0 (0%)	0 (0%)	1 (1.2%)	0 (0%)
Total patients excluded from MRM analysis	8 (11.9%)	11 (10%)	18 (21.7%)	5 (6.0%)
Missing GA measurement at M6 only	1 (1.5%)	7 (6.4%)	3 (3.6%)	6 (7.1%)
Missing GA measurement at M12 only	10 (14.9%)	9 (8.1%)	11 (13.3%)	7 (8.3%)
No missing GA measurements(a)	48 (71.6%)	83 (75.5%)	51 (61.5%)	66 (78.6%)
Total patients included in MRM analysis	59 (88.0%)	99 (90.0%)	65 (78.3%)	79 (94.1%)

BL = Baseline; M6 = Month 6; M12 = Month 12

(a) = complete observations

In total, 53 (18.5%) patients withdrew from the trial during the first 12 months. Of the patients who withdrew during the first 12 months, 2 patients were from the ~~Zimura~~ACP 1 mg group (7.7% withdrawals), 12 patients were from the combined ~~Zimura~~ACP 2 mg group (17.9% withdrawals), 25 patients were from the ~~Zimura~~ACP 4 mg group (30.1% withdrawals) and 14 patients were from the combined sham group (12.7% withdrawals). GA measurements for patients who withdrew from the study prior to the 12 month time point may have been included in the MRM analysis, as detailed in the table above.

Sensitivity analyses. We performed several sensitivity analyses to assess the impact of missing data on the robustness of the GATHER1 trial results. The analyses we performed were based on approaches that the FDA generally recommends sponsors of investigational products use to evaluate their clinical data. Based on these analyses, and accounting for the data missing from our data set because of patient withdrawals or for other reasons, the statistical analysis for the 12 month data from the GATHER1 trial appear to be robust. Descriptions of these sensitivity analyses and their outcomes are summarized below. For a description of the thresholds we used to determine statistical significance on the primary efficacy endpoint, see the paragraph below the tables below under "Primary Efficacy Endpoint Data."

•A "shift imputation" approach, in which missing data are imputed, or replaced, by values calculated from similar patients with observed values, plus a defined shift. The analysis is repeated assuming a progressively larger shift with each iteration. The analysis becomes increasingly conservative as the shift increases (because missing values are replaced by worse values than would have been observed, had the values not been missing). The shift is increased until a tipping point is reached and statistical significance is lost. If significance is lost for smaller shift values, the results of the analyses are sensitive to missing data, whereas if significance is lost for larger shift values, the results of the analyses are robust to missing data.

A shift of at least 0.05 mm in terms of square root of GA growth was required to lose statistical significance for both the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg groups. The difference between the ~~Zimura~~ACP treatment groups and the corresponding sham groups, in terms of mean change of square root of GA growth, was 0.11 mm for the ~~Zimura~~ACP 2 mg group and 0.12 mm for the ~~Zimura~~ACP 4 mg group, so a shift of 0.05 mm represents more than 40% of the observed treatment effect, which is large.

•Arbitrary imputation approaches, in which missing data are replaced by:

◦the mean value of the same treatment group, which seems a reasonable imputation approach since it replaces missing values by the mean of all observed values in the same treatment group;

◦the mean value of the comparator treatment group, which is a very conservative approach. If there is a treatment effect, missing values in the sham control group are replaced by better values, on average, from the ~~Zimura~~ACP treatment group, while missing values in the ~~Zimura~~ACP treatment group are replaced by worse values, on average, from the sham control group;

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◦the mean value of both treatment groups, which is a conservative approach because it assumes no treatment effect for missing values; and

◦the mean value of the sham control group, which is also a conservative approach because it draws only upon data from the sham control group, which by definition did not have any treatment benefit.

•A “pattern mixture model imputation” approach, which is a technically complex model and is especially useful when data are suspected to be missing “not at random”.

Statistical significance for the reduction in mean rate of GA growth for the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg groups as compared to the corresponding sham groups was retained for the pattern mixture model imputation approach, which suggests again that the results of the analyses are robust to missing data, even if these data had been missing not at random.

Based on our sensitivity analyses, and accounting for the data missing from our data set because of patient withdrawals or for other reasons, we believe the statistical analysis for the 12 month data from the GATHER1 trial is robust.

Primary Efficacy Endpoint Data

The prespecified primary efficacy endpoint was an anatomic endpoint, the mean change in rate of GA growth over 12 months, as measured by FAF based on readings at three time points: baseline, month 6 and month 12, calculated using the square root transformation of the GA area. The readings were performed by an independent masked reading center. The primary efficacy endpoint data are summarized in the following table:

Mean Rate of Change in GA Area from Baseline to Month 12

(MRM Analysis) (Square Root Transformation)

Cohort

~~Zimura~~ACP 2 mg(N = 67)

Sham 2 mg(N = 110)

Difference

P-value

% Difference

Mean Change in GA(a) (mm)

0.292(b)

0.402(b)

0.11

0.0072(c)

27.38%

Cohort

~~Zimura~~ACP 4 mg(N = 83)

Sham 4 mg(N = 84)

Difference

P-value

% Difference

Mean Change in GA(a) (mm)

0.321

0.444

0.124

0.0051(c)

27.81%

(a)Based on the least squares mean from the MRM model.

(b)These least squares means are estimates from the MRM model, drawing on all available data, including data from groups with different randomization ratios in Part 1 and Part 2, and should not be interpreted as directly observed data.

(c)Reflects statistically significant p-value; Hochberg procedure was used for significance testing.

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The analysis of the mean change in GA growth for ~~Zimura~~ACP 2 mg as compared to Sham 2 mg was adjusted for the fact that this dose of ~~Zimura~~ACP was tested in the two parts of the trial, which had different randomization ratios. The least squares mean changes in GA in Part 1 and Part 2 are shown separately in the following table:

Mean Rate of Change in GA Area from Baseline to Month 12

(MRM Analysis) (Square Root Transformation)

Cohort

~~Zimura~~ACP 2 mg(N = 25)

Sham 2 mg(N = 26)

Difference

Part 1

Mean Change in GA(a) (mm)

0.329

0.42249

0.093

(a)Based on the least squares mean from the MRM model.

Cohort

~~Zimura~~ACP 2 mg(N = 42)

Sham 2 mg(N = 84)

Difference

Part 2

Mean Change in GA(a) (mm)

0.308

0.42245

0.114

(a)Based on the least squares means from the MRM model.

When the data from the ~~Zimura~~ACP 2 mg comparisons from each Part of the trial are analyzed using the MRM model, which includes a regression factor by part, the mean difference in GA growth over 12 months between the ~~Zimura~~ACP 2 mg and sham control groups is 0.110 mm.

Statistical significance is established by performing statistical analysis on a data set to assess the degree to which an observed outcome is likely to be associated with variability in the studied patient population or chance as compared to the impact of the investigational product being studied. A higher degree of statistical significance is associated with a lower p-value. Typically, a two-sided p-value of 0.05 or less represents statistical significance when performing only a single prespecified primary analysis for a single primary endpoint. However, when multiple doses of a drug are tested, a more stringent statistical method that accounts for multiple comparisons must be applied. For this purpose, we used the Hochberg multiple comparison procedure to assess the statistical significance of the results observed in the GATHER1 trial. Under the Hochberg procedure, it is necessary to use a stricter standard for statistical significance (a two-sided p-value of 0.025 or less) for any particular dose. For GATHER1, the results for the primary efficacy endpoint observed for both the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg groups, as compared to the corresponding sham group, achieved p-values of 0.0072 and 0.0051, respectively, both of which are less than 0.025, indicating that both results were statistically significant.

Observed GA Data (non-square root transformation)

In addition to analyzing the mean rate of change in GA area at month 12 using the square root transformation of the GA area (measured in millimeters (mm)), we also analyzed the mean rate of change in GA area using the observed GA area (without the square root transformation, measured in square millimeters (mm2)), with the MRM model. This descriptive analysis was also part of the prespecified statistical analysis plan for this trial. The observed mean GA area data for the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg groups as compared to the corresponding sham control groups are summarized in the following table:

Mean Rate of Change in GA Area from Baseline to Month 12

(MRM Analysis) (Observed)

Cohort

~~Zimura~~ACP 2 mg(N = 67)

Sham 2(N = 110)

Difference

% Difference

Mean Change in GA(a) (mm2)

1.592(b)

2.290(b)

0.697

30.45%

Cohort						~~Zimura~~ACP 4 mg(N = 83)						Sham(N = 84)						Difference						% Difference
Mean Change in GA(a) (mm2)						2.061						2.77						0.709						25.59%

(a)Based on the least squares mean from the MRM model.

Secondary Efficacy Endpoints Data

The prespecified secondary endpoints in this trial were the mean change in BCVA from baseline to month 12 and the mean change in LL BCVA from baseline to month 12, both as measured by ETDRS letters. Testing for visual acuity serves as an important safety assessment to assure that the decrease in visual acuity in the ~~Zimura~~ACP treatment groups was not different from

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~~from~~ the sham control groups. Because we believe that BCVA is not the optimal assessment to evaluate the impact of GA on patients’ functional vision, we included vision in the prespecified statistical analysis as a secondary, and not as a primary, endpoint.

The GATHER1 trial was not designed to reliably assess differences in mean changes in BCVA or LL BCVA with statistical significance. Data for the secondary endpoints are summarized in the following tables:

Mean Change in BCVA from Baseline to Month 12

(MRM Analysis) (ETDRS letters)

Cohort

~~Zimura~~ACP 2 mg(N = 67)

Sham 2 mg(N = 110)

Difference

Mean Change in BCVA(a)

-7.90(b)

-9.29(b)

1.39

Cohort

~~Zimura~~ACP 4 mg(N = 83)

Sham 4 mg(N = 84)

Difference

Mean Change in BCVA(a)

-3.79

-3.51

-0.28

(a) Based on the least squares mean from the MRM model.

(b) These least squares means are estimates from the MRM model, drawing on all available data, including data from groups with different randomization ratios in Part 1 and Part 2, and should not be interpreted as directly observed data.

Mean Change in LL BCVA from Baseline to Month 12

(MRM Analysis) (ETDRS letters)

Cohort

~~Zimura~~ACP 2 mg(N = 67)

Sham 2 mg(N = 110)

Difference

Mean Change in LL BCVA(a)

-1.03(b)

-1.41(b)

0.38

Cohort

~~Zimura~~ACP 4 mg(N = 83)

Sham 4 mg(N = 84)

Difference

Mean Change in LL BCVA(a)

1.53

2.97

-1.44

(a) Based on the least squares mean from the MRM model.

(b) These least squares means are estimates from the MRM model, drawing on all available data, including data from groups with different randomization ratios in Part 1 and Part 2, and should not be interpreted as directly observed data.

~~Zimura~~ACP 1 mg 12-Month Efficacy Data

Efficacy data from patients receiving ~~Zimura~~ACP 1 mg was not part of the prespecified statistical analysis. The total number of patients randomized to the ~~Zimura~~ACP 1 mg group (26 patients) is relatively small, and the trial was not powered to reliably assess differences in outcomes for these patients as compared to patients in the sham control group in Part 1 (26 patients). However, we performed descriptive analyses on the 12 month data for patients in the ~~Zimura~~ACP 1 mg as compared to the patients in the sham control group in Part 1 of the trial to aid our assessment of whether a dose response relationship was present across treatment groups included in the clinical trial.

GA area data for the ~~Zimura~~ACP 1 mg group and the sham group from Part 1 of the trial are summarized in the following tables:

Summary of GA Area (mm) and Mean Percentage Change from Baseline to Month 12

(Square Root Transformation)

Cohort	~~Zimura~~ACP 1 mg(N = 26)	Sham Part 1(N = 26)
Mean Sq. Root of GA at BL, mm (SD)	2.591 (0.827)	2.623 (0.687)
Mean Sq. Root of GA at M12, mm (SD)	3.055 (0.604)	3.021 (0.722)
Difference	0.464	0.398
Mean % Change(a) (SD)	14.48% (8.2%)	16.49% (7.2%)

BL = Baseline; M12 = Month 12

(a) Mean % Change in GA area is an average of the percentage change in GA area observed for each patient.

Although the sample size for the ~~Zimura~~ACP 1 mg group is small, we believe the apparent reduction in mean percentage change in GA area from baseline to month 12 in the ~~Zimura~~ACP 1 mg group as compared to the sham control group in Part 1, when

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combined with the statistically significant results observed for the primary efficacy endpoint for the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg groups as compared to their corresponding sham control groups, suggest a potential dose response relationship across treatment groups.

18-Month Data

The primary purpose of the 18 month time point was to gather additional safety data. This trial was not designed to assess, and the prespecified statistical analysis plan for the trial did not include assessing, the statistical significance of the 18 month efficacy data for the treatment groups as compared to the corresponding sham control groups. The reduction in the mean rate of GA growth over 18 months was 28.11% for the ~~Zimura~~ACP 2 mg group as compared to the corresponding sham control group and 29.97% for the ~~Zimura~~ACP 4 mg group as compared to the corresponding sham control group. The descriptive p-values for the treatment effects at month 18 were p=0.0014 for the ~~Zimura~~ACP 2 mg group and p=0.0021 for the ~~Zimura~~ACP 4 mg group. The analysis of the 18-month efficacy data is descriptive only.

GA Growth Data over 18 Months

The mean rate of change in GA growth over 18 months was measured by FAF based on readings at four time points (baseline, month 6, month 12 and month 18) and was calculated using the square root transformation of the GA area. The FAF images were assessed by an independent masked reading center. The prespecified statistical analysis plan used MRM to compare data for the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg groups to the corresponding sham groups. Detailed data are shown below (the p-values for the 18 month statistical analyses are descriptive in nature):

Mean Rate of Change in Geographic Atrophy (GA) Area from Baseline to Month 18

(Square Root Transformation)

Cohort	~~Zimura~~ACP 2 mg(N = 67)	Sham(N = 110)	Difference	% Difference	P-Value(Descriptive)
Mean Change in GA(a) (mm)	0.430	0.599	0.168	28.11%	0.0014
Cohort	~~Zimura~~ACP 4 mg(N = 83)	Sham(N = 84)	Difference	% Difference	P-Value(Descriptive)
Mean Change in GA(b) (mm)	0.391	0.559	0.167	29.97%	0.0021

(a) Based on least squares means from MRM model, drawing on all available data at the month 18 time point, including data from groups with different randomization ratios in Part 1 and Part 2, and should not be interpreted as directly observed data.

(b) These least squares means are estimates of the MRM model, drawing on all available data, at the month 18 time point.

The graphs below illustrate the difference in mean rate of GA growth between each of the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg treatment groups and their corresponding sham control groups based on the MRM analysis at both 12 months and 18 months.

Primary Efficacy Endpoint Met at 12 Months			Decrease in GA Growth Over 18 Months
Zimura 2 mg vs Sham			Zimura 2 mg vs Sham
ACP 2 mg vs Sham			ACP 2 mg vs Sham
(Square Root Transformation)			(Square Root Transformation)

ITT Population; Based on the least squares means from MRM model drawing on all available data at the respective 12 month and 18 month analysis time points, including data from groups with different randomization ratios in Part 1 and Part 2, and should not be interpreted as directly observed data; Hochberg procedure used for significance testing for 12 month data.

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Primary Efficacy Endpoint Met at 12 Months			Decrease in GA Growth Over 18 Months
Zimura 4 mg vs Sham			Zimura 4 mg vs Sham
ACP 4 mg vs Sham			ACP 4 mg vs Sham
(Square Root Transformation)			(Square Root Transformation)

ITT Population; Based on the least squares means from the MRM model drawing on all available data at the respective 12 month and 18 month analysis time points; Hochberg procedure used for significance testing for 12 months data.

18-Month ~~Zimura~~ACP 2 mg GA Data by Part

Consistent with the analysis performed at 12 months, the analysis of the mean change in GA growth for ~~Zimura~~ACP 2 mg as compared to the corresponding sham control group over 18 months was adjusted for the fact that this dose of ~~Zimura~~ACP was tested in both Part 1 and Part 2 of the trial, each of which had different randomization ratios.

The least squares mean changes in GA in Part 1 and Part 2 at month 18 are shown separately in the following table:

Mean Rate of Change in GA Area from Baseline to Month 18

(MRM Analysis) (Square Root Transformation)

Cohort

~~Zimura~~ACP 2 mg(N = 25)

Sham(N = 26)

Difference

% Difference

Part 1

Mean Change in GA(a) (mm)

0.464

0.635

0.170

26.84%

(a)Based on the least squares mean from the MRM model.

Cohort

~~Zimura~~ACP 2 mg(N = 42)

Sham(N = 84)

Difference

% Difference

Part 2

Mean Change in GA(a) (mm)

0.440

0.608

0.168

27.67%

(a)Based on the least squares means from the MRM model.

When the data for the ~~Zimura~~ACP 2 mg groups from each Part of the trial as compared to the corresponding sham control groups are analyzed using the MRM model, which includes a regression factor by part, the mean difference in GA growth over 18 months between the ~~Zimura~~ACP 2 mg and sham control groups is 0.168 mm, representing a 28.11% relative benefit in the ~~Zimura~~ACP 2 mg group as compared to the corresponding sham control group.

Observed 18-Month GA Data (non-square root transformation)

In addition to analyzing the mean rate of change in GA area at month 18 using the square root transformation of the GA area (measured in millimeters (mm)), we also analyzed the mean rate of change in GA area using the observed GA area (without the square root transformation, measured in square millimeters (mm2)), with the MRM model. This descriptive

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analysis was also part of the prespecified statistical analysis plan for this trial. The observed mean GA area data for the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg groups as compared to the corresponding sham control groups are summarized in the following table:

Mean Rate of Change in GA Area from Baseline to Month 18

(MRM Analysis) (Observed)

Cohort

~~Zimura~~ACP 2 mg(N = 67)

Sham 2(N = 110)

Difference

% Difference

Mean Change in GA(a) (mm2)

2.431(b)

3.587(b)

1.156

32.24%

Cohort						~~Zimura~~ACP 4 mg(N = 83)						Sham(N = 84)						Difference						% Difference
Mean Change in GA(a) (mm2)						2.460						3.486						1.026						29.44%

(a)Based on the least squares mean from the MRM model.

18-Month Visual Acuity Data

In addition to analyzing mean change in GA area, we also performed pre-specified analyses of the mean change in BCVA from baseline to month 18 and the mean change in LL BCVA from baseline to month 18, both as measured by ETDRS letters. Testing for visual acuity serves as an important safety assessment to assure that the decrease in visual acuity in the ~~Zimura~~ACP treatment groups was not clinically different from the sham control groups.

The GATHER1 trial was not designed to reliably assess differences in mean changes in BCVA or LL BCVA with statistical significance. Data for the mean change in BCVA and LL BCVA at month 18 are summarized in the following tables:

Mean Change in BCVA from Baseline to Month 18

(MRM Analysis) (ETDRS letters)

Cohort

~~Zimura~~ACP 2 mg(N = 67)

Sham(N = 110)

Difference

Mean Change in BCVA(a)

-12.7(b)

-15.1(b)

2.37

Cohort

~~Zimura~~ACP 4 mg(N = 83)

Sham(N = 84)

Difference

Mean Change in BCVA(a)

-4.27

-7.07

2.80

(a) Based on the least squares mean from the MRM model.

(a)These least squares means are estimates from the MRM model, drawing on all available data, including data from groups with different randomization ratios in Part 1 and Part 2, and should not be interpreted as directly observed data.

Mean Change in LL BCVA from Baseline to Month 18

(MRM Analysis) (ETDRS letters)

Cohort

~~Zimura~~ACP 2 mg(N = 67)

Sham(N = 110)

Difference

Mean Change in LL BCVA(a)

-2.72(b)

-3.10(b)

0.37

Cohort

~~Zimura~~ACP 4 mg(N = 83)

Sham(N = 84)

Difference

Mean Change in LL BCVA(a)

2.85

1.68

1.17

(a) Based on the least squares mean from the MRM model.

(b) These least squares means are estimates from the MRM model, drawing on all available data, including data from groups with different randomization ratios in Part 1 and Part 2, and should not be interpreted as directly observed data.

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~~Zimura~~ACP 1 mg 18-Month Efficacy Data

We performed descriptive analyses on the 18 month data for patients in the ~~Zimura~~ACP 1 mg group as compared to the patients in the sham control group in Part 1 of the trial.

The mean rate of change in GA area for the ~~Zimura~~ACP 1 mg group and the corresponding sham group from Part 1 of the trial over 18 months is summarized in the following table:

Summary of GA Area (mm) and Mean Percentage Change from Baseline to Month 18

(Square Root Transformation)

Cohort	~~Zimura~~ACP 1 mg(N = 26)	Sham(N = 26)
Mean Sq. Root of GA at BL, mm	2.591	2.623
Mean Sq. Root of GA at M18, mm	3.258	3.230
Difference	0.667	0.607
Mean % Change(a)	21.91%	23.87%

BL = Baseline; M18 = Month 18

(a) Mean % change in GA area is an average of the percentage change in GA area observed for each patient.

Although the sample size for the ~~Zimura~~ACP 1 mg group is small, we believe the apparent reduction in mean percentage change in GA area from baseline to month 18 in the ~~Zimura~~ACP 1 mg group as compared to the sham control group, when compared with the results observed in the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg groups as compared to their corresponding sham control groups, may suggest a potential dose response relationship across treatment groups.

18-Month Safety Data

Based on our review of the safety data in the trial, ~~Zimura~~ACP was generally well tolerated after 18 months of administration. During the trial, there were no investigator-reported ~~Zimura~~ACP-related adverse events, no ~~Zimura~~ACP-related intraocular inflammation, no ~~Zimura~~ACP-related increased intraocular pressure, no cases of endophthalmitis, and no discontinuations attributed by investigators to ~~Zimura~~ACP in the trial. Through month 18, the reported incidence of CNV in the untreated fellow eye was 11 patients (3.8%), and in the study eye was 3 patients (2.7%) in the sham control group, 2 patients (7.7%) in the ~~Zimura~~ACP 1 mg group, 8 patients (11.9%) in the ~~Zimura~~ACP 2 mg group, and 13 patients (15.7%) in the ~~Zimura~~ACP 4 mg group. The most frequently reported ocular adverse events were related to the injection procedure. The numbers below are based on investigator-reported adverse events occurring during the 18-month duration of the trial for all patients.

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The number of patients with one or more serious TEAEs organized by MedDRA system organ class are set forth in the table below:

Patients with One or More Serious TEAEs in Any Organ Class

	Part 1			Part 2
	Zimura 1 mg(N = 26)	Zimura 2 mg(N = 25)	Sham(N = 26)	Zimura 2 mg(N = 42)	Zimura 4 mg(N = 83)	Sham 4 mg(N = 84)
	ACP 1 mg(N = 26)	ACP 2 mg(N = 25)	Sham(N = 26)	ACP 2 mg(N = 42)	ACP 4 mg(N = 83)	Sham 4 mg(N = 84)
Blood and lymphatic system disorders	0	0	0	0	1 (1.2%)	0
Cardiac disorders	1 (3.8%)	0	1 (3.8%)	1 (2.4%)	2 (2.4%)	3 (3.6%)
Eye disorders	0	0	0	1 (2.4%)	1 (1.2%)	0
Gastrointestinal disorders	1 (3.8%)	1 (4.0%)	2 (7.7%)	0	2 (2.4%)	6 (7.1%)
General disorders and administration site conditions	0	0	0	1 (2.4%)	0	0
Hepatobiliary disorders	0	1 (4.0%)	1 (3.8%)	0	1 (1.2%)	0
Infections and infestations	0	1 (4.0%)	0	2 (4.8%)	8 (9.6%)	2 (2.4%)
Injury, poisoning and procedural complications	0	1 (4.0%)	1 (3.8%)	1 (2.4%)	3 (3.6%)	2 (2.4%)
Metabolism and nutrition disorders	0	0	2 (7.7%)	0	0	0
Musculoskeletal and connective tissue disorders	1 (3.8%)	0	0	0	0	3 (3.6%)
Benign, malignant and unspecified neoplasms (including cysts and polyps)	0	0	1 (3.8%)	1 (2.4%)	1 (1.2%)	3 (3.6%)
Nervous system disorders	1 (3.8%)	1 (4.0%)	2 (7.7%)	2 (4.8%)	3 (3.6%)	2 (2.4%)
Psychiatric disorders	0	0	1 (3.8%)	0	0	1 (1.2%)
Respiratory, thoracic and mediastinal disorders	0	1 (4.0%)	0	0	2 (2.4%)	5 (6.0%)
Vascular disorders	0	0	0	0	0	1 (1.2%)

Of the reported serious TEAEs that were eye disorders, one TEAE was an ~~ischaemic~~ischemic optic neuropathy (in the ~~Zimura~~ACP 2 mg group) and one TEAE was a retinal detachment (in the ~~Zimura~~ACP 4 mg group). Neither of these TEAEs were reported as related to ~~Zimura~~ACP.

The number of patients with one or more TEAEs, including serious TEAEs, identified by the investigator as related to the study drug (~~Zimura~~ACP or sham) are set forth in the table below:

Reported TEAEs Related to ~~Zimura~~ACP or Sham

Part 1

Part 2

Zimura 1 mg(N = 26)

Zimura 2 mg(N = 25)

Sham(N = 26)

Zimura 2 mg(N = 42)

Zimura 4 mg(N = 83)

Sham 4 mg(N = 84)

ACP 1 mg(N = 26)

ACP 2 mg(N = 25)

Sham(N = 26)

ACP 2 mg(N = 42)

ACP 4 mg(N = 83)

Sham 4 mg(N = 84)

Subjects with at least one TEAE

The number of patients with one or more ocular TEAEs in the study eye are set forth in the table below:

Reported Ocular TEAEs in Study Eyes

	Part 1			Part 2
	Zimura 1 mg(N = 26)	Zimura 2 mg(N = 25)	Sham(N = 26)	Zimura 2 mg(N = 42)	Zimura 4 mg(N = 83)	Sham 4 mg(N = 84)
	ACP 1 mg(N = 26)	ACP 2 mg(N = 25)	Sham(N = 26)	ACP 2 mg(N = 42)	ACP 4 mg(N = 83)	Sham 4 mg(N = 84)
Eye disorders	12 (46.2%)	11 (44.0%)	6 (23.1%)	28 (66.7%)	61 (73.5%)	39 (46.4%)
Eye disorders related to injection procedure	4 (15.4%)	5 (20.0%)	2 (7.7%)	18 (42.9%)	46 (55.4%)	24 (28.6%)

The number of patients with one or more ocular TEAEs in the study eye, identified by the investigator as related to the study drug (~~Zimura~~ACP or sham) is set forth in the table below:

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Reported Ocular TEAEs in the Study Eye Related to ~~Zimura~~ACP or Sham

Part 1

Part 2

Zimura 1 mg(N = 26)

Zimura 2 mg(N = 25)

Sham(N = 26)

Zimura 2 mg(N = 42)

Zimura 4 mg(N = 83)

Sham 4 mg(N = 84)

ACP 1 mg(N = 26)

ACP 2 mg(N = 25)

Sham(N = 26)

ACP 2 mg(N = 42)

ACP 4 mg(N = 83)

Sham 4 mg(N = 84)

Subjects with at least one TEAE

In addition to us collecting investigator-reported adverse events, the independent masked reading center performed multi-modal imaging analysis. Multi-modal imaging analysis is a process used to assess patient retinal findings by reviewing different image types, in this case optical coherence tomography, or OCT, images and fluorescein angiography, to provide a more comprehensive view of the patient's retinal tissue. OCT is an ultra-high resolution imaging technology commonly used to visualize the retinal tissue. OCT is capable of rendering images in multiple dimensions and from multiple perspectives, and is an imaging technique commonly used by retinal specialists to diagnose, treat and follow patients with CNV. Fluorescein angiography is a technique that involves injection of a fluorescent dye into the systemic circulation and capturing images showing the circulating dye during transit through the retinal circulation using a specialized camera. In this trial, the reading center's multi-modal imaging analysis identified one additional case of macular CNV for a patient in the ~~Zimura~~ACP 4 mg group at month 12. Because this patient's investigator did not detect the CNV, the patient remained in the trial through month 18.

Post-hoc Analysis of GATHER1 Data inusing ~~connection~~the ~~with~~FDA ~~the~~Required ~~GATHER2~~Analysis ~~SPA~~of Primary Efficacy Endpoint

In parallel discussions with those for the GATHER2 SPA, the FDA indicated that, as part of a future NDA for ~~Zimura~~ACP, the results from GATHER1 will be considered using the original prespecified primary efficacy endpoint analysis, as described above, together with a post-hoc analysis using the same FDA-preferred method that will be used for the GATHER2 trial (mean rate of growth (slope) estimated based on GA area measured by FAF in the relevant timepoints). The 12 month and 18 month results of this post-hoc analysis, as compared to the results of the original prespecified analysis for GATHER1, for the ~~Zimura~~ACP 2 mg and ~~Zimura~~ACP 4 mg treatment arms as compared to their corresponding sham arms, are described below. Safety results from GATHER1 were not impacted as part of this analysis.

~~Although~~ACP we2 ~~believe~~mg that the results of the post-hoc analysis from the GATHER1 trial are consistent with the positive results from the original prespecified analysis from the trial, any analyses, whether prespecified or post-hoc, that are intended toData

support an application for marketing approval are a matter of review for the FDA and other regulatory authorities.


MRM Analysis	ACP 2 mg (N = 67)	Sham (N = 110)	Difference	% Difference	P-Value
12 Month Sq. Rt. Transformation:
Mean Rate of Change in GA Area (mm)	0.292	0.402	0.110	27.38%	0.0072(a)
Mean Rate of GA Growth (Slope) (mm)	0.283	0.392	0.109	27.73%	0.0063(b)
12 Month Observed Data:
Mean Rate of Change in GA Area (mm2)	1.592	2.29	0.697	30.45%	0.0059(b)
Mean Rate of GA Growth (Slope) (mm2)	1.221	1.889	0.668	35.37%	0.0050(b)
18 Month Sq. Rt. Transformation:
Mean Rate of Change in GA Area (mm)	0.430	0.599	0.168	28.11%	0.0014(b)
Mean Rate of GA Growth (Slope) (mm)	0.451	0.607	0.156	25.75%	0.0027(b)
18 Month Observed Data:
Mean Rate of Change in GA Area (mm2)	2.431	3.587	1.156	32.24%	0.0009(b)
Mean Rate of GA Growth (Slope) (mm2)	1.914	2.951	1.037	35.13%	0.0023(b)

Zimura 2 mg Data

MRM Analysis	Zimura 2 mg(N = 67)	Sham(N = 110)	Difference	% Difference	P-Value
12 Month Sq. Rt. Transformation:
Mean Rate of Change in GA Area (mm)	0.292	0.402	0.110	27.38%	0.0072(a)
Mean Rate of GA Growth (Slope) (mm)	0.283	0.392	0.109	27.73%	0.0063(b)
12 Month Observed Data:
Mean Rate of Change in GA Area (mm2)	1.592	2.29	0.697	30.45%	0.0059(b)
Mean Rate of GA Growth (Slope) (mm2)	1.221	1.889	0.668	35.37%	0.0050(b)
18 Month Sq. Rt. Transformation:
Mean Rate of Change in GA Area (mm)	0.430	0.599	0.168	28.11%	0.0014(b)
Mean Rate of GA Growth (Slope) (mm)	0.451	0.607	0.156	25.75%	0.0027(b)
18 Month Observed Data:
Mean Rate of Change in GA Area (mm2)	2.431	3.587	1.156	32.24%	0.0009(b)
Mean Rate of GA Growth (Slope) (mm2)	1.914	2.951	1.037	35.13%	0.0023(b)

Explanatory notes:

•the estimates for the ~~Zimura~~ACP 2 mg group vs. sham are from the MRM model, drawing on all available data, including data from groups with different randomization ratios in Part 1 and Part 2 of the trial, and should not be interpreted as directly observed data;

(a) indicates prespecified primary endpoint; statistically significant;

(b) indicates descriptive p-value.

~~Zimura~~ACP 4 mg Data

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MRM Analysis	~~Zimura~~ACP 4 mg(N = 83)	Sham(N = 84)	Difference	% Difference	P-Value
12 Month Sq. Rt. Transformation:
Mean Rate of Change in GA Area (mm)	0.321	0.444	0.124	27.81%	0.0051(a)
Mean Rate of GA Growth (Slope) (mm)	0.307	0.416	0.109	26.31%	0.0100(b)
12 Month Observed Data:
Mean Rate of Change in GA Area (mm2)	2.061	2.770	0.709	25.59%	0.0082(b)
Mean Rate of GA Growth (Slope) (mm2)	1.674	2.273	0.599	26.34%	0.0147(b)
18 Month Sq. Rt. Transformation:
Mean Rate of Change in GA Area (mm)	0.391	0.559	0.167	29.97%	0.0021(b)
Mean Rate of GA Growth (Slope) (mm)	0.373	0.512	0.139	27.11%	0.0086(b)
18 Month Observed Data:
Mean Rate of Change in GA Area (mm2)	2.460	3.486	1.026	29.44%	0.0034(b)
Mean Rate of GA Growth (Slope) (mm2)	2.142	3.010	0.868	28.82%	0.0106(b)

Explanatory notes:

(a) indicates prespecified primary endpoint; statistically significant;

(b) indicates descriptive p-value.

~~Zimura~~ACP 2 mg Data by Part

As previously discussed, we enrolled patients for the GATHER1 trial in two different parts, Part 1 and Part 2, with different dosages and randomization ratios in each Part. Twenty-five patients receiving ~~Zimura~~ACP 2mg were enrolled in Part 1 of the trial and 42 patients receiving ~~Zimura~~ACP 2mg were enrolled in Part 2 of the trial.

Below are the month 12 and month 18 results for the ~~Zimura~~ACP 2 mg group as compared to its corresponding sham group, for both Part 1 and Part 2 of the trial, using both the original prespecified primary efficacy endpoint analysis for the GATHER1 trial and the post-hoc analysis using the FDA-preferred method that ~~will~~is be used for the GATHER2 trial:

Part 1 Only Data

MRM Analysis	~~Zimura~~ACP 2 mg(N = 25)	Sham(N = 26)	Difference	% Difference
12 Month Sq. Rt. Transformation:
Mean Rate of Change in GA Area (mm)	0.329	0.422	0.093	22.07%
Mean Rate of GA Growth (Slope) (mm)	0.307	0.423	0.116	27.39%
12 Month Observed Data:
Mean Rate of Change in GA Area (mm2)	1.910	2.593	0.683	26.35%
Mean Rate of GA Growth (Slope) (mm2)	1.655	2.238	0.584	26.08%
18 Month Sq. Rt. Transformation:
Mean Rate of Change in GA Area (mm)	0.464	0.635	0.170	26.84%
Mean Rate of GA Growth (Slope) (mm)	0.446	0.630	0.184	29.23%
18 Month Observed Data:
Mean Rate of Change in GA Area (mm2)	2.789	4.103	1.314	32.03%
Mean Rate of GA Growth (Slope) (mm2)	2.482	3.393	0.911	26.85%

Part 2 Only Data

MRM Analysis

~~Zimura~~ACP 2 mg(N = 42)

Sham(N = 84)

Difference

% Difference

12 Month Sq. Rt. Transformation:

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Mean Rate of Change in GA Area (mm)	0.308	0.422	0.114	27.02%
Mean Rate of GA Growth (Slope) (mm)	0.303	0.424	0.121	28.51%
12 Month Observed Data:
Mean Rate of Change in GA Area (mm2)	1.743	2.434	0.690	28.36%
Mean Rate of GA Growth (Slope) (mm2)	1.419	2.154	0.735	34.14%
18 Month Sq. Rt. Transformation:
Mean Rate of Change in GA Area (mm)	0.440	0.608	0.168	27.67%
Mean Rate of GA Growth (Slope) (mm)	0.474	0.622	0.148	23.85%
18 Month Observed Data:
Mean Rate of Change in GA Area (mm2)	2.550	3.649	1.099	30.12%
Mean Rate of GA Growth (Slope) (mm2)	2.203	3.264	1.061	32.51%

~~Post-Hoc~~GATHER2: ~~Analysis~~Ongoing Phase 3 Clinical Trial Assessing Safety and Efficacy of ~~GATHER1~~ACP ~~data~~2 -mg ~~Foveal~~for ~~Preservation~~GA Secondary to AMD

In ~~February~~September 2022, we announced ~~the~~positive ~~results from a post~~12-~~hoc~~month ~~analysis~~data ~~that evaluated various GA growth parameters to explore the rate of disease progression within various regions in the fovea in a subset of patients~~ from the ~~GATHER1~~GATHER2 trial. The post-hoc analysis evaluated GA growth in five standardized regions in the retina for patients for whom images were available at relevant time points, which consisted of 47 patients from the Zimura 2 mg group and 79 patients from the corresponding sham control group. The five regions included the central foveal region, consisting of a 2 mm diameter circle around the foveal center point, and four quadrants, temporal, nasal, superior and inferior, in a concentric 8 mm diameter circle around the foveal center point. The accompanying schematic illustrates the five standardized regions:

We observed a reduction in lesion growth in the five standardized regions surrounding and including the central foveal area for patients receiving Zimura 2 mg as compared to patients receiving sham over a period of 18 months. We believe the results of this subgroup analysis are consistent with the primary analysis results in the ITT population in the GATHER1 trial. The accompanying graphs illustrate the results:

Decrease in GA growth observed in patients receiving Zimura 2 mg versus patients receiving sham injections in five standardized regions and in line with circumferential progression found in natural history, square-root transformed (mm)

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OPH2001: Completed Phase 1/2a Clinical Trial of Zimura for GA Secondary to Dry AMD

In 2011, we completed a multicenter, uncontrolled, open label Phase 1/2a clinical trial to evaluate the safety and tolerability of Zimura administered as a monotherapy in patients with GA. We enrolled 47 patients in this trial. We randomly assigned patients in this trial to one of two dose groups. Patients received a total of five intravitreal injections of either 0.3 mg or 1 mg of Zimura over a 36-week treatment period. Patients received an intravitreal injection of Zimura at day 0, week 4, week 8, week 24 and week 36 of the trial, with a final follow-up visit at week 48.

Zimura was generally well-tolerated in this trial. We did not observe any evidence of drug related adverse events. We also did not observe any incidence of conversion to wet AMD in eyes treated with Zimura. Adverse events were primarily ocular adverse events in the study eye which were related to the injection procedure.

In addition, we performed assessments of visual acuity to detect any potential decrease in vision associated with intravitreal injections, the administered drug or natural progression of the disease if left untreated. We did not identify any drug related safety issues through measurements of visual acuity.

Our Phase 1/2a clinical trial was an uncontrolled study with a small sample size and was not powered to detect a difference between Zimura dose groups, or the efficacy of Zimura monotherapy, with statistical significance. The primary purpose of the study was to assess safety and tolerability. However, during the more frequent dosing period, which is the first 24 weeks, we observed a trend, in favor of the higher of two dose groups, of a relative reduction in the mean growth of the GA lesion area, as measured by fundus autofluorescence images read by an independent reading center.

The mean growth from baseline in the GA lesion area during the first 24 weeks of the trial, when the injections were administered more regularly, was 1.00 mm2 for the 24 patients receiving the 0.3 mg dose and 0.78 mm2 for the 23 patients receiving the 1 mg dose. When the injections were administered on a reduced dosing schedule during the subsequent 24 weeks,

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this relative trend in reduced growth in GA lesion area was no longer present.

The following graph sets forth the mean change in GA lesion area from baseline for the two treatment groups over the course of the trial.

We believe this apparent trend in the relative reduction of mean growth in GA lesion area when Zimura was dosed more frequently, together with the relative loss of the benefit when Zimura was dosed less frequently, may suggest a possible drug effect.

GATHER2: Ongoing Phase 3 Clinical Trial Assessing Safety and Efficacy of Zimura 2 mg for GA Secondary to AMD

Trial Design

In this trial, we enrolled 448 patients, who were randomized into two groups: a first group receiving monthly administrations of ~~Zimura~~ACP 2 mg for 12 months, and a second group receiving monthly administrations of sham. In accordance with our SPA with the FDA, the prespecified primary efficacy endpoint will be the mean rate of growth (slope) estimated based on GA area measured by FAF in at least three timepoints: baseline, month 6 and month 12. At month 12, we ~~are~~ re-~~randomizing~~randomized patients in the ~~Zimura~~ACP 2 mg arm to receive either monthly or every other month administrations of ~~Zimura~~ACP 2 mg, and patients receiving monthly administrations of sham ~~will~~ continue to receive monthly administrations of sham. We plan to treat and follow patients for 24 months in total.

The key ophthalmic inclusion criteria for GATHER2 include the following:

•non-foveal GA secondary to dry AMD;

•total GA area between 2.5 mm2 and 17.5 mm2, inclusive;

•if GA is multifocal, at least one focal lesion should measure 1.25 mm2 or greater;

•GA in part within 1500 microns from the foveal center; and

•Snellen equivalent BVCA in the study eye between 20/25 and 20/320, inclusive.

As discussed above, when we initiated the GATHER1 trial, we did not believe that reliable measurements of GA by FAF images for patients with CNV in the study eye could be performed. Therefore, in the clinical trial protocol for the GATHER1 trial, we indicated that patients in any arm of the trial who developed CNV in the study eye, as observed by the investigator, would be removed from the trial and any future study treatments and assessments. Based on third-party clinical data published since the GATHER1 trial commenced and discussions with our independent reading center, we believe that GA for patients developing CNV in the study eye who receive standard of care anti-VEGF treatment for the CNV, could potentially be assessed by FAF. Based on the foregoing, the protocol for GATHER2 provides that patients ~~will~~ undergo monthly OCT imaging, and if an investigator suspects that a patient has CNV or if a patient experiences a decrease in visual acuity, as measured by a loss of more than five ETDRS letters between a visit and the immediately prior visit, the independent masked reading center will confirm whether the patient has CNV using multi-modal imaging. In the event a CNV case is confirmed, the investigator will treat the CNV with one of two anti-VEGF agents, Lucentis or Eylea® (aflibercept), in accordance with the label for that anti-VEGF agent. These patients will remain in the trial and measurements of these patients' GA are included in the primary efficacy analysis if their FAF images can be assessed by the masked reading center.

We initiated an open-label extension study for patients who completed the GATHER2 trial; information about this study is described further below.

Baseline Characteristics

We collected baseline characteristics for all patients participating in the GATHER2 trial, which are presented below for each treatment group. These baseline characteristics include the intent-to-treat, or ITT, population, which includes all

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patients who were randomized in the trial and who received at least one dose of study drug in the relevant treatment group. For patients within each treatment group, where a numerical measurement was collected, we calculated the mean and standard deviation, or SD, for each measurement. SD is a statistical measure of the variability of a particular measurement within a patient population. Generally, two-thirds of all patients fall within approximately one SD, plus or minus, of the mean for any particular measurement. Based on these data, we believe that the baseline characteristics were balanced across the treatment groups.


	Treatment Group
Baseline Characteristic	ACP 2 mg (N = 225)	Sham (N = 222)
Mean age, years (SD)	76.3 (8.6)	76.7 (8.8)
Female gender, number (%)	154 (68.4%)	156 (70.3%)
Active smokers, number (%)	106 (47.1%)	107 (48.2%)
Caucasian race, number (%)	182 (80.9%)	186 (83.8%)
Iris color, number (%):
Light	93 (41.3%)	109 (49.1%)
Medium	96 (42.7%)	79 (35.6%)
Dark	36 (16.0%)	34 (15.3%)
Mean intraocular pressure, mmHg (SD)	15.2 (2.5)	14.9 (2.6)
Non-subfoveal GA, number (%)	225 (100%)	222 (100%)
Multifocal GA, number (%)	178 (79.1%)	178 (80.2%)
GA size of greater than or equal to 4 disc areas, number (%)	54 (24.0%)	64 (28.8%)
Mean GA area, mm2 (SD)	7.48 (4.01)	7.81 (3.89)
Mean Sq. Root of GA area, mm (SD)	2.641 (0.714)	2.707 (0.696)
Bilateral GA, number (%)	212 (94.0%)	210 (95.0%)
Mean BCVA, ETDRS letters (SD)	70.9 (8.9)	71.6 (9.4)
Mean LL BCVA, ETDRS letters (SD)	41.0 (19.7)	39.6 (19.6)
Patients with Hyperautofluorescence - Banded/Diffuse, number (%)	217 (96.4%)	218 (98.2%)
Height, cm (SD)	164.6 (10.6)	164.0 (9.4)
Weight, kg (SD)	75.9 (18.3)	75.0 (15.8)

12-Month Safety Data

In GATHER2, there were no events of endophthalmitis, no intraocular inflammation events, no events of vasculitis and no ischemic optic neuropathy events through month 12. The most frequently reported ocular adverse events were related to the injection procedure, including transient intraocular pressure.

The incidence of CNV in the study eye through month 12 was 15 patients (6.7%) in the ACP 2 mg group and 9 patients (4.1%) in the sham control group. An independent masked reading center assessed the macular CNV, or MNV, cases in GATHER2 at the 12-month timepoint for exudative macular neovascularization, or eMNV, and non-exudative macular neovascularization, or neMNV (versus peripapillary neovascularization, where the neovascularization is located around the optic nerve and not encroaching on the macula). As previously disclosed, the reading center classifies cases of MNV as exudative or non-exudative based on the following OCT criteria:

•Exudative MNV, or eMNV, is MNV that presents with new onset fluid in either the subretinal space or the intraretinal space. The subretinal space is the area on OCT between the RPE and photoreceptor cells. The intraretinal space is the area on OCT containing the photoreceptors and other neurosensory cells of the retina.

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•Non-exudative MNV, or neMNV, is neovascularization located in the macula but which does not present with new onset fluid in the subretinal or intraretinal spaces. In some cases, isolated fluid may be present in the sub-RPE space, which is the area between the RPE and Bruch's membrane, a layer of tissue directly beneath the RPE separating the RPE from the choroid. A case is also considered to be neMNV when the MNV may not be visible but both a double-layer sign and sub-RPE fluid are present. A double-layer sign is characterized by a shallow elevation of the RPE typically caused by the accumulation of fluid or debris in the sub-RPE space.

The following tables provide further detail on these adverse events of interest in GATHER2:

Reported Adverse Events of Interest


	Endophthalmitis	Intraocular Inflammation	Ischemic Optic Neuropathy
ACP 2mg (N=225)	0	0	0
Sham (N=222)	0	0	0

Reported Choroidal Neovascularization Cases


	eMNV (%)	neMNV (%)	Peripapillary CNV (%)	Total CNV (%)
ACP 2mg (N=225)	11 (4.9%)	1 (0.5%)	3 (1.3%)	15 (6.7%)
Sham (N=222)	7 (3.2%)	0	2 (0.9%)	9 (4.1%)

The number of patients having treatment emergent adverse events, or TEAEs, organized by MedDRA system organ class, a standard method of reporting adverse events, for which there are two percent or greater of such TEAE among the patients in any treatment group, are set forth in the table below:

Patients with TEAEs in any Organ Class for which TEAE Comprises 2% or Greater of Patients in any Treatment Group


	Treatment Group
Organ Class	ACP 2 mg (N = 225)	Sham (N = 222)
Blood and lymphatic system disorders	4 (1.8%)	5 (2.3%)
Cardiac disorders	22 (9.8%)	16 (7.2%)
Ear and labyrinth disorders	1 (0.4%)	5 (2.3%)
Eye disorders	110 (48.9%)	84 (37.8%)
Gastrointestinal disorders	16 (7.1%)	13 (5.9%)
General disorders and administration site conditions	7 (3.1%)	10 (4.5%)
Infections and infestations	59 (26.2%)	58 (26.1%)
Injury, poisoning and procedural complications	36 (16.0%)	32 (14.4%)
Investigations	31 (13.8%)	10 (4.5%)
Metabolism and nutrition disorders	9 (4.0%)	8 (3.6%)
Musculoskeletal and connective tissue disorders	22 (9.8%)	24 (10.8%)
Benign, malignant and unspecified neoplasms (including cysts and polyps)	9 (4.0%)	16 (7.2%)
Nervous system disorders	14 (6.2%)	28 (12.6%)
Psychiatric disorders	6 (2.7%)	4 (1.8%)
Renal and urinary disorders	10 (4.4%)	5 (2.3%)
Respiratory, thoracic and mediastinal disorders	10 (4.4%)	8 (3.6%)
Skin and subcutaneous tissue disorders	8 (3.6%)	10 (4.5%)
Vascular disorders	14 (6.2%)	13 (5.9%)

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The number of patients having ocular TEAEs in the study eye for which there are two percent or greater of such TEAE among the patients in any treatment group, are set forth in the table below:

Ocular TEAEs in any Organ Class in Study Eyes for which TEAE Comprises 2% or Greater of Patients in any Treatment Group


	Treatment Group
Organ Class	ACP 2 mg (N = 225)	Sham (N = 222)
Eye disorders	104 (46.2%)	80 (36.0%)
Infections and infestations	3 (1.3%)	5 (2.3%)
Injury, poisoning and procedural complications	5 (2.2%)	1 (0.5%)
Investigations	21 (9.3%)	2 (0.9%)

Among the eye disorder ocular TEAEs, two of the TEAEs were reported as serious in the ACP 2 mg group, as compared to three TEAEs in the sham group. In the ACP 2 mg group, both serious TEAEs were cases of CNV. In the sham group, one serious TEAE was a CNV case, one was a case of visual acuity reduced and one was a case of visual acuity reduced transiently.

Among the ocular cases of injury, poisoning and procedural complications, all were procedural complications of intravitreal injection or sham administration. None of these cases were serious.

All 23 ocular investigation cases were cases of increased intraocular pressure, or IOP. None of these cases were serious. Of the 21 cases in the ACP 2 mg group, 20 of them were transient in nature; of the 20 transient cases, 19 of them resolved the same day. The single non-transient case in the ACP 2 mg group was for a patient with glaucoma at baseline. The increased incidence of increased IOP is expected for an intravitreal injection as compared to a sham procedure. Patients in the sham group had a barrel of a syringe placed against the eye to simulate the pressure of an injection but no needle penetrates the eye.

12-Month Efficacy Data

The primary efficacy endpoint, in accordance with our SPA with the FDA, is the mean rate of growth (slope) estimated based on GA area, as measured by FAF based on readings at three timepoints: baseline, month 6 and month 12. The FAF images were assessed by an independent masked reading center. We performed the pre-specified primary analysis of the endpoint by using the square root transformation of the GA area and we performed the pre-specified supportive analysis of the endpoint by using the observed GA area (without square root transformation). Detailed data for the primary efficacy endpoint with both the primary analysis and supportive analysis are shown in the accompanying table:

Mean Rate of Growth (Slope) in GA Area from Baseline to Month 12


MMRM Analysis (mixed model of repeated measures)	ACP 2 mg (N = 225)	Sham (N = 222)	Difference	% Difference	P-Value
Mean Rate of GA Growth (Slope) (mm) (Square Root Transformation)	0.336	0.392	0.056	14.3%	0.0064(a)
Mean Rate of GA Growth (Slope) (mm2) (Observed)	1.745	2.121	0.376	17.7%	0.0039(b)

Explanatory notes - in the above presentation:

(a) Indicates pre-specified primary endpoint analysis; statistically significant;

(b) Indicates descriptive p-value.

We also analyzed the mean change in GA area from baseline to month 12 in GATHER2 using a point analysis, which was the pre-specified primary efficacy endpoint analysis in GATHER1. This analysis was performed based on FAF readings at

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~~measured~~the bysame athree ~~loss~~time ofpoints ~~more~~(baseline, ~~than~~month ~~five~~6, ~~ETDRS letters between a visit~~ and ~~the~~month ~~immediately~~12) ~~prior~~as ~~visit,~~ the ~~independent~~slope ~~masked reading center will confirm whether the patient has CNV using multi-modal imaging~~analyses. InThe ~~the~~results ~~event~~for ~~a CNV case is confirmed,~~ the ~~investigator will treat the CNV with one of two anti~~12-~~VEGF~~month ~~agents,~~point ~~Lucentis~~analysis orwere ~~Eylea®~~consistent ~~(aflibercept), in accordance~~ with the ~~label~~slope ~~for~~analyses ~~that anti-VEGF agent. These patients will remain in the trial~~ and ~~measurements~~are ofdescribed ~~these patients' GA will be included in the primary efficacy analysis if their FAF images can be assessed by the masked reading center~~below.

~~Trial~~The ~~Conduct~~following tables show the GATHER2 efficacy results for both (A) the mean rate of change in GA area from baseline to month 12 using a point analysis and (B) the mean rate of growth (slope) in GA area over 12 months. These results are provided using both the square root transformation and the observed GA areas.

In July 2021, we completed patient enrollment for GATHER2, four months ahead of our original schedule. In response to the COVID-19 pandemic, we and our clinical trial sites implemented a number of initiatives to protect the safety and well-being of our patients and to ensure they are able to attend their scheduled study visits. We continue to closely monitor the COVID-19 pandemic and the impact it may have on this trial.


MMRM Analysis	ACP 2 mg (N = 225)	Sham (N = 222)	Difference	% Difference	P-Value
Sq. Rt. Transformation
Mean Change in GA Area (mm)	0.333	0.392	0.059	15.0%	0.0056(b)
Mean Rate of GA Growth (Slope) (mm)	0.336	0.392	0.056	14.3%	0.0064(a)
Observed Area
Mean Change in GA Area (mm2)	1.936	2.341	0.405	17.3%	0.0027(b)
Mean Rate of GA Growth (Slope) (mm2)	1.745	2.121	0.376	17.7%	0.0039(a)

InExplanatory ~~particular,~~notes we continue to monitor patient retention in this trial. We are targeting and remain on track for an injection fidelity rate at month 12 of greater than 90%. The injection fidelity rate for GATHER1 at 12 months was 87%. We believe injection fidelity, which is calculated by dividing the total number of actual injections for all patients by the total number of expected injections based on the total number of patients enrolled in the trial, to be an accurate and meaningful measure of patient retention. In addition, more than 84% of the scheduled first-~~year~~ ~~visits~~ in the ~~GATHER2~~above ~~trial, which consists of all study visits up to and including the timepoint for assessing the primary efficacy endpoint, have been completed or elapsed.~~presentation:

We(a) Indicates ~~expect top~~pre-~~line~~specified ~~data~~primary ~~from~~endpoint ~~this trial to be available during the second half of 2022, approximately one year following the enrollment of the last patient plus the time needed for database lock and~~ analysis.; Westatistically ~~are actively working with our third-party imaging and other vendors to review and prepare the GATHER2 data for database lock.~~significant;

~~Requirements~~(b) Indicates ~~for~~descriptive ~~Marketing Approval of Zimura in GA~~p-value.

ToAs ~~obtain~~part ~~marketing~~of ~~approval for Zimura for~~ the ~~treatment of GA, we expect that we will need to obtain favorable results from a total of two independent, adequate and well~~pre-~~controlled~~specified ~~pivotal~~statistical ~~clinical~~analysis ~~trials,~~plan ~~demonstrating~~for ~~the safety and efficacy of Zimura in this indication. To establish efficacy~~GATHER2, we ~~believe~~also itanalyzed ~~would be sufficient to demonstrate statistically significant results showing a clinically relevant reduction in~~ the mean rate of growth ~~of GA over 12 months, based on measurements over three time points~~ (~~baseline, month 6 and month 12~~slope) in ~~two~~GA ~~independent~~area ~~trials.~~for WeACP ~~selected~~2 ~~this~~mg ~~measure~~ as ~~the~~compared ~~primary~~to ~~endpoint~~sham for ~~the~~pre-specified ~~GATHER1~~patient ~~trial~~subgroups based on ~~prior~~baseline ~~interactions~~lesion ~~with the FDA~~size, asbaseline ~~well~~visual ~~as our understanding of clinical trials for other investigational products in development for the treatment of GA. We designed the GATHER1 trial as a well-controlled screening trial such that~~acuity, inbaseline ~~the~~autofluorescence ~~event that the prespecified primary efficacy endpoint results were statistically significant~~pattern, ~~the trial could potentially serve as one of the two pivotal clinical trials typically required for marketing approval. Based on the results we have received~~age, ~~the statistical analysis that we have performed~~ and additional discussions we have had with the FDA, we believe that the safety and efficacy results from the GATHER1 trial would satisfy the FDA’s requirements as one of the two pivotal clinical trials typically required for marketing approvalgender. ACP In2 ~~the~~mg ~~paragraphs~~showed ~~that~~a ~~follow,~~reduction ~~we describe~~ in ~~detail~~ the ~~basis~~mean ~~for~~rate ~~our belief about the sufficiency~~ of ~~the~~growth ~~GATHER1~~(slope) ~~trial~~in ~~and,~~GA ifarea ~~the data from this trial are positive, the GATHER2 trial, to support an application~~ for ~~marketing~~all ~~approval~~analyzed ~~for GA~~subgroups.

~~Requirements~~The pre-specified supportive endpoints in GATHER2 included the mean change in best corrected visual acuity, or BCVA, and the mean change in low luminance best corrected visual acuity, or LL BCVA, from baseline to month 12. For BCVA, a favorable trend for ~~Safety~~ACP ~~Data~~2 mg was observed, which is consistent with GATHER1. For LL BCVA, a favorable trend was not observed.

~~Zimura~~Trial ~~has~~Conduct generally been well tolerated in our clinical trials to date. In the GATHER1 trial, there were no investigator reported ocular serious adverse events, Zimura-related adverse events, cases of Zimura-related intraocular inflammation, cases of Zimura-related increased intraocular pressure, cases of endophthalmitis, or discontinuations attributed by investigators to Zimura. We believe the investigator reported CNV rate in the study eye for patients receiving Zimura as compared to sham and ~~the~~Patient untreated fellow eyes during the trial is within an acceptable range when compared to published clinical trial data for another complement inhibitor currently in development for GA. The most frequently reported ocular adverse events in the GATHER1 trial were related to the injection procedure. Retention

ToWe ~~demonstrate~~achieved ~~the safety of Zimura to~~ a ~~degree~~12-month ~~sufficient~~injection tofidelity ~~support~~rate ~~marketing~~for ~~approval,~~GATHER2 ~~we believe that the FDA and potentially other regulatory authorities would require data from a minimum~~ of ~~300~~92.5%. ~~patients~~The ~~having~~12-month ~~received~~injection ~~the~~fidelity ~~dose~~rate ~~of Zimura~~ for ~~which~~GATHER1 wewas ~~are~~87%. ~~seeking~~The ~~approval,~~injection orfidelity arate ~~higher~~is ~~Zimura~~calculated ~~dose,~~by ~~independent~~dividing ofthe ~~indication,~~total ~~for~~number ~~a minimum~~ of 12actual ~~months,~~injections ~~with 24-month safety data available~~ for ~~some portion, but not~~ all, ~~of these 300~~ patients. ~~Based~~by on the ~~safety~~total ~~profile~~number of ~~Zimura~~expected ~~observed~~injections tobased ~~date~~on ~~and~~ the total number of patients ~~treated~~enrolled ~~across~~in ~~our~~the ~~Zimura~~trial. ~~clinical~~We ~~trials, we~~ believe ~~that~~injection ~~the~~fidelity ~~remaining~~to ~~minimum~~be ~~safety~~the ~~requirements~~most ~~could~~important ~~potentially~~and bestringent ~~satisfied~~measure byof ~~the~~patient ~~GATHER2~~retention ~~trial,~~because init ~~which~~reflects wethe ~~plan~~timely toadministration ~~treat~~of ~~and~~the ~~follow~~study ~~patients~~drug ~~for~~into 24the ~~months~~patient’s eye.

The number of patients who withdrew or otherwise discontinued from the GATHER2 trial during the first 12 months was 25 (11.1%) in the ACP 2 mg group and 17 (7.7%) in the sham control group. We continue to focus on patient retention and closely monitor the COVID-19 pandemic and its effect on the trial. We remain masked as to the treatment of the patients in the trial.

Post-Hoc Time-to-Event Analysis from GATHER1 and GATHER2

We conducted an exploratory time-to-event analysis from the GATHER1 and GATHER2 clinical trials evaluating reduction in vision loss with ACP 2 mg versus sham treatment. The post-hoc analysis for vision loss from these pivotal trials signals up to a 59% reduction in rate of vision loss with ACP 2 mg compared to sham treatment at 12 months. Vision loss in this analysis was defined as a loss of ≥15 letters (EDTRS) in BCVA from baseline measured at any two consecutive visits up to month 12. This analysis will be presented at the upcoming Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting from April 23-27, 2023.

The results were consistent in the GATHER1 and GATHER2 clinical trials independently, signaling a 44% reduction (Hazard Ratio 0.56 with 95% CI, 0.15-2.06) and a 59% percent reduction (Hazard Ratio 0.41 with 95% CI, 0.17-1.00) respectively in the rate of vision loss with ACP 2 mg compared to sham over the first 12 months of treatment. In a combined analysis of GATHER1 and GATHER2 shown in the accompanying graph, patients treated with ACP 2 mg experienced a 56% reduction (Hazard Ratio 0.44, with 95% CI, 0.21-0.92) in the rate of vision loss compared to sham over the first 12 months of treatment. This post hoc analysis evaluates the potential vision loss signal through 12 months of treatment and is exploratory in nature.

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~~Requirements~~ISEE2009: Open Label Extension Study for ~~Efficacy~~Patients ~~Data~~Who Completed the GATHER2 Trial

~~Statistical Significance.~~ In ~~our~~September ~~GATHER1 trial~~2022, ~~the~~we ~~reduction~~iniated inan ~~the~~open-label ~~mean~~extension ~~rate~~study, ofor ~~GA growth over 12 months using~~ the ~~square~~OLE ~~root~~study, ~~transformation~~which ~~was~~is ~~0.110~~an mminternational, (pmulti-~~value~~center =clinical ~~0.0072)~~trial ~~for~~assessing the ~~Zimura~~safety 2of mgintravitreal ~~group~~administration asof ~~compared~~ACP toin ~~the~~patients ~~corresponding~~who ~~sham~~completed ~~control~~their ~~group~~month ~~and~~24 ~~0.124~~visits mmin ~~(p-value~~the =GATHER2 0trial.~~0051)~~ ~~for~~All ~~the~~patients ~~Zimura~~participating 4in ~~mg group as compared to~~ the ~~corresponding~~OLE ~~sham~~study ~~control~~will ~~group,~~receive ~~corresponding~~monthly todoses anof ~~approximate~~ACP ~~27%~~2 ~~relative~~mg, ~~reduction~~regardless inof the ~~mean~~treatment ~~rate~~arm of(ACP GAor ~~growth~~sham ~~over~~procedure) 12that ~~months~~they ~~when~~were ~~compared~~randomized ~~with~~to ~~sham.~~in ~~These~~the ~~data~~GATHER2 ~~for~~trial. ~~both~~The ~~dose~~trial ~~groups~~will ~~were~~continue ~~statistically~~until ~~significant. See~~each ~~above~~patient ~~under~~has ~~“Primary~~completed ~~Efficacy~~their ~~Endpoint~~month ~~Data”~~18 ~~for~~study avisit ~~discussion~~or ofuntil ~~the~~ACP ~~procedures~~is wecommercially ~~used~~available toin ~~confirm~~ the ~~statistical~~relevant ~~significance of these data~~jurisdiction.

InOPH2001: Completed ~~clinical~~Phase 1/2a ~~trials,~~Clinical itTrial ~~is common for data for some number~~ of ~~subjects~~ACP ~~to be missing~~ for assessments performed throughout the trial. The degree of data that is missing from a clinical data set can impact the results and conclusions, including their statistical significance. See above under “Statistical Analysis for Efficacy Measures” for information regarding the GA ~~measurement~~Secondary ~~data~~to ~~that~~Dry was missing from the analysis of the primary efficacy endpoint in the GATHER1 trial, as well as a description of the sensitivity analyses we performed. Based on our sensitivity analyses, and accounting for the data missing from our data set because of patient withdrawals or for other reasons, we believe the statistical analysis for the 12 month data from the GATHER1 trial is valid. AMD

~~Although~~In 2011, we ~~seek~~completed toa ~~apply~~multicenter, ~~our enrollment criteria consistently~~uncontrolled, ~~there~~open ~~may~~label bePhase 1/2a ~~instances~~clinical ~~when~~trial anto ~~investigator~~evaluate ~~proposes that a patient participate in~~ the ~~trial~~safety and ~~the~~tolerability ~~reading~~of ~~center~~ACP ~~determines~~administered ~~that,~~as ~~although~~ a ~~patient~~monotherapy ~~may not meet all criteria precisely, participation~~ in ~~the~~patients ~~trial~~with ~~is warranted based on the overall~~ GA ~~pattern and size~~. ~~For~~ ~~example,~~We ~~this~~enrolled ~~can~~47 ~~result~~patients in ~~the~~this ~~enrollment~~trial. ofWe ~~patients~~randomly ~~with~~assigned ~~baseline~~patients GAin ~~area~~this ~~slightly~~trial ~~below~~to ~~1 disc area, as was the case with~~ one ~~patient in each~~ of ~~the~~two ~~Zimura~~dose 4groups. mgPatients ~~group~~received ~~and~~a ~~the~~total ~~Part~~of 2five ~~sham~~intravitreal ~~control~~injections ~~group (which is part~~ of ~~the~~either ~~comparison~~0.3 ~~for~~mg ~~both~~or ~~the~~1 ~~Zimura 2~~ mg ~~and~~of ~~Zimura~~ACP 4over mga ~~groups)~~36-week intreatment ~~the GATHER1 trial~~period. ~~These~~Patients ~~patients~~received ~~were~~an ~~included~~intravitreal ininjection ~~the~~of ~~ITT~~ACP ~~analysis~~at ~~for~~day ~~our~~0, ~~primary~~week ~~efficacy~~4, ~~endpoint. The~~week ~~FDA~~8, orweek 24 ~~other~~and ~~regulatory~~week ~~authorities~~36 ~~may~~of ~~not~~the ~~agree~~trial, with ~~the~~a ~~inclusion~~final offollow-up ~~these~~visit ~~patients~~at inweek ~~our statistical analysis~~48.

~~Clinical~~ACP ~~Relevance.~~was ~~Clinical~~generally ~~relevance~~well-tolerated ~~refers to an assessment of how meaningful the observed outcome is or would be for patients. The FDA and other regulatory authorities consult with clinicians~~ in ~~the~~this ~~field of study to advise on the relevance of an observed outcome for patients~~trial. ~~Our~~We ~~GATHER1~~did ~~and~~not ~~GATHER2~~observe ~~trials~~any ~~use~~evidence ~~anatomic endpoints measuring the reduction~~ of GAdrug ~~growth~~related asadverse ~~the primary efficacy endpoints~~events. We ~~obtained~~also adid ~~written~~not ~~agreement~~observe ~~with~~any ~~the~~incidence ~~FDA through the GATHER2 SPA that the mean rate~~ of ~~growth~~conversion ~~(slope)~~to ~~estimated~~wet ~~based~~AMD ~~on GA area, measured by FAF~~ in ateyes ~~least~~treated ~~three~~with ~~time points: Baseline, Month 6, and Month 12, and the design and planned analysis of the GATHER2 trial adequately address the objectives necessary to support a regulatory submission~~ACP. ~~Since~~Adverse ~~established~~events ~~literature~~were ~~and~~primarily ~~clinical~~ocular ~~experience~~adverse ~~indicate~~events ~~that~~in ~~patients' functional vision is impacted by~~ the ~~growth~~study ofeye ~~the GA over time,~~ which ~~ultimately~~were ~~leads~~related to ~~severe vision loss, we believe that reduction of GA growth would have a meaningful impact on~~ the ~~patients’~~injection ~~well-being and quality of life and therefore is clinically relevant~~procedure.

~~Adequate~~In ~~and~~addition, ~~Well-Controlled.~~we Inperformed ~~addition~~assessments of visual acuity to ~~statistical~~detect ~~significance~~any ~~and~~potential ~~clinical~~decrease ~~relevance~~in vision associated with intravitreal injections, ~~pivotal~~the ~~clinical~~administered ~~trials~~drug ~~must~~or benatural ~~adequate~~progression ~~and~~of ~~well-controlled~~the disease if left untreated. We ~~believe:~~did not identify any drug related safety issues through measurements of visual acuity.

• Our Phase 1/2a clinical trial was an uncontrolled study with a small sample size and was not powered to detect a difference between ACP dose groups, or the ~~method~~efficacy of ~~selecting~~ACP ~~subjects~~monotherapy, ~~for~~with ~~GATHER1~~statistical ~~and~~significance. ~~GATHER2~~The ~~was~~primary ~~based~~purpose onof the ~~same~~study ~~prospectively~~was ~~defined~~to ~~inclusion~~assess safety and ~~exclusion~~tolerability. ~~criteria~~However, ~~and~~during ~~provided~~the ~~adequate~~more ~~assurance~~frequent ~~that~~dosing ~~they~~period, ~~have~~which is the first 24 weeks, we observed a trend, in favor of the higher of two dose groups, of a relative reduction in the mean growth of the GA ~~secondary~~lesion toarea, ~~AMD;~~as measured by fundus autofluorescence images read by an independent reading center.

•the randomized method of assigning patients to GATHER1 and GATHER2 treatment groups and corresponding sham control groups minimizes potential confounding factors and bias, and is intended to ensure comparability of the groups for all pertinent variables; and

•GATHER1 and GATHER2 are appropriately masked. The primary endpoint was objectively measured by an independent masked reading center. Adequate measures were taken to minimize bias on the part of the subject, the investigator, the reading center and the sponsor.

We believe, based on the above and other aspects of the designs of the two trials and their similar primary efficacy endpoints and statistical analysis plans, that both trials are adequate and well-controlled to establish the efficacy and safety of Zimura for GA. GATHER2 is intended to provide independent substantiation of the statistically significant results we observed in GATHER1.

Our Regulatory Pathway Following GATHER1 and GATHER2

Based on the foregoing, assuming that Zimura’s safety profile remains consistent with findings observed to date and subject to regulatory review of the GATHER1 trial results, we believe that one additional international, randomized, double-masked, sham controlled, Phase 3 clinical trial is needed to demonstrate the safety and efficacy of Zimura in GA in a manner

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~~sufficient~~ The tomean ~~support~~growth ~~an application for marketing approval~~ from ~~the~~baseline ~~FDA and EMA~~ in ~~this indication. We designed~~ the GATHER2 trial in accordance with this belief and understanding. Our belief and understanding of the remaining clinical requirements to demonstrate the safety and efficacy of Zimura for the treatment of GA inlesion aarea ~~manner~~during ~~sufficient to support an application for marketing approval from~~ the ~~FDA~~first ~~and~~24 weeks ~~EMA is based on our review~~ of the ~~data from the GATHER1~~ trial ~~as well as discussions with the FDA. As described above~~, inwhen ~~parallel discussions with those for~~ the ~~GATHER2~~injections ~~SPA,~~were ~~the~~administered ~~FDA~~more ~~indicated that~~regularly, aswas ~~part~~1.00 ofmm2 ~~a future NDA~~ for ~~Zimura,~~ the ~~results~~24 ~~from~~patients ~~GATHER1~~receiving ~~will be considered using~~ the ~~original~~0.3 ~~prespecified~~mg ~~primary~~dose ~~efficacy endpoint analysis (mean rate of change in GA area over 12 months measured by FAF at three timepoints: baseline, month 6~~ and ~~month~~0.78 ~~12),~~mm2 ~~together with a post-hoc analysis using the same FDA-preferred method that we are using~~ for the ~~GATHER2~~23 ~~trial~~patients ~~(mean~~receiving ~~rate of growth (slope) estimated based on GA area measured by FAF in~~ the ~~relevant~~1 ~~timepoints)~~mg dose. WeWhen ~~believe~~ the ~~GATHER1~~injections ~~data,~~were ~~when~~administered ~~analyzed~~on ~~using~~a ~~the~~reduced ~~FDA's~~dosing ~~preferred~~schedule ~~method,~~during ~~are consistent with and supportive of~~ the ~~results~~subsequent ~~from the original prespecified analysis. However~~24 weeks, itthis isrelative ~~possible~~trend ~~that~~in ~~unexpected~~reduced orgrowth ~~inconsistent~~in ~~findings~~GA ~~could~~lesion ~~emerge~~area aswas weno ~~continue~~longer ~~to evaluate the unmasked, individual patient data, which could cause us to evaluate and change our conclusions about this data~~present.

InThe ~~July~~following ~~2021,~~graph wesets ~~received~~forth ~~a written agreement from~~ the ~~FDA~~mean ~~under~~change ain ~~SPA~~GA ~~for~~lesion ~~the~~area ~~overall design of GATHER2. We believe that the safety and efficacy data we will collect~~ from ~~the~~baseline ~~GATHER2 trial, if positive, would satisfy the FDA’s and could potentially satisfy the EMA's requirements as the second pivotal clinical trial typically required~~ for ~~marketing approval. If~~ the ~~12-month~~two ~~results~~treatment ~~from~~groups ~~GATHER2~~over ~~are positive, we plan to file applications with~~ the ~~FDA~~course ~~and the EMA for marketing approval~~ of ~~Zimura for GA. Our expectations regarding~~ the ~~minimum clinical requirements to demonstrate the safety and efficacy of Zimura for GA may change as new regulatory or third party information becomes available~~trial. We have not had any interactions to date with the EMA regarding the GATHER1 data or the design of GATHER2. Ultimately, for the GATHER1 and GATHER2 trials to be accepted as pivotal trials, the FDA, EMA and other regulatory authorities would need to agree that the overall data package meet the applicable requirements with an acceptable safety profile and a clinically relevant efficacy outcome with statistical significance, and that the data support an overall favorable benefit-to-risk determination.

~~Zimura~~We -believe ~~Planned~~this ~~Phase~~apparent 3trend ~~Clinical~~in ~~Trial~~the ~~for~~relative ~~Patients~~reduction ~~With~~of ~~Intermediate~~mean ~~AMD~~growth in GA lesion area when ACP was dosed more frequently, together with the relative loss of the benefit when ACP was dosed less frequently, may suggest a possible drug effect.

~~Post-hoc~~Regulatory ~~Analyses~~Pathway offor ~~GATHER1~~Marketing ~~Data~~Approval of ACP in ~~Drusen,~~GA ~~iRORA~~secondary ~~and~~to ~~cRORA~~AMD

WeTo ~~conducted~~obtain ~~additional~~marketing ~~post-hoc~~approval ~~analyses~~of onACP for the ~~GATHER1~~treatment ~~data~~of GA secondary to AMD, inwe ~~which~~expect that we ~~evaluated~~will ~~the~~need ~~progression~~favorable ofresults ~~iRORA~~from toa ~~cRORA~~total of two independent, adequate and ~~the~~well-controlled ~~progression~~pivotal ofclinical ~~drusen~~trials, todemonstrating ~~iRORA~~the orsafety ~~cRORA,~~and efficacy of ACP in ~~patients~~this ~~treated~~indication. ~~with~~We ~~Zimura~~believe 2the mgresults aswe ~~compared~~have toobtained ~~patients~~from inour ~~the~~GATHER1 ~~corresponding~~and ~~sham~~GATHER2 ~~group.~~trials ~~Drusen,~~satisfy ~~iRORA~~this requirement and ~~cRORA~~provide ~~represent~~below ~~progressive~~further ~~stages~~explanation offor ~~AMD.~~this belief.

~~The~~FDA ~~post-hoc~~Requirements ~~analysis~~and data show a 19.6% absolute reduction in the rate of progression from drusen to iRORA or cRORA, for the Zimura 2 mg group as compared to sham at 18 months, representing a relative reduction of 72%. The data also show a 21.8% absolute reduction in the rate of progression from iRORA to cRORA for the Zimura 2 mg group as compared to sham at 18 months, representing a relative reduction of 52%. The following graphs illustrate these results:Status

~~Proportion~~Based ofon ~~patients~~our ~~that~~interactions ~~progress~~with ~~from~~the ~~drusen~~FDA, we believe it would be sufficient to ~~iRORA~~establish orefficacy ~~cRORA~~by showing statistically significant results on the primary efficacy endpoint in the GATHER1 and GATHER2 trials, which is based on measuring GA area growth using FAF. The FDA required analysis for the primary efficacy endpoint is the mean rate of growth (~~Zimura~~slope) 2estimated mgbased on GA area measured by FAF over at least three timepoints: baseline, month 6, and month 12. Both GATHER1 and GATHER2 demonstrated a statistically significant reduction in the mean rate of GA area growth (slope) compared to sham) when analyzed using the FDA's required analysis.

~~Proportion~~Based ofon ~~patients~~our ~~that~~interactions ~~progress~~with ~~from~~the ~~iRORA~~FDA, we believe it would be sufficient to ~~cRORA~~establish ~~(Zimura~~safety 2by mgusing ~~compared~~the safety data collected over 12 months and 18 months from the GATHER1 trial and over 12 months from the GATHER2 trial. We plan to ~~sham)~~provide additional supportive safety data from our other completed and ongoing trials of ACP in patients with GA, wet AMD, IPCV and STGD1.

We have had a number of interactions with the FDA on our development and regulatory pathway for ACP in GA secondary to AMD, including:

•In July 2021, we obtained a SPA from the FDA for the overall design of GATHER2. Based on the information we submitted, the FDA determined that the design and planned analysis of GATHER2 adequately addressed the objectives necessary to support a future regulatory submission.

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~~Planned~~•Over ~~Phase~~2021 3and ~~Clinical~~2022, ~~Trial~~we inhad ~~Intermediate~~a number of additional interactions with the FDA on the requirements for and the content of our planned NDA of ACP for the treatment of GA secondary to AMD, which clarified our regulatory pathway in this indication.

We•In ~~were~~November ~~encouraged~~2022, by the ~~results~~FDA ofgranted ~~the~~breakthrough ~~post-hoc~~therapy ~~analyses,~~designation ~~and~~for ~~plan~~ACP tofor ~~initiate~~GA asecondary ~~Phase~~to ~~3 clinical trial studying Zimura in patients with intermediate~~ AMD. Webased ~~expect~~on ~~this~~the ~~trial to be an international, randomized, double~~12-~~masked,~~month ~~sham-controlled,~~results multi-center trial with approximately 200 patients per treatment group. We expect to treat and follow patients for 24 months. We are currently evaluating other aspects of the design of this trial, including patient inclusion criteria and primary efficacy endpoints. We plan to obtain feedback from ~~regulatory~~GATHER1 ~~authorities on our plans for this trial~~ and ~~our development strategy in this indication, before initiating this trial during the second half of 2022~~GATHER2.

~~Zimura~~•In December 2022, we completed rolling submission of the NDA for ACP for the treatment of GA secondary to AMD, with the clinical and non-clinical ~~STGD1~~portions ~~Trials~~ of the NDA submitted in November 2022 and the chemistry, manufacturing and controls portion of the NDA submitted in December 2022.

~~STAR: Ongoing~~In ~~Phase~~February 2b2023, ~~Clinical~~the ~~Trial~~FDA accepted the NDA for filing and granted us priority review with a PDUFA target action date of ~~Zimura~~August 19, 2023. The FDA indicated in their acceptance letter that, as of the time of the FDA acceptance letter, they did not identify any potential review issues and were not currently planning an Advisory Committee meeting for ~~STGD1~~ACP.

WeEMA ~~initially~~and ~~completed~~The ~~patient~~Medicines enrollment for this clinical trial in February 2019 with a total of 95 patients enrolled, none of whom have any remaining study visits. In July 2020, we reopened enrollment in this trial in the United States. We continue to enroll patients and ~~plan~~Healthcare toProducts ~~enroll~~Regulatory ~~approximately~~Agency 25(MHRA) ~~additional~~Requirements ~~patients, with the goal of enrolling a total of approximately 120 patients. We continue to monitor the COVID-19 pandemic closely~~ and ~~may need to slow down or stop patient enrollment in certain geographies depending on the local situation.~~ Plans

We believe that the safety and efficacy data we have collected to date from the GATHER1 and GATHER2 trials, which are over 18 months and 12 months, respectively, are adequate to support MAA submissions for both the EMA and the MHRA. Our belief is subject to feedback from the EMA and MHRA, with whom we expect to have interactions during the first half of 2023.

We plan to submit MAAs to the EMA and the MHRA for marketing approval of ACP for the treatment of GA secondary to AMD during 2023, following our planned interactions with regulatory authorities in Europe.

ACP - Potential Pathway in Intermediate AMD

Post-hoc Analyses of GATHER1 Data in Drusen, iRORA and cRORA

We conducted additional post-hoc analyses on the GATHER1 data, in which we evaluated the progression of iRORA to cRORA, and the progression of drusen to iRORA or cRORA, in patients treated with ACP 2 mg as compared to patients in the corresponding sham group. Drusen, iRORA and cRORA represent progressive stages of AMD.

The post-hoc analysis data show a 19.6% absolute reduction in the rate of progression from drusen to iRORA or cRORA, for the ACP 2 mg group as compared to sham at 18 months, representing a relative reduction of 72%. The data also show a 21.8% absolute reduction in the rate of progression from iRORA to cRORA for the ACP 2 mg group as compared to sham at 18 months, representing a relative reduction of 52%. The following graphs illustrate these results:

Proportion of patients that progress from drusen to iRORA or cRORA (ACP 2 mg compared to sham)

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Proportion of patients that progress from iRORA to cRORA (ACP 2 mg compared to sham).

We plan to conduct a similar post-hoc analysis on the GATHER2 data.

Plans in Intermediate AMD

As previously disclosed, we were encouraged by the results of the above post-hoc analyses of the GATHER1 data and were planning to initiate a clinical trial evaluating ACP for the treatment of intermediate AMD, subject to feedback from the FDA and other regulatory authorities. In September 2022, we obtained favorable feedback from the FDA on our development plans. As a result of our interactions with the FDA, we do not believe we need to conduct a new clinical trial of ACP in patients with intermediate AMD. We are continuing further discussions with the FDA on using the GATHER1 and GATHER2 clinical trial data included in the current NDA submission to support treatment of GA associated with earlier stage disease, including in patients with intermediate AMD.

ACP - STGD1 Trials

STAR: Ongoing Phase 2b Clinical Trial of ACP for STGD1

We initially completed patient enrollment for this clinical trial in February 2019 with a total of 95 patients enrolled, none of whom have any remaining study visits. In July 2020, we reopened enrollment in this trial in the United States. We continue to enroll patients and plan to enroll approximately 25 additional patients, with the goal of enrolling a total of approximately 120 patients.

All initially enrolled patients were, and any newly enrolled patients are, randomized in a 1:1 ratio as follows:

•~~Zimura~~ACP 2 mg, followed by ~~Zimura~~ACP 2mg 14 days later, monthly for three months during an induction phase; followed by ~~Zimura~~ACP 4 mg, administered as two injections of ~~Zimura~~ACP 2 mg on the same day, monthly for 15 additional months during a maintenance phase; and

•a sham injection, followed by a sham injection 14 days later, monthly for three months; followed by two sham injections on the same day, monthly for 15 months.

We plan to evaluate the primary efficacy endpoint in this trial at 18 months. The primary efficacy endpoint is an anatomic endpoint, the mean rate of change in the area of ellipsoid zone defect, as measured by en-face OCT. OCT allows the demonstration of various layers of the retinal tissue, including the ellipsoid zone, which is a part of the photoreceptor cells. Scientific literature correlates defects in the ellipsoid zone with the loss of visual acuity and visual dysfunction. The ellipsoid zone is rendered in OCT images as a defined layer of photoreceptor cell segments. Areas of defects in the ellipsoid zone can be detected and measured by en-face OCT, which shows an OCT image from the perspective of looking at the retina head-on.

We have not previously studied ~~Zimura~~ACP in STGD1 patients and thus do not have any clinical data regarding the effect of ~~Zimura~~ACP in STGD1. We previously engaged the Foundation Fighting Blindness to provide us with data from the Foundation Fighting Blindness's publicly available ProgStar study, the largest natural history study on Stargardt disease to date. We have used this natural history data, as well as the perspectives of the key opinion leaders involved in the ProgStar study, as resources to assist in the design of the STAR trial. As STGD1 is an orphan indication, to our knowledge there is only very limited natural history data currently available regarding the variability of the planned primary efficacy endpoint in the STGD1 patient population we enrolled in this trial. Given the information above, this trial could be underpowered to demonstrate a potential clinical benefit for Zimura in this indication.

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used this natural history data, as well as the perspectives of the key opinion leaders involved in the ProgStar study, as resources to assist in the design of the STAR trial. As STGD1 is an orphan indication, to our knowledge there is only very limited natural history data currently available regarding the variability of the planned primary efficacy endpoint in the STGD1 patient population we enrolled in this trial. Given the information above, this trial could be underpowered to demonstrate a potential clinical benefit for ACP in this indication.

Similar to GATHER1, STAR is designed to be a Phase 2b screening trial, with the potential to demonstrate statistically significant results depending on the magnitude of the potential benefit observed. If the results are positive and statistically significant, we believe this trial could potentially serve as a clinical trial that can support an application for marketing approval. However, we have not yet engaged with the FDA or the EMA about this belief and expectation.

Even though we have reopened patient enrollment, we have been and plan to remain masked to the treatment condition of all patients in the trial. In addition, we have not reviewed and do not plan to review or analyze efficacy data for any patients in the trial, until the 18-month data has been collected and analyzed for all patients enrolled in the trial. ~~We expect data from this trial will be available after the top-line data from the GATHER2 trial.~~

~~Zimura~~ACP - Wet AMD Trials

OPH2000: Completed Phase 1/2a Clinical Trial of ~~Zimura~~ACP for Wet AMD

In 2009, we completed a multicenter, uncontrolled, ascending dose and parallel group, open-label, first in human Phase 1/2a clinical trial to evaluate the safety and tolerability of multiple intravitreal injections of ~~Zimura~~ACP given in combination with multiple doses of Lucentis 0.5 mg in patients with wet AMD. We enrolled 60 patients in this trial, of which 58 were treatment-naïve patients, and two were treatment-experienced patients.

Patients were treated at one of five ~~Zimura~~ACP dose levels: 0.03 mg, 0.3 mg, 1 mg, 2 mg and 3 mg. ~~Zimura~~ACP was generally well tolerated in this trial when tested in combination with Lucentis. None of the patients experienced any dose limiting toxicities at any of the dose levels tested. We observed only a single adverse event assessed by the investigators to be related to ~~Zimura~~ACP, mild subcapsular cataract in one patient in the group treated with ~~Zimura~~ACP 2 mg. Despite this event, this patient's visual acuity improved during the study. Adverse events were primarily ocular adverse events in the study eye which were related to the injection procedure. One patient from the 0.3 mg ~~Zimura~~ACP treatment group withdrew from the trial as a result of a serious adverse event of bacteremia unrelated to study drug or injection procedure, which resulted in a subsequent fatality. Another patient from the 0.3 mg treatment group withdrew from the trial due to the investigator's decision. Systemic adverse events in this trial were not frequently reported. No systemic adverse events were assessed as drug related.

Our Phase 1/2a clinical trial was an uncontrolled study with a small sample size and was not powered to detect a difference between ~~Zimura~~ACP dose groups or the efficacy of ~~Zimura~~ACP combination therapy with statistical significance. The primary purpose of the study was to assess safety and tolerability. In addition to our safety assessment, however, we also performed assessments of visual acuity. There was a general trend towards an improvement in visual acuity seen in all treatment groups. We focused our assessment of vision outcomes on the subgroup of 43 treatment-naïve patients who had received all six ~~Zimura~~ACP injections at the same dosage. We observed a mean increase in visual acuity from baseline at all time points for these patients, based on the number of ETDRS letters the patient could read. For this subgroup, at week 24 of the trial, we noted improvements in mean visual acuity from baseline as follows: 13.6 letters for the 13 patients receiving the 0.3 mg dose, 11.7 letters for the 15 patients receiving the 1 mg dose and 15.3 letters for the 15 patients receiving the 2 mg dose. In this subgroup, 22 patients (51%) gained at least 15 ETDRS letters, defined as significant visual gain, consisting of six patients (46%) in the 0.3 mg dose group, seven patients (47%) in the 1 mg dose group and nine patients (60%) in the 2 mg dose group.

OPH2004: Discontinued Phase 2a Trial of ~~Zimura~~ACP for Treatment-Experienced Wet AMD Patients

During the fourth quarter of 2015, we initiated an open-label Phase 2a clinical trial to evaluate ~~Zimura~~ACP’s potential role when administered in combination with anti-VEGF therapy for the treatment of wet AMD in anti-VEGF treatment-experienced patients who did not respond adequately to anti-VEGF monotherapy. In 2017, following our reassessment of our ~~Zimura~~ACP development programs, we stopped enrolling patients in this trial as we determined that we would initiate a new ~~Zimura~~ACP wet AMD trial, the OPH2007 trial described below, for treatment-naïve patients. One patient continued to receive treatment in this trial until the first half of 2018. This patient did not experience any drug-related adverse events and there were no unexpected safety issues.

~~OPH2007: Completed Phase 2a Clinical Trial of Zimura for Treatment-Naïve Wet AMD Patients~~38

In 2018, we completed a randomized, dose-ranging, open-label, multi-center Phase 2a clinical trial of Zimura in combination with Lucentis 0.5 mg to evaluate the safety of different dosing regimens of Zimura in combination with an anti-VEGF agent in treating wet AMD. We enrolled and treated a total of 64 treatment-naïve patients for this trial. We assigned patients in this trial to one of four groups:

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~~•In~~ OPH2007: Completed ~~Groups~~Phase 12a ~~and~~Clinical 2,Trial ~~consisting~~ of ~~ten~~ACP ~~patients~~for inTreatment-Naïve ~~each~~Wet ~~group,~~AMD ~~patients received monthly combination therapy consisting of Lucentis 0.5 mg followed by, in Group 1, Zimura 4 mg two days later and in Group 2, Zimura 2 mg on the same day as the Lucentis treatment;~~Patients

In 2018, we completed a randomized, dose-ranging, open-label, multi-center Phase 2a clinical trial of ACP in combination with Lucentis 0.5 mg to evaluate the safety of different dosing regimens of ACP in combination with an anti-VEGF agent in treating wet AMD. We enrolled and treated a total of 64 treatment-naïve patients for this trial. We assigned patients in this trial to one of four groups:

•In Groups 1 and 2, consisting of ten patients in each group, patients received monthly combination therapy consisting of Lucentis 0.5 mg followed by, in Group 1, ACP 4 mg two days later and in Group 2, ACP 2 mg on the same day as the Lucentis treatment;

•In Groups 3 and 4, consisting of 22 patients in each group, patients received dosages in two phases, consisting of:

◦first, an induction phase from day one to the second month, during which the patients received Lucentis 0.5 mg followed by ~~Zimura~~ACP 2 mg on the same day, followed by ~~Zimura~~ACP 2 mg fourteen days later; and

◦second, a maintenance phase from the third month to the fifth month, during which the patients received, in Group 3, Lucentis 0.5 mg followed by ~~Zimura~~ACP 2 mg on the same day and in Group 4, ~~Zimura~~ACP 2 mg followed two days later with Lucentis 0.5 mg and ~~Zimura~~ACP 2 mg.

From a safety perspective, ~~Zimura~~ACP combination therapy with Lucentis was generally well tolerated after six months of treatment. The most frequently reported ocular adverse events were related to the injection procedure. We did not observe any adverse events attributable to ~~Zimura~~ACP combination therapy.

Our Phase 2a clinical trial was an uncontrolled trial with a small sample size designed to assess safety at different dosages and to detect a potential efficacy signal. This trial was not designed to detect a statistically significant difference between ~~Zimura~~ACP dose groups or to evaluate the efficacy of ~~Zimura~~ACP combination therapy with statistical significance.

We evaluated the mean change in BCVA at the six-month timepoint as compared to baseline. The data are summarized as follows:

•In Group 1, the mean change in visual acuity was 9.0 ETDRS letters with a median of 7.0 letters, and 40% of the patients gained greater than or equal to three lines of vision, or 15 ETDRS letters, defined as significant visual gain;

•In Group 2, the mean change in visual acuity was 10.2 ETDRS letters with a median of 16.0 letters, and 60% of patients gained greater than or equal to 15 ETDRS letters;

•In Group 3, the mean change in visual acuity was 10.7 ETDRS letters with a median of 10.0 letters, and 40.9% of patients gained greater than or equal to 15 ETDRS letters; and

•In Group 4, the mean change in visual acuity was 9.9 ETDRS letters with a median of 11.0 letters, and 18.2% of patients gained greater than or equal to 15 ETDRS letters.

~~Zimura~~ACP - IPCV Trials

OPH2002: Completed Phase 2a Clinical Trial of ~~Zimura~~ACP for IPCV

In late 2014, we initiated a very small, uncontrolled, open-label, Phase 2a clinical trial to evaluate ~~Zimura~~ACP’s potential role when administered in combination with anti-VEGF agents for the treatment of IPCV in treatment-experienced patients for whom anti-VEGF monotherapy failed. IPCV is an age-related disease that is similar to wet AMD and is commonly characterized by leakage under the RPE, subretinal hemorrhage and RPE detachment. We enrolled four patients in the trial. None of the patients had a greater than 15-ETDRS letter decrease in visual acuity, which is considered a significant loss in visual acuity, following treatment in this study. None of the patients experienced any drug-related adverse events and there were no unexpected safety issues from this trial.

OPH2006: Discontinued Phase 2a Trial of ~~Zimura~~ACP for IPCV

In late 2017, we initiated a randomized, dose-ranging, open-label Phase 2a clinical trial of ~~Zimura~~ACP in combination with Eylea in treatment-experienced patients with IPCV. We did not enroll any patients in this clinical trial and decided to ~~discontinue this clinical trial.~~

~~IC-500: HtrA1 Inhibitor Product Candidate~~39

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~~preclinical~~discontinue ~~development.~~this Weclinical ~~are currently developing IC-500 for the treatment of GA and evaluating HtrA1 inhibition as a potential treatment for other stages of AMD and potentially other age-related retinal diseases~~trial.

IC-500: HtrA1 Inhibitor Product Candidate

In October 2018, we acquired from funds controlled by Versant Ventures a number of HtrA1 inhibitors. In previous experiments conducted before the acquisition, these HtrA1 inhibitors showed high affinity and specificity for HtrA1 when tested in vitro. In 2020, we selected the lead compound from this group of HtrA1 inhibitors, which we call IC-500, for preclinical development. We are currently developing IC-500 for the treatment of GA and evaluating HtrA1 inhibition as a potential treatment for other stages of AMD and potentially other age-related retinal diseases.

The HtrA1 gene encodes for an enzyme that may affect cellular structure, function and homeostasis, which is the dynamic equilibrium maintained in cells and tissue required for normal physiology. Genetic linkage studies, including a study published in Molecular Vision in 2017, show a correlation between the expression of HtrA1 and a certain set of genes conferring risk for AMD. A study of post-mortem eyes from subjects with AMD published in EBioMedicine in 2018 found overexpression of HtrA1 in RPE cells as compared to the eyes of non-AMD subjects. Additionally, the overexpression of HtrA1 was found, in an in vitro experiment published in the same article, to lead to alterations and disruptions in the morphology and function of RPE cells. Although the causal pathway between expression of HtrA1 and AMD is still not well understood, we believe that these findings suggest that HtrA1 overexpression may play a role in AMD and that molecules involved in the regulation and inhibition of HtrA1 may have therapeutic benefit in the treatment of GA as well as other stages of AMD and potentially other age-related retinal diseases.

We are continuing the preclinical development of IC-500. InWe ~~early~~have ~~2021,~~developed wea ~~reviewed~~formulation ~~our~~that ~~IC-500~~we ~~development~~believe ~~program~~will be safe and ~~explored~~effective ~~the~~for ~~potential~~intravitreal ofadministration ainto ~~less~~the ~~frequent~~eye, ~~dosing~~and ~~regimen~~are ~~than~~conducting ~~monthly~~cGMP ~~dosing.~~manufacturing Inactivities ~~2021,~~for weIC-500. ~~initiated~~We aare ~~number~~conducting ofadditional preclinical ~~tolerability~~studies ~~and~~to ~~pharmacokinetic~~optimize ~~studies~~the ~~for~~dosage, delivery and formulation of IC-500, and ~~we are~~ planning for IND-enabling ~~GLP~~ toxicology studies. Weto ~~anticipate~~start ~~that~~later ~~the~~in ~~start~~2023. ofBased ~~the~~on ~~IND-enabling~~current ~~toxicology~~timelines ~~studies~~and ~~will~~subject beto ~~later~~successful ~~than~~preclinical ~~what~~development weand ~~originally~~cGMP ~~planned~~manufacturing, ~~primarily~~we ~~due~~expect to ~~the~~submit ~~limited~~an ~~availability~~IND ~~of study slots at CROs attributable~~ to ~~rising~~the ~~demand~~FDA for ~~their services as well as increased absenteeism of staff at those CROs in wake of the COVID~~IC-19500 ~~pandemic~~during ~~and~~ the ~~recent~~first ~~Omicron~~half ~~variant~~of 2024.

We have developed a formulation that we believe will be safe and effective for intravitreal administration into the eye, and are conducting current Good Manufacturing Practices, or cGMP, manufacturing activities for IC-500. Based on current timelines and subject to successful preclinical development and cGMP manufacturing, we expect to submit an IND to the FDA for IC-500 in mid-2023.

Gene Therapy Research and Development Programs

~~Since~~As ~~2017,~~we ascontinue weto ~~evaluated~~assess our strategic priorities and the market for orphan and age-related retinal diseases ~~with~~and ~~unmet medical needs, as well as the~~ available technologies infor ~~development~~addressing tothose ~~potentially~~unmet ~~address~~medical ~~these~~ needs, we ~~have~~continue ~~been~~to ~~encouraged~~believe byin ~~the prospects for~~ gene therapy as a ~~potential~~promising ~~treatment~~mechanism ~~option~~of action for the treatment of many retinal diseases. We ~~in-licensed~~continue ~~two~~to ~~gene~~advance ~~therapy~~our ~~product~~minigene ~~candidates~~research ~~(IC-100~~programs ~~and~~for ~~IC-200)~~LCA10, STGD1 and ~~established~~USH2A, ~~collaborative~~respectively. ~~gene~~We ~~therapy~~describe ~~sponsored~~below ~~research~~the ~~programs~~December ~~with~~2022 ~~three~~transaction ~~leading academic research institutions~~ in ~~the~~which ~~United~~Opus ~~States.~~acquired ~~These~~all ~~sponsored~~of ~~research~~our ~~programs~~rights, ~~were~~title ~~focused~~and oninterests ~~generating~~in ~~data~~and to ~~support~~our ~~the~~assets ~~preclinical~~primarily ~~development~~related ofto our former gene therapy product candidates ~~and~~IC-100 ~~discovering~~ and ~~developing~~IC-200, ~~other~~which ~~novel~~we ~~gene~~previously ~~therapy~~developed ~~technologies~~for torhodopsin-mediated ~~treat~~autosomal adominant ~~number~~retinitis ofpigmentosa ~~orphan~~and BEST1-related IRDs., respectively.

Since 2021, as we evaluated the results from our preclinical toxicology and efficacy studies for IC-100 and IC-200 and assessed the additional resources that would be needed to advance those programs in light of our focus on Zimura and other strategic goals, we have been considering our development options for both product candidates. We are currently planning to seek a collaborator for the future development and potential commercialization of IC-100 and IC-200. We continue to believe in gene therapy as a promising mechanism of action for the treatment of many retinal diseases. We continue to advance our minigene research programs, which we have transitioned to us from the University of Massachusetts Medical School, or UMMS.

The Potential of Gene Therapies for Retinal Diseases

Gene therapy consists of delivering DNA encoding for a functional protein to a target tissue to facilitate protein synthesis using a recipient's existing cellular machinery. Gene therapy can be used to replace a non-functional protein produced innately by the subject as a result of a genetic mutation or as a means of producing and delivering a therapeutic protein that would not otherwise be produced within the body. Many IRDs are monogenic, meaning they are caused by mutations in a single gene, and therefore could potentially be addressed by a gene replacement approach. ~~For~~ genetic diseases where the mutant protein has toxic effect, we have been encouraged by the potential for a “knockdown” and “replace” approach in which gene therapy not only can introduce a wildtype version of the gene into the host body but also can suppress the expression of the mutant gene. Furthermore, because gene therapy may result in a lasting, or even permanent, addition to a host body's genetic code, gene therapy has potential for an extended treatment effect through a single administration. We therefore believe that gene therapy also holds promise as a potential treatment for age-related and other non-orphan retinal diseases, especially for diseases where patients might otherwise require chronic therapy over years, if not decades.

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Currently, most gene therapies for application in the eye are administered via subretinal injection. Subretinal injection is a surgical procedure in which the gene therapy vector is injected by a retinal surgeon into the potential space between the photoreceptors and the RPE and often as close as practicable to the site of desired protein expression. Once the vector is present in the target tissue area, the process by which the gene of interest is inserted into host cells by the delivery vehicle can begin. This process is referred to as transduction and the gene therapy delivery vehicle is referred to as a vector.

Gene Therapy Products and AAV Vectors

A gene therapy product typically includes the gene of interest, or transgene, together with a promoter sequence. The composition of the transgene may differ from that of the wildtype form of the gene—for example, the gene may be modified to increase the expression of the target protein. Promoters are DNA sequences that are linked to a gene and control the transcription of a gene into RNA in the host body's cells. There are cell-specific promoters, which tend to drive gene expression in particular cell or tissue types - for example, the RPE and photoreceptors. The choice of the specific promoter that is to be linked to a given transgene is an important consideration in constructing a gene therapy product.

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in particular cell or tissue types - for example, the RPE and photoreceptors. The choice of the specific promoter that is to be linked to a given transgene is an important consideration in constructing a gene therapy product.

The promoter-transgene combination is packaged together into a delivery vehicle to facilitate localization within the relevant tissue within the body. Gene therapies are typically delivered via viral vectors and among those, AAV has become the most common choice for gene therapy applications inside the eye. AAV is a small, non-pathogenic virus. To create the vector, the DNA encoding the AAV viral genes is removed, disarming the virus, and is replaced with the therapeutic gene sequence. In addition to AAV, other gene delivery vehicles include vectors derived from lentivirus and non-viral based vectors.

We are focused on AAV gene therapies, as AAV vectors have generally been found to transduce RPE, photoreceptors and other retinal cells at a high rate, and their safety profile in humans is relatively well-documented as compared to other delivery vehicles, such as lentiviral vectors. Gene editing approaches, such as CRISPR, in which the host DNA is modified, altered or removed via therapeutic intervention, are also emerging as a potential treatment options for genetic diseases. Unlike lentiviral vectors or gene editing approaches, with AAV gene therapy, the delivered genetic cargo does not incorporate into or alter the host cell's existing DNA and chromosomes, but rather remains separate in the host cell, where it can be transcribed by the host cell's existing machinery.

There are several naturally-occurring serotypes of AAV, including AAV2, AAV5, AAV8 and AAV9, as well as countless synthetic AAV serotypes. The AAV genome consists of two genetic sequences: a "Rep" gene that encodes for certain viral life-cycle proteins, and a "Cap" gene that encodes for proteins that form the viral capsid, which is the outer shell of the AAV. Recombinant AAV vectors can be created by combining the Rep sequence for one AAV serotype with the Cap sequence for another AAV serotype. For example, a recombinant AAV 2/5 vector is produced using the AAV2 Rep sequence and the AAV5 Cap sequence to package the transgene inside an AAV5 capsid. Because different capsid proteins have different transduction capabilities within different types of cells, the selection of the capsid serotype is an important consideration in constructing an AAV gene therapy product.

One of the primary limitations with AAV gene therapy is AAV's packaging capacity: an AAV vector can hold only up to approximately 4,700 base pairs of DNA, whereas the genes associated with a number of monogenic IRDs, such as the CEP290 gene associated with LCA10 and the ABCA4 gene associated with STGD1, exceed that size. A possible solution to the size limitation would be to develop a minigene form of transgene that would be small enough to fit within the packaging capacity of AAV, but large enough for the resulting protein to maintain its function. Another potential limitation for AAV and other viral vector gene therapies is the potential to trigger an immune response. Because many types of AAV are naturally occurring, gene therapy patients may have built up neutralizing antibodies to specific AAV serotypes prior to gene therapy administration, which may result in an inflammatory immune response and tissue damage. The safety profile of AAV, however, is well-documented, and furthermore, the relative isolation of the human eye and ocular immune system within the body may mitigate the potential immune response from the administration of AAV into the eye. Our current gene therapy programs, which are described in further detail below, use AAV vectors for delivery of the genetic cargo to cells within the retina.

IC-100: RHO-adRP Product Candidate

In June 2018, we entered into an exclusive global license agreement with the University of Florida Research Foundation, or UFRF, and the University of Pennsylvania, or Penn, for rights to develop and commercialize IC-100, our novel AAV gene therapy product candidate for the treatment of RHO-adRP. There are over 150 known mutations in the RHO gene that can result in RHO-adRP. In individuals with RHO-adRP, the rhodopsin that is produced by the mutant gene is toxic. The construct for our RHO-adRP product candidate combines in a single AAV2/5 vector:

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•a transgene for a highly-efficient, novel short hairpin RNA, or shRNA, designed to target and "knockdown" expression of the subject's innate rhodopsin, regardless of the specific mutation a subject has, with

•a transgene for a healthy rhodopsin protein that is resistant to the shRNA.

Our RHO-adRP construct was tested by investigators at Penn in a naturally occurring canine model of RHO-adRP, resulting in long term, i.e., over 8 months, anatomic and functional preservation of the photoreceptors, which was demonstrated with histology and electrophysiology. The investigators had initially tested a dual vector construct in which the shRNA and the healthy RHO transgenes were delivered by different AAV vectors. The investigators found, however, that the dual vector approach caused inflammation and other complications in the retina, leading the investigators to develop this single vector construct. The results from these experiments were published by scientists at Penn and UF in PNAS in August 2018 in a paper titled: "Mutation-independent Rhodopsin Gene Therapy by Knockdown and Replacement with a Single AAV Vector."

We worked with a gene therapy contract development and manufacturing organization, or CDMO, to develop a manufacturing process for IC-100, and this CDMO produced and we released a cGMP batch of IC-100. In addition, we and Penn conducted a number of preclinical studies of IC-100 and a natural history study of RHO-adRP patients.

We have completed two preclinical toxicology studies of IC-100, one of which was a toxicology and efficacy study in the naturally occurring canine model of RHO-adRP and the other study was a GLP toxicology study in non-human primates. We tested the same three doses of IC-100 in both studies. In the canine study, we believe the results demonstrated there was efficacy across all three dose groups. We observed, through clinical examination, ocular inflammation in the high dose group in the canines and at varying degrees at different dosing levels in the non-human primates. Because of the different findings across the two species, we planned to discuss with the FDA the results from these toxicology studies and the design of our planned first-in-human clinical trial before submitting an IND. The FDA advised, in lieu of this meeting, additional discussion should be conducted during the 30-day IND review period following IND submission.

We have been considering our development options for this product candidate and currently plan to seek a collaborator for the future development and potential commercialization of IC-100.

IC-200: Product Candidate for BEST1-Related IRDs

In April 2019, we entered into an exclusive global license agreement with Penn and UFRF for rights to develop and commercialize IC-200, our novel AAV gene therapy product candidate for the treatment of Best disease and other BEST1-related IRDs. Investigators at Penn and UFRF tested IC-200 in a naturally occurring autosomal recessive canine model for Best disease, resulting in the reversal of subretinal lesions and micro-detachments associated with the canine disease. The results of this work were published in PNAS in February 2018 in a paper titled: "BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure." We believe the results from these experiments in a naturally occurring canine disease model with distinct phenotypic similarities to human Best disease demonstrate the potential therapeutic benefit of IC-200 for BEST1-related IRDs.

We worked with a gene therapy CDMO to develop a manufacturing process for IC-200, and this CDMO produced and we released a cGMP batch of IC-200. In addition, we and Penn conducted a number of preclinical studies of IC-200 and natural history studies of patients with BEST1-related IRDs, which included a preclinical toxicology and efficacy study of IC-200 in the naturally occurring canine model of Best disease. We believe the results of the toxicology and efficacy study show IC-200 had an efficacy effect in these canines with minimal adverse effects from inflammation or other safety issues.

We have been considering our development options for this product candidate and currently plan to seek a collaborator for the future development and potential commercialization of IC-200.

Minigene Programs

~~AAV~~ Starting ~~vectors~~in ~~are~~2018, ~~generally~~we ~~limited~~funded asseveral asponsored ~~delivery~~research ~~vehicle~~programs byat the ~~size~~University of ~~their~~Massachusetts ~~genetic~~Medical ~~cargo~~School, ~~which~~or isUMMS, ~~restricted~~seeking to ~~approximately~~use 4a minigene approach to develop new gene therapies for several orphan IRDs. These programs (miniCEP290,~~700~~ ~~base~~miniABCA4 ~~pairs~~and ofminiUSH2A) ~~genetic~~are ~~code~~described below. ~~The~~In ~~use~~July of2021, ~~minigenes~~we ~~seeks~~hired toseveral ~~deliver~~employees awho ~~smaller~~were ~~but~~previously ~~still~~at ~~functional~~UMMS ~~form~~and ofworking aon ~~larger~~these ~~gene~~sponsored ~~packaged~~research ~~into~~programs, aincluding ~~standard-size~~the ~~AAV~~principal ~~delivery~~investigator ~~vector~~for these programs. ~~The~~ ~~goal~~We ofhave ~~minigene~~transitioned ~~therapy~~the ispreclinical research activities for these programs from UMMS to ~~deliver~~us aand ~~gene~~have ~~expressing~~established a ~~protein~~laboratory ~~that,~~for ~~although~~these ~~smaller~~employees ~~than~~to ~~the~~continue ~~naturally~~working ~~occurring~~on ~~protein,~~these isprograms ~~nonetheless~~and ~~functional~~other ~~for~~preclinical ~~purposes~~ocular ofresearch ~~treating~~and ~~the~~development ~~associated disease~~activities.

Starting in 2018, we funded several sponsored research programs at UMMS seeking to use a minigene approach to develop new gene therapies for several orphan IRDs. These programs (miniCEP290, miniABCA4 and miniUSH2A) are described below. In July 2021, we hired four individuals who were previously at UMMS and working on these sponsored research programs, including the principal investigator for these programs. We have transitioned the preclinical research

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activities for these programs from UMMS to us and have established a laboratory for these employees to continue working on these programs and other preclinical ocular research and development activities.

miniCEP290 Program for LCA10

Our miniCEP290 program is targeting LCA10, which is associated with mutations in the CEP290 gene. The naturally occurring CEP290 gene is approximately 8,000 base pairs. In a 2018 publication in Human Gene Therapy, researchers at UMMS presented their findings that injection of a CEP290 minigene into a newborn mouse model for LCA10 resulted in rescue of photoreceptor cells, as evidenced by both anatomical and functional measures. The goal of our sponsored research with UMMS was to create and evaluate other CEP290 minigene constructs in the mouse model and optimize the effect observed in that publication.

We were encouraged by the results of the sponsored research. One of the new minigene constructs shows five times longer duration of functional rescue of the photoreceptors as compared to what was observed in the 2018 publication. In July 2019, we entered into a license agreement with the University of Massachusetts, or UMass, for exclusive development and commercialization rights to this program. UMMS continued experiments to optimize the constructs, which were delayed during 2020 because of restrictions placed by UMMS on animal research activities as a result of the COVID-19 pandemic. We have identified a lead construct from this program and are considering preclinical development options.

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commercialization rights to this program. UMMS continued experiments to optimize the constructs, which were delayed during 2020 because of restrictions placed by UMMS on animal research activities as a result of the COVID-19 pandemic. We have identified a lead construct from this program and are considering preclinical development options.

miniABCA4 Program for STGD1

Our miniABCA4 program is targeting STGD1, which is associated with mutations in the ABCA4 gene. The size of the naturally occurring ABCA4 gene is approximately 7,000 base pairs. As part of the sponsored research, UMMS generated and evaluated several ABCA4 minigene constructs in both in vitro and in vivo experiments, which yielded what we believe to be encouraging results. We ~~are~~conducted ~~conducting~~ additional experiments to optimize the constructs and assess their efficacy in the mouse model. We have identified a lead construct from this program and are considering preclinical development options.

UMMS granted us an option to obtain an exclusive license to certain patent applications for this program.

miniUSH2A Program for USH2A-Related IRDs

The miniUSH2A program seeks to develop a mutation independent, minigene therapy for the vision loss associated with USH2A mutations, including vision loss associated with Usher 2A and USH2A-associated nonsyndromic autosomal recessive retinitis pigmentosa. Some of the activities in this program were delayed during 2020 as a result of the closure of UMMS animal research laboratories due to the COVID-19 pandemic. UMMS generated and evaluated several USH2A minigene constructs in in vitro experiments and we are planning to evaluate their efficacy in animals. The animal experiments ~~have~~were ~~been~~ delayed as a result of transitioning the work from UMMS to us. We are considering our next steps for this research program.

UMMS granted us an option to obtain an exclusive license to certain patent applications for this program.

Opus Asset Purchase Agreement

As part of our previously stated strategy to seek a licensee for IC-100 and IC-200, in December 2022, IVERIC bio Gene Therapy LLC, or the Iveric Subsidiary, our wholly owned subsidiary, entered into an asset purchase agreement with Opus, or the Opus APA, pursuant to which Opus acquired all rights, title and interests in and to Iveric Subsidiary's assets primarily related to IC-100 and IC-200, including Iveric Subsidiary's exclusive license agreements with the University of Florida Research Foundation, Incorporated, or UFRF, and the Trustees of the University of Pennsylvania, or Penn, for both product candidates and certain related sponsored research agreements.

In accordance with the terms of the Opus APA, Iveric Subsidiary received (i) an upfront payment in the amount of $500,000 and (ii) 2,632,720 shares of the Series Seed Preferred Stock of Opus, pursuant to a stock issuance agreement, or the Opus SPA, that the parties entered into currently with the Opus APA, resulting in Iveric Subsidiary's ownership of a high single-digit percentage of the outstanding capital stock of Opus on a fully diluted basis. The Opus APA and the Opus SPA provide for Opus to issue additional shares of capital stock that will maintain Iveric Subsidiary's ownership at a mid to high single-digit percentage of the fully diluted outstanding capital stock of Opus through Opus’s next round of financing in which it raises a specified minimum amount of gross proceeds. Iveric Subsidiary is also eligible to receive (i) contingent development and regulatory milestone payments of up to $12.8 million and (ii) additional sales milestone payments of up to $98.9 million from Opus. Further, Iveric Subsidiary will receive, on a country-by-country and product-by-product basis, an earn-out of a low single-digit percentage on net sales of IC-100 and IC-200.

The Opus APA also contains customary representations, warranties, covenants and indemnification obligations made by Iveric Subsidiary and Opus.

Opus will be responsible for all further research, development, and commercialization of IC-100 and IC-200 globally and replaced Iveric Subsidiary as the exclusive licensee under the license agreements with UFRF and Penn. However, under certain circumstances, Iveric Subsidiary may have certain rights with respect to the potential future commercialization of IC-100 and/or IC-200.

The sale of IC-100 and IC-200 pursuant to the Opus APA closed in December 2022. We have filed the Opus APA and the Opus SPA as exhibits to this Annual Report on Form 10-K, with confidential portions redacted. The foregoing descriptions of the Opus APA and Opus SPA are qualified in their entirety by reference to such agreements as filed.

Manufacturing

We do not currently own or operate manufacturing facilities for the production of clinical or commercial quantities of ~~Zimura~~ACP, IC-500, ~~IC-100, IC-200~~ or any other product candidate we may develop. ~~Although~~We wehave ~~rely~~not ~~and~~yet ~~intend~~conducted toany ~~continue~~process todevelopment ~~rely~~or ~~upon third-party contract~~ manufacturing ~~organizations,~~for ~~or CMOs, to produce~~ our ~~products~~minigene ~~and~~programs. ~~product~~Although ~~candidates,~~ we ~~have~~rely ~~personnel~~and ~~with~~intend ~~experience~~to continue to ~~manage~~rely ~~the~~upon third-party ~~CMOs~~contract ~~that we have engaged or may engage to produce our product candidates.~~

Manufacturing of pharmaceutical and biological products is a process that involves procurement of starting materials, chemical synthesis or cell culture processing in controlled environments, purification and post-production testing and analysis before the product can be released. Manufacturing processes can be complex and difficult to develop, especially for products such as oligonucleotides and gene therapies. Even when a manufacturing process is successfully developed, there are challenges associated with scaling up a manufacturing process to produce quantities sufficient for clinical trials or potential commercial sales and producing high-quality materials consistently using a clearly defined manufacturing process. The manufacture of pharmaceutical and biological products is subject to FDA review and oversight. Having a well-defined process that can be validated is crucial to obtaining FDA approval of any product candidate we may bring forward.

Zimura Manufacturing

The process for manufacturing Zimura consists of chemical synthesis, purification, pegylation, purification and finally freeze drying to form a powder, which is the active pharmaceutical ingredient, or API. Each of these steps involves relatively common unit operations. In a separate process that follows the freeze drying, the Zimura API is dissolved in a liquid solution

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~~that~~manufacturing ~~includes~~organizations, ~~certain~~or ~~chemicals~~CMOs, ~~and~~to ~~then~~produce isour ~~aseptically~~products ~~filled~~and ~~into~~product ~~vials~~candidates, ~~from~~we ~~which~~have ~~the~~personnel ~~intravitreal~~with ~~injection~~experience ~~solution~~to ismanage ~~drawn. This process of rendering~~ the ~~API~~third-party ~~into~~CMOs athat ~~liquid~~we ~~solution~~have ~~and~~engaged ~~placing~~or itmay ~~into~~engage ~~vials is referred~~ to asproduce ~~fill/finish~~our ~~services~~product candidates.

InManufacturing ~~early~~of ~~2017,~~pharmaceutical weand ~~completed~~biological ~~the~~products ~~small~~is ~~scale~~a ~~manufacture~~process ofthat ~~multiple~~involves ~~batches~~procurement of ~~Zimura~~starting ~~drug~~materials, ~~substance~~chemical ~~that~~synthesis weor ~~are~~cell ~~using~~culture toprocessing ~~support~~in ~~clinical~~controlled ~~drug~~environments, ~~supply~~purification ~~for~~and ~~the~~post-production ~~GATHER2~~testing ~~trial~~ and ~~the~~analysis ~~expanded~~before ~~STAR~~the ~~trial.~~product Wecan ~~are~~be ~~working~~released. ~~with~~Manufacturing ~~our~~processes ~~historical~~can ~~contract~~be ~~manufacturer~~complex ~~for~~and ~~Zimura~~difficult ~~drug~~to ~~substance~~develop, ~~Agilent~~especially ~~Technologies,~~for ~~Inc.,~~products orsuch ~~Agilent,~~as tooligonucleotides ~~scale~~and upgene ~~and~~therapies. ~~potentially~~Even ~~validate~~when ~~the~~a manufacturing process ~~for~~is ~~Zimura~~successfully ~~drug substance. In parallel~~developed, wethere are ~~working~~challenges ~~with~~associated ~~a new contract manufacturer~~ with ~~the~~scaling ~~goal~~up ofa ~~assessing~~manufacturing ~~whether~~process ~~this~~to ~~manufacturer can~~ produce ~~Zimura~~quantities ~~drug~~sufficient ~~substance~~for atclinical antrials ~~adequate~~or ~~scale for~~ potential commercial ~~use.~~sales Weand ~~have~~producing ~~experienced~~high-quality ~~issues~~materials ~~during~~consistently ~~technology~~using ~~transfer~~a ofclearly ~~the~~defined ~~existing~~ manufacturing process ~~to this manufacturer, which has resulted in delays to our timelines with this manufacturer~~. ~~Subject~~The tomanufacture ~~successful completion~~ of ~~scale~~pharmaceutical up and ~~validation~~biological ~~activities,~~products weis ~~currently~~subject ~~plan~~ to ~~use~~FDA ~~Agilent~~review ~~as the primary source of supply of Zimura drug substance upon launch, if approved,~~ and ~~the~~oversight. Having ~~new manufacturer as~~ a ~~second~~well-defined ~~source~~process ~~of supply of Zimura drug substance. Validation requires~~ that ~~we demonstrate that the drug substance produced through the scaled up process~~ can be ~~produced~~validated ~~consistently,~~is ~~delivering~~crucial ~~quality~~to ~~product~~obtaining ~~within~~FDA aapproval ~~range~~ of ~~acceptable~~any ~~specifications.~~product Wecandidate ~~are~~we ~~continuing~~may ~~analytical~~bring ~~method development and qualification with our contract manufacturers and laboratories~~forward.

~~Starting~~ACP in 2020, we have worked with a contract manufacturer to provide us with additional supply of finished Zimura drug product to support our needs for the GATHER2 trial and the expanded STAR trial. We believe we have sufficient finished Zimura drug product for these two clinical trials. In addition, we are working with our historical fill/finish manufacturer, Ajinomoto Bio-Pharma Services, or Ajinomoto, on fill/finish of Zimura drug product with a new vial, which we believe will allow us to support a more efficient and robust fill/finish operation at a commercial scale. Ajinomoto has produced finished Zimura drug product using the new vial, which we plan to use for a portion of the second-year study visits for patients in the GATHER2 trial. We believe Ajinomoto has the capacity to supply us with finished Zimura drug product with the new vial for our expected commercial supply needs upon launch, if approved. Manufacturing

WeThe ~~order~~process ~~the~~for ~~polyethylene~~manufacturing ~~glycol~~ACP consists of chemical synthesis, orpurification, ~~PEG~~pegylation, ~~starting~~purification ~~material~~and ~~used~~finally freeze drying to ~~make~~form a ~~Zimura~~powder, ~~drug~~which ~~substance~~is ~~from~~the aactive ~~sole~~pharmaceutical ~~source~~ingredient, ~~third-party~~or ~~manufacturer~~API. ~~outside~~Each ~~the~~of ~~United~~these ~~States~~steps involves relatively common unit operations. In Wea ~~currently~~separate ~~procure~~process that follows the ~~supply~~freeze ondrying, athe ~~purchase~~ACP ~~order~~API ~~basis~~is ~~and~~dissolved ~~are~~in ~~continuing~~a ~~discussions~~liquid ~~regarding~~solution athat ~~long-term~~includes ~~supply~~certain ~~agreement~~chemicals ~~with~~and ~~this~~then ~~manufacturer~~is ~~for~~aseptically filled into vials from which the ~~PEG~~intravitreal ~~starting~~injection ~~material.~~solution Weis ~~believe~~drawn. ~~this~~This ~~supplier~~process ~~will~~of ~~have~~rendering the ~~capacity~~API tointo ~~supply~~a usliquid ~~with~~solution ~~the~~and ~~PEG~~placing ~~that~~it weinto ~~will~~vials ~~need~~is ~~for~~referred ~~commercial~~to ~~manufacturing~~as fill/finish.

~~Zimura~~We ~~Sustained~~are ~~Release~~working ~~Delivery~~with our historical contract manufacturer for ACP drug substance, Agilent Technologies, Inc., or Agilent, to scale up and potentially validate the manufacturing process for ACP drug substance. In 2022, Agilent completed the manufacture of multiple batches of ACP drug substance at a larger scale, a scale which we believe can support potential commercial launch, if approved. We are continuing to work with Agilent on additional scale up and validation activities. In parallel, we are working with a new contract manufacturer with the goal of assessing whether this manufacturer can produce ACP drug substance at an adequate scale for potential commercial use. Subject to successful completion of scale up and validation activities, we currently plan to use Agilent as the primary source of supply of ACP drug substance upon launch, if approved, and the new manufacturer as a second source of supply of ACP drug substance.

We are ~~exploring~~working ~~lifecycle~~with ~~management~~our ~~initiatives~~historical ~~for~~fill/finish ~~Zimura~~manufacturer, ~~with~~Ajinomoto ~~efforts~~Bio-Pharma ~~focused~~Services, onor ~~potential~~Ajinomoto, ~~sustained~~on ~~release~~fill/finish ~~delivery~~of ~~technologies.~~ACP ~~Our~~drug ~~goal~~product iswith ~~to derive~~ a ~~formulation~~new ofvial, ~~Zimura~~which ~~with~~we abelieve ~~sustained~~will ~~release~~allow ~~delivery~~us ~~technology~~to ~~that~~support ~~reduces~~a ~~the~~more ~~frequency~~efficient ofand ~~intravitreal~~robust ~~injections~~fill/finish ~~that~~operation at a ~~patient~~commercial ~~must~~scale. ~~undergo,~~Ajinomoto ~~while~~has ~~maintaining~~produced ~~comparable~~ACP ~~efficacy~~drug ~~and~~product ~~safety~~using tothe ~~monthly~~new ~~injections.~~vial, Wewhich ~~have~~we ~~been~~are ~~exploring~~using for a ~~number~~portion of ~~potential~~the ~~sustained~~second-year ~~release~~study ~~delivery~~visits ~~technologies~~for ~~with~~patients ~~various~~in ~~technology~~the ~~providers.~~GATHER2 ~~Preliminary~~trial ~~evaluation~~and offor the ~~sustained~~OLE ~~release~~study. ~~delivery~~We ~~technologies~~believe ~~and~~Ajinomoto has the ~~resulting~~capacity ~~formulations~~to issupply ~~ongoing.~~us Wewith ~~intend~~ACP todrug ~~evaluate~~product ~~multiple~~with ~~sustained~~the ~~release~~new ~~delivery~~vial ~~technologies~~ for ~~Zimura~~our expected commercial supply needs upon launch, ~~and~~if ~~may~~approved. ~~pursue~~We are continuing discussions with Ajinomoto for long-term ~~development~~supply ~~collaborations~~of ~~with~~ACP ~~technologies~~drug ~~that~~product ~~meet~~and ~~our~~are ~~feasibility~~assessing ~~and~~additional ~~other~~suppliers ~~criteria~~of ACP drug product.

We order the polyethylene glycol, or PEG, starting material used to make ACP drug substance from a sole source third-party manufacturer outside the United States. We currently procure the supply on a purchase order basis and are continuing discussions regarding a long-term supply agreement with this supplier for the PEG starting material. We believe this supplier has the capacity to supply us with the PEG at the scale that we will need for commercial manufacturing.

We have also engaged a manufacturer to package ACP drug product to produce finished goods for potential commercial distribution.

Sustained Release Delivery Technologies for ACP

We are exploring lifecycle management initiatives for ACP with efforts focused on potential sustained release delivery technologies. Our goal is to derive a formulation of ACP with a sustained release delivery technology that reduces the frequency of intravitreal injections that a patient must undergo, while maintaining comparable efficacy and safety to monthly injections. We plan to develop these sustained release delivery technologies for GA and earlier stages of AMD.

One of the technologies that we are evaluating is DelSiTech’s proprietary silica-based sustained release technology. We have been encouraged by the results of preliminary feasibility studies of ACP formulated with DelSiTech’s silica-based technology and as a result, in June 2022 we entered into a license agreement with DelSiTech, or the DelSiTech License Agreement, under which we obtained a worldwide, exclusive license under specified patent rights and know-how to develop and commercialize new formulations of ACP using DelSiTech’s silica-based technology for treating diseases of the human eye.

In addition to DelSiTech’s technology, we continue to evaluate other sustained release delivery technologies for ACP. If any of the other resulting formulations are promising, we may pursue long-term development collaborations with those technologies.

IC-500 Manufacturing

The process for manufacturing IC-500 consists of chemical synthesis, purification and spray drying to form a powder, which is the spray dried active pharmaceutical ingredient, or SDAPI. Each of these steps involves relatively common unit operations. In a separate process that follows the spray drying, the IC-500 SDAPI is dispersed in a liquid solution to form a suspension that includes certain pharmaceutical excipients and then is aseptically filled into vials and terminally sterilized. The filled drug product suspension is then diluted to the clinical dose concentration using a diluent. This process of rendering the SDAPI into a liquid suspension and placing it into vials, from which the intravitreal injection is drawn, is referred to as fill/finishing.

We have engaged multiple contract manufacturers to support the various processes necessary for the scale-up and cGMP manufacturing of IC-500 drug substance and drug product for larger scale batches for potential clinical trials.

Gene Therapy Manufacturing

The manufacture of AAV gene therapies requires the use of high quality starting materials, such as plasmids and cells. Plasmids are circular double-stranded DNA that can exist separately from chromosomes in cells. A plasmid can be engineered and transfected into cells to express a specific transgene with different combinations of AAV serotypes. The plasmids and cells are generally sourced from a limited number of qualified suppliers.

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The process for ~~producing~~manufacturing ~~AAV~~IC-500 ~~vectors typically~~ consists of ~~growing~~chemical ~~the~~synthesis, ~~cells~~purification and spray drying to form a powder, ~~transfection~~which ofis the ~~cells~~spray ~~with~~dried ~~appropriate~~active ~~plasmids~~pharmaceutical ~~and~~ingredient, ~~harvesting~~or ~~the~~SDAPI. ~~viral~~Each ~~vectors~~of ~~from~~these ~~the~~steps ~~cell~~involves ~~culture~~relatively common unit operations. ~~The~~ ~~subsequent~~In ~~purification~~a separate process that follows the spray drying, the IC-500 SDAPI is ~~designed~~dispersed in a liquid solution to ~~capture,~~form ~~purify~~a ~~and~~suspension ~~concentrate~~that ~~the~~includes ~~viral~~certain ~~vector~~pharmaceutical ~~product~~excipients ~~while~~and ~~removing~~then ~~process~~is aseptically filled into vials and ~~product-related~~terminally ~~impurities~~sterilized. The ~~purified~~filled ~~AAV~~drug ~~vector~~product suspension is then ~~formulated,~~diluted ~~filtered~~to the clinical dose concentration using a diluent. This process of rendering the SDAPI into a liquid suspension and ~~filled~~placing it into vials, from which the intravitreal injection ~~solution~~ is drawn, is referred to as fill/finishing.

We ~~obtain~~have ~~the~~engaged ~~plasmids~~multiple ~~that~~contract ~~are~~manufacturers ~~used~~to ~~for~~support ~~IC-100~~the ~~and~~various ~~IC-200~~processes ~~from~~necessary afor ~~single~~the ~~third~~scale-~~party~~up ~~supplier on a purchase order basis. We worked with a gene therapy CDMO for preclinical~~ and ~~Phase~~cGMP ~~1/2~~manufacturing ~~clinical supply~~ of IC-~~100~~500 ~~and IC-200~~ drug substance and drug product. ~~This~~for ~~CDMO~~larger ~~has~~scale ~~produced,~~batches ~~and~~for wepotential ~~have~~clinical ~~released,~~trials. aWe ~~cGMP~~are ~~batch~~continuing ofpreclinical ~~IC-100~~studies ~~and~~to aoptimize ~~cGMP~~the ~~batch~~dosage, delivery and formulation of IC-~~200~~500.

Human Capital

Our Workforce

As of ~~January~~December 31, 2022, we had 94163 full-time employees, compared to 5789 full-time employees as of ~~January~~December 31, 2021. These employees support key areas of our business and operations, including commercial planning and operations, medical affairs, clinical development and clinical operations, regulatory affairs and drug safety, data management, scientific research, process and analytical development, drug substance and drug product manufacturing, quality control, materials and supply chain management, and quality assurance, as well as our general and administrative functions and public company infrastructure. We ~~plan to~~ continue to hire strategically to support key areas of our business, including the hiring of ~~medical~~a ~~science~~commercial ~~liaisons~~sales force. ~~The~~We ~~following~~expect ~~are~~to ~~additional~~complete ~~data~~the ~~about~~hiring of our ~~full-time~~commercial ~~employees~~team of approximately 120 individuals, asincluding a field based sales force of ~~January~~between 3150 and 70 representatives, ~~2022:~~by early April 2023. Diversity is a key factor that we are considering in our hiring of a sales force.

~~•67~~The following are inadditional ~~research~~data ~~and~~about ~~development,~~our ~~manufacturing~~full-time ~~and~~employees, ~~quality~~as ~~control~~of ~~and~~December ~~assurance;~~31, 2022:

•3249% ~~have~~of ~~M.D.,~~our ~~O.D.,~~workforce ~~Pharm.D.~~are ~~or Ph.D. degrees~~women;

•45% ~~self-identify~~of our workforce are racially diverse (which we define as ~~women;~~Asian, African American, Native American and Hispanic);

•4544% ~~self-identify~~of our leadership roles (which we define as ~~racial~~Director orlevel ~~ethnic~~and ~~minorities;~~above) are women and 44% of those in leadership roles are racially diverse;

•3231% ~~reside~~of inour aExecutive ~~state~~Leadership ~~where~~Team weare dowomen; ~~not have any physical offices (currently, New Jersey, New York~~ and ~~Massachusetts).~~

In•38% ~~addition to our full-time employees, we engage various consultants and advisors to support key areas~~ of our ~~business,~~Executive ~~including~~Leadership ~~formulating~~Team our research and development, manufacturing, commercialization and lifecycle management strategies. Many of these consultants and advisors have specialized expertise that also makes them attractive for other companies. We generally engage them as independent contractors and they are ~~generally~~racially ~~free to work for other companies, subject to the terms of any non-compete arrangements that we enter into with them~~diverse.

~~Human~~Throughout ~~Capital~~2022, ~~Initiatives~~we promoted 12.7% of our workforce into leadership roles. Of these promotions, 47% are women and 43% are racially diverse.

~~During~~Compensation ~~the COVID-19 pandemic, we increased our efforts to support our employees~~ and transitioned to full-time remote working in March 2020. We conducted numerous surveys over the course of the year to gauge employee sentiment and understand their needs. Throughout the pandemic, we have provided employees with technology and training sessions to support remote working. We took efforts to enhance company communication, such as holding weekly company meetings to provide business updates and provide a forum for guest speakers, including several offering education in best practices for remote working and general wellness. Our employees adopted various software tools to support virtual communication and collaboration, both internally and with third parties. Benefits

~~Starting~~We inbelieve ~~the~~that ~~middle~~our ofemployees ~~2021,~~are wevital ~~adopted~~to ~~health~~our ~~and~~company's ~~safety~~success. ~~policies~~To ~~for~~attract ~~employees~~and ~~who~~retain ~~started~~talent, ~~voluntarily~~we ~~returning~~provide tocompetitive ~~the~~compensation ~~office.~~and Webenefits ~~have~~to ~~also~~our ~~adopted~~workforce, aincluding ~~vaccination~~two ~~policy~~medical ~~and~~plans weto ~~provide~~choose ~~COVID-19~~from ~~testing~~along towith ~~employees~~generous ~~who~~Health ~~regularly~~Reimbursement ~~work~~Account inand ~~our~~Health ~~offices~~Savings Account offerings. We ~~continue~~also tooffer ~~provide~~generous ~~flexible~~vacation ~~work~~and ~~policies~~parental ~~to support our employees~~leave. WeStarting ~~continue~~in to2023, ~~monitor~~we increased the ~~COVID-19~~offering ~~situation~~periods ~~closely and, other than~~ for our ~~laboratory-based~~ employees, ~~currently expect~~ to ~~continue~~join ~~working~~our ~~predominantly~~Employee inStock aPurchase ~~hybrid~~Plan ~~(partially~~from ~~remote,~~two ~~partially~~to infour ~~office)~~times ~~working~~per ~~model for the foreseeable near future~~year.

InOur ~~2021,~~turnover werate ~~continued~~for to2022 ~~develop~~was ~~our new employee integration and professional development programs~~6. ~~Similar to 2020~~2%, ~~most~~which ofis ~~our~~low ~~newly~~compared ~~hired employees in 2021 joined us as remote- or hybrid-based employees, and we continued~~ to ~~enhance~~ our ~~new~~peers ~~employee~~in ~~orientation program. For 2021, we continued to expand~~ our ~~training programs for new and continuing employees~~industry.

Culture and People Initiatives

In January 2023, we launched a new corporate narrative to articulate our mission, vision, aspiration and values to reflect our growth and evolution from a development focused organization to a commercial stage organization. We are conducting surveys and focus groups with our employees on our new corporate narrative.

We continue to operate under a hybrid working model (partially remote, partially in office) and expect to continue to do so for the foreseeable near future, with a mix of office-based, field based and laboratory based employees. As we have grown in headcount, we continue to have weekly company meetings to provide business updates and enhance our new employee onboarding programs.

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In ~~mid-2020~~2022, we ~~formed~~rolled out an employee ~~committee~~volunteering ~~on diversity, equity~~ and ~~inclusion,~~company ormatch ~~CDEI,~~program. toBased ~~assess~~on ~~issues~~available ~~of diversity~~information, ~~equity~~in ~~and~~2022, ~~inclusion~~over ~~among~~25% of our workforce ~~and~~donated ~~provide~~funds ~~recommendations.~~to Inor ~~2021,~~volunteered wetime ~~worked~~for tocharitable ~~implement~~organizations, ~~some~~including offor ~~the~~Genspace ~~recommendations~~NYC, ~~from~~a ~~the~~Brooklyn ~~CDEI,~~community ~~including~~lab ~~conducting~~that ~~trainings~~we onsponsor. ~~topics~~Our ~~such~~committee asfor ~~unconscious~~diversity, ~~bias~~equity and ~~interviewing~~inclusion, ~~skills.~~which Wewe ~~entered~~established ~~into~~in a2020, ~~corporate~~continues ~~sponsorship~~to ~~with~~find ~~Genspace~~ways ~~NYC,~~to aencourage ~~community~~employee ~~life~~volunteering ~~sciences~~and ~~lab~~fundraising infor ~~Brooklyn~~charitable organizations, ~~New~~and ~~York.~~bring Wein ~~also~~outside ~~rolled~~speakers ~~out~~on antopics ~~employee~~such ~~volunteering~~as living with disabilities and ~~company~~overcoming ~~match~~unconscious ~~program~~bias.

Sales and Marketing

WeOur ~~expect that our~~ commercial strategy for ~~any of our product candidates~~ACP, ~~including~~as ~~whether~~well toas ~~retain~~for ~~commercial~~any ~~rights~~other ~~and market and sell the~~ product candidate ~~ourselves~~that ormay tobe ~~utilize collaboration~~approved, ~~distribution or other marketing arrangements with third parties in some or all geographic markets,~~ will be determined based on a variety of factors, including the size and nature of the patient population, the disease area, the particular indication for which the product candidate is approved, the territory in which the product candidate may be marketed and the commercial potential for such product candidate, including coverage by payors. InFor ~~addition~~example, we believe more than 90% of GA patients are covered by Medicare Part B, which uses a buy-and-bill reimbursement model for physician administered drugs. As part of our strategy, we will determine whether to retain commercial rights and market and sell the product candidate ourselves or to utilize collaboration, distribution or marketing arrangements with third parties in some or all geographic markets. We expect our commercial strategy will vary depending on whether the disease is typically treated by general ophthalmology practitioners, specialists, such as retina specialists, or other sub-specialists, and the degree and potential degree of acceptance of our product candidate by the relevant physicians in various markets. For example, in the United States, retina specialists perform most of the medical procedures involving diseases of the back of the eye, including intravitreal injections. We believe that retina specialists in the United States are sufficiently concentrated and have experience with the buy-and-bill model such that we could effectively promote an approved buy-and-bill product ~~candidate~~ to these specialists. We also understand that a majority of GA patients in the United States currently are not cared for by retina specialists and instead see general ophthalmologists (GOs) and optometrists (ODs);, ~~this~~many ~~will~~of bewhom aare ~~factor~~adept at diagnosing GA patients and referring them to retinal specialists for any available treatments. We have factored in these marketplace dynamics in developing our sales and marketing strategy for ~~Zimura~~ACP for GA.

We are ~~working~~continuing to build our commercial capabilities and infrastructure, ~~and~~including ~~develop~~ our own sales and marketing ~~strategy~~organization, ~~for~~in ~~the~~anticipation of our potential launch of ~~Zimura~~ACP in the United States for GA, if approved. IfWe we are ~~successful~~actively inhiring ~~expanding~~qualified ~~the~~personnel ~~potential~~across ~~label~~core ~~for~~commercial ~~Zimura~~functions toincluding ~~intermediate~~sales, ~~AMD~~marketing, patient access and~~/or~~ ~~STGD1~~reimbursement, ~~which~~analytics and operations, inand ~~contrast~~product distribution. We expect to GAcomplete ~~and~~the ~~other~~hiring ~~forms~~for ofour ~~AMD~~commercial team by early April 2023, iswith a ~~condition~~total ~~affecting~~of approximately 120 individuals, including a ~~more~~field ~~limited~~based ~~number~~sales force of ~~individuals,~~between 50 and 70 representatives. We believe our ~~commercial~~field ~~strategy~~sales ~~for~~force ~~Zimura~~will ~~may~~be ~~change~~capable of covering all of the key retina specialist accounts across the United States by the time of our PDUFA target action date of August 19, 2023.

Competition

The development and commercialization of new drug products is highly competitive. We face competition with respect to our product candidates from major pharmaceutical companies, specialty pharmaceutical companies and biotechnology companies, as well as generic and biosimilar companies, worldwide. Potential competitors also include academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing and commercialization. Some of these competitive products and therapies are based on scientific approaches that are the same as or similar to our approaches, and others are based on entirely different approaches. We also will face similar competition with respect to any product candidates that we may seek to develop or commercialize in the future. ~~In particular, many companies are pursuing gene therapy approaches for orphan and age-related retinal diseases.~~

Based on publicly available information, we are aware of the following ~~research and development programs that may be~~ competitive ~~with~~products ~~programs~~and ~~we are pursuing~~programs. Other competitive programs may exist of which we are not aware.

Competitive considerations for GA or dry AMD:

•WeIn ~~are~~February ~~aware that LumiThera~~2023, ~~Inc.~~the ~~has~~FDA ~~a medical device using its LT-300 light delivery system, which is~~ approved in the European Union for the treatment of dry AMD. In addition, there are a number of products in preclinical and clinical development by third parties to treat GA or dry AMD. In general, these product candidates can be categorized based on their proposed mechanisms of action. The mechanisms of action for these product candidates include complement system and inflammation suppression, visual cycle modulators, antioxidants and neuroprotectants, cell and gene therapies and vascular perfusion enhancers. We are aware that AstraZeneca PLC (which acquired Alexion Pharmaceuticals, Inc. in 2021), Annexon Inc., Apellis Pharmaceuticals, Inc., or Apellis’s, ~~Applied Genetic Technologies Corporation~~pegylated, orsynthetic ~~AGTC,~~peptide ~~Biogen~~targeting ~~Inc.,~~complement ~~Gemini~~protein ~~Therapeutics~~C3, ~~Inc.~~pegcetacoplan, ~~Gyroscope~~for ~~Therapeutics (which was recently acquired by Novartis AG), IONIS Pharmaceuticals, Inc. (in collaboration with Roche AG), Janssen Pharmaceuticals Inc. (which acquired its program through~~ the ~~acquisition~~treatment of ~~Hemera Biosciences, LLC), MorphoSys AG, NGM Biopharmaceuticals Inc. and Novartis AG each have complement inhibitors in development for~~ GA orsecondary ~~dry~~to AMD,. ~~including,~~This inproduct ~~the cases of Gemini Therapeutics, Gyroscope Therapeutics and Janssen Pharmaceuticals, complement inhibitor gene therapies and AGTC and Gemini Therapeutics each~~ has a ~~research~~dosing ~~program~~regimen onof ~~complement~~once ~~factor~~every H25 ~~gene~~to ~~therapy~~60 days. WeIn ~~believe~~December ~~that~~2022, ~~the most advanced of these programs is~~ Apellis's ~~pegylated,~~submitted ~~synthetic~~an ~~peptide~~MAA ~~targeting~~to ~~complement~~the ~~protein~~EMA. ~~C3, for which~~ Apellis announced ~~top-line~~that ~~data~~the ~~from~~EMA ~~two~~had ~~Phase~~validated 3their ~~clinical~~MAA ~~trials in September 2021~~ and ~~Apellis~~the ~~stated it would file an~~ application ~~for~~was ~~marketing~~under ~~approval~~review, with ~~the~~a ~~FDA~~decision ~~during~~expected ~~the~~in ~~second~~early ~~quarter of 2022~~2024.

•We are aware that LumiThera, Inc. has a medical device using its LT-300 light delivery system, which is approved in the European Union for the treatment of dry AMD. In addition, there are a number of products in preclinical and clinical development by third parties to treat GA or dry AMD. In general, these product candidates can be categorized based on their proposed mechanisms of action. The mechanisms of action for these product candidates include complement system and inflammation suppression, visual cycle modulators, antioxidants and neuroprotectants, cell and gene therapies and vascular perfusion enhancers. We are aware that AstraZeneca PLC (which acquired Alexion Pharmaceuticals, Inc. in 2021), Akari Therapeutics, Plc, Annexon Inc., Apellis, Applied Genetic Technologies

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~~Apellis~~Corporation, ~~could~~or ~~obtain~~AGTC, ~~marketing~~Biogen ~~approval~~Inc., ~~for~~Gemini ~~its~~Therapeutics, ~~product~~Inc. ~~candidate~~(which merged with Disc Medicine, Inc.), Gyroscope Therapeutics (which was acquired by Novartis AG), IONIS Pharmaceuticals, Inc. (in ~~advance~~collaboration with Roche AG), Janssen Pharmaceuticals Inc. (which acquired its program through the acquisition of ~~when~~Hemera weBiosciences, ~~might~~LLC), ~~reasonably~~Kanaph ~~expect~~Therapeutics toInc, ~~obtain~~NGM ~~marketing~~Biopharmaceuticals ~~approval~~Inc. ~~for~~and ~~Zimura~~Novartis AG each have complement inhibitors in development for GA or ~~IC-500~~dry AMD, including, in GAthe cases of Gyroscope Therapeutics and Janssen Pharmaceuticals, ifcomplement atinhibitor ~~all~~gene therapies and in the cases of AGTC and Gemini Therapeutics, research programs on complement factor H gene therapy. We believe that the most advanced of these programs is Apellis's, as described above. Moreover, we are aware that several other companies, including ~~Abbvie Pharmaceuticals, Inc.,~~ Allegro Ophthalmics, LLC, Alkeus Pharmaceuticals Inc., Astellas Pharma Inc., Aviceda Therapeutics, Boehringer Ingelheim, Lineage Cell Therapeutics, Inc. (which was acquired by Roche AG), Ocugen, Inc., ONL Therapeutics, Inc., Regenerative Patch Technologies, Roche AG, ~~and~~ Stealth BioTherapeutics Corp. and Visus Therapeutics, are pursuing development programs for the treatment GA or dry AMD using different mechanisms of action outside of the complement system, including Genentech, Inc. (an affiliate of Roche AG) and Gemini Therapeutics, which are pursuing HtrA1 inhibition as a mechanism of action. We believe that the most advanced HtrA1 inhibitor program in development iswas Genentech's monoclonal antibody HtrA1 inhibitor, which iswas ~~currently~~ being studied in a Phase 2 clinical trial ~~and~~until ~~whose~~it ~~results~~was ~~are~~discontinued ~~expected to become available~~ in ~~2022~~October ~~or 2023~~2022.

Competitive considerations for Stargardt disease:

•There are a number of products in preclinical research and clinical development by third parties to treat Stargardt disease. We are aware that AGTC, Alkeus Pharmaceuticals, Inc., Beam Therapeutics Inc., Biogen, Generation Bio Co., Kubota Vision Inc. (formerly Acucela), Lin BioScience, Inc., ProQR Therapeutics N.V., or ProQR, and Spark Therapeutics (a subsidiary of Roche AG) each have research or development programs in Stargardt disease. Three of these programs, Alkeus, Kubota and Lin BioScience, are exploring the use of oral therapeutics, while AGTC, Nightstar and Spark are each using a gene therapy approach, Beam is using a base editing approach, and ProQR is using an RNA-based approach. Kubota’s product candidate, to which the FDA and the EMA granted orphan drug designation in August 2020, is in Phase 3 development while Alkeus’s product candidate is in Phase 2 development. In addition, several academic organizations have early stage programs in Stargardt disease.

Competitive considerations for RHO-adRP:

•We are aware that ProQR is developing an RNA-based therapeutic for RHO-adRP, for which it is currently conducting a Phase 1/2 clinical trial. Ocugen, Inc. is developing a preclinical gene therapy for RHO-adRP, for which the FDA granted orphan drug designation in July 2020. In addition, Biogen has a preclinical AAV gene therapy program in RHO-adRP. Editas Medicine, Inc. is also developing a preclinical gene editing product candidate for this disease. We are also aware that multiple academic institutions have early stage gene therapy development programs in RHO-adRP.

Competitive considerations for BEST1-related IRDs:

•We are aware that Biogen has a preclinical AAV gene therapy program for one or more BEST1-related IRDs.

Competitive considerations for LCA10:

•We are aware that Editas Medicine, Inc. has a gene editing program for LCA10, for which a Phase 1/2 clinical trial is ongoing, ProQR is developing an RNA-based therapeutic for LCA10 that is currently in Phase 2/3 development, Generation Bio Co. has a preclinical program that utilizes ~~ceDNA~~close ended DNA technology to target LCA10 and Oxford Biomedica plc is developing a lentiviral gene therapy program for LCA10 that is in preclinical development. In addition, several academic institutions have preclinical programs in LCA10.

Competitive considerations for USH2A-related IRDs:

•There are a number of products in preclinical research and clinical development by third parties to treat USH2A-related IRDs. We are aware that ProQR is pursuing two RNA based approaches for different mutations causing Usher 2A, one of which is currently in Phase 1/2 clinical development and the other of which is in preclinical development. We are also aware that Editas Medicine, Inc., Odylia Therapeutics and Wave Life Sciences, Inc. are exploring potential programs in USH2A-related IRDs.

Intellectual Property

Our success depends in part on our ability to obtain and maintain proprietary protection for our product candidates, technology and know-how, to operate without infringing the proprietary rights of others and to prevent others from infringing our proprietary rights. We seek to protect our proprietary position, among other methods and where patent protection is available, by filing U.S. and certain foreign patent applications related to our proprietary technology, inventions and improvements that are important to the development of our business, and by maintaining our issued patents. ~~For~~We ~~our~~also ~~collaborative~~rely ~~gene~~upon ~~therapy~~trade ~~sponsored~~secrets, ~~research programs~~know-how, wecontinuing ~~have~~technological ~~generally~~innovation ~~relied~~and onin-licensing ~~our~~opportunities ~~university~~to ~~collaborators~~develop toand ~~perform~~maintain our proprietary position.

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research and generate data to support new patent applications, and to file, prosecute and maintain any patents or patent applications resulting from the sponsored research with our input. We also rely upon trade secrets, know-how, continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position.

Our patent portfolio includes the following:

•patents and patent applications in-licensed from Archemix Corp., or Archemix:

•patents and patent applications covering ~~Zimura~~ACP's composition-of-matter, which have issued in the United States, the countries covered by the European Patent Organisation, which we refer to as the EPO Countries, China, Japan and certain other jurisdictions, and which are expected to expire in ~~the United States and the EPO Countries in~~ 2025 ~~and elsewhere~~, ~~including~~subject ~~China~~to ~~and~~any ~~Japan,~~patent interm ~~2026~~extensions; and

•patents and patent applications covering the treatment of certain complement mediated disorders with ~~Zimura~~ACP, ~~Zimura~~ACP for use in a method of treating certain complement mediated disorders or a composition comprising ~~Zimura~~ACP for treating certain complement mediated disorders, which have issued in the United States, the EPO Countries, China, Japan and certain other jurisdictions, and which are expected to expire in ~~the EPO Countries in~~ 2025, 2026 and ~~elsewhere~~2027, ~~including~~subject ~~the~~to ~~United~~any ~~States~~patent ~~and~~term ~~Japan, in 2026~~extensions; and

•patents and patent applications owned by IVERIC bio, Inc.:

•patents and patent applications covering ~~formulations,~~ methods of use for treating GA, Stargardt disease, IPCV and other conditions, and other proprietary technology relating to ~~Zimura~~ACP, which ~~have~~include ~~resulted~~two inissued United States patents with claims covering methods offor ~~using~~treating ~~Zimura~~GA towith ~~treat~~ACP GA that ~~have been allowed by the USPTO and~~ are expected to expire in 2034, subject to any patent term extensions, and ~~others~~patent applications that are pending in the United States, the EPO Countries, China, Japan and certain other jurisdictions, which, if granted, are expected to expire in 2034, 2038 and 2040, subject to any patent term adjustments or extensions; and

•patent applications covering methods of using ~~Zimura~~ACP to treat intermediate AMD and other forms of AMD, which are pending under the Patent Cooperation Treaty, or PCT, and which, if granted, are expected to expire in 2041, subject to any patent term adjustments or extensions; and

•patents and patent applications owned by our subsidiary Orion Ophthalmology LLC, or Orion:

•three families of ~~composition-of-matter~~patents and ~~method-of-treatment~~ patent applications covering compositions and methods of use of IC-500 and other HtrA1 inhibitors owned by Orion, some of which ~~have~~are ~~resulted in~~ issued patents in the United States or claims that have been allowed by the USPTO, as well as issued patents or allowed claims in other jurisdictions, all of which are expected to expire in 2037, and others are pending in the United States, the EPO Countries, China, Japan and certain other jurisdictions, which, if granted, are expected to expire in 2037, subject to any patent term adjustments or extensions; and

•~~patents and~~ patent applications in-licensed ~~from~~by ~~UFRF~~Iveric ~~and~~Subsidiary ~~Penn~~from UMass:

•~~patents~~two ~~covering~~families ~~composition-~~of~~-matter~~ ~~and~~patent ~~method-of-treatment~~applications relating to ~~IC-100~~certain ~~and the~~ proprietary ~~RHO-adRP~~minigene ~~AAV~~ technology offor ~~UFRF and Penn, which have issued in~~ the ~~United~~treatment ~~States~~of ~~and~~diseases ~~are~~associated ~~expected~~with tomutations ~~expire~~ in ~~2037, and applications covering~~ the ~~same~~CEP290 ~~subject~~gene, ~~matter~~which ~~that~~ are pending in the United States, the EPO ~~countries~~Countries, ~~Japan~~China and certain other jurisdictions, and which, if granted, are expected to expire in ~~2037;~~2038 and 2040, respectively, subject to any patent term adjustments or extensions.

~~•two~~The ~~families~~term of ~~composition-~~individual patents depends upon the legal term for patents in the countries in which they are granted. In most countries, including the United States, the patent term is generally 20 years from the earliest claimed filing date of a non-provisional patent application in the applicable country. In the United States, a patent’s term may, in certain cases, be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S. Patent and Trademark Office in examining and granting a patent, or may be shortened if a patent or patent application claims patentably indistinct subject matter as another commonly owned patent or patent application having an earlier expiration date and ~~method-~~the patentee terminally disclaims the portion of the term beyond such earlier expiration date. The Hatch-~~treatment~~Waxman Act permits a patent ~~applications~~term ~~relating~~extension of up to ~~the~~five ~~proprietary~~years ~~RHO-adRP~~beyond ~~AAV~~the ~~technology~~expiration date of ~~UFRF~~a ~~and~~U.S. ~~Penn,~~patent ~~one~~as ~~family~~partial compensation for the length of ~~which~~time a drug is ~~pending~~undergoing inclinical ~~the~~development ~~United~~or ~~States,~~under ~~and~~regulatory ~~both~~review ~~families~~while ~~are~~the ~~pending~~patent is in force. A patent term extension cannot extend the ~~EPO~~remaining ~~Countries,~~term ~~Japan~~of ~~and~~a ~~certain~~patent ~~other~~beyond ~~jurisdictions,~~a ~~which,~~total ifof ~~granted~~14 years from the date of product approval, ~~are~~only ~~expected~~one patent applicable to ~~expire~~each inregulatory ~~2037~~review period may be extended and ~~2039~~only those claims covering the approved drug, ~~respectively;~~a ~~and~~method for using it or a method for manufacturing it may be extended.

~~•patent~~Similar ~~applications~~provisions ~~covering~~are ~~composition-of-matter~~available in the EPO Countries and ~~method-of-treatment~~certain ~~relating~~other toforeign ~~proprietary~~jurisdictions ~~BEST1~~to ~~AAV~~extend ~~technology~~the ~~from~~term ~~UFRF,~~of ~~which~~a ~~are~~patent ~~pending~~that incovers ~~the~~an ~~United~~approved ~~States,~~drug. In the ~~EPO Countries~~future, ~~Japan~~if and ~~certain~~when ~~other~~our ~~jurisdictions,~~product ~~and~~candidates ~~which,~~receive ifapproval ~~granted~~by the FDA or foreign regulatory authorities, ~~are~~we ~~expected~~expect to ~~expire~~apply infor ~~2039;~~patent ~~and~~term extensions on issued patents covering those products, depending upon

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~~•patent~~the ~~applications~~length ~~covering~~of ~~methods~~the ofclinical ~~treating~~trials ~~autosomal~~for ~~dominant~~each ~~BEST1-related~~drug ~~IRDs~~and other factors. If ACP is approved and ~~autosomal~~we ~~recessive~~elect ~~BEST1-related~~a ~~IRDs,~~composition ~~which~~of ~~are~~matter ~~pending~~patent ~~under~~for ~~the~~patent ~~PCT~~term extension, ~~and~~we ~~which,~~expect ifto ~~granted,~~be ~~are~~eligible ~~expected~~for up to ~~expire~~the full five years of patent term extension in ~~2041;~~the United States and for a similar length of time under the corresponding mechanism in the EPO Countries.

•The expiration dates referred to above are without regard to any patent ~~applications~~term ~~in-licensed~~adjustments ~~from~~or ~~UMass:~~potential patent term extension or other market exclusivity that may be available to us. See “—Government Regulation and Product Approvals” below for a description of market exclusivity mechanisms that may be available to us.

•two families of composition-of-matter and method-of-treatment patent applications relating to certain proprietary minigene technology for the treatment of diseases associated with mutations in the CEP290 gene, which are pending in the United States, the EPO Countries and China, and which, if granted, are expected to expire in 2038 and 2040, respectively.

The term of individual patents depends upon the legal term for patents in the countries in which they are granted. In most countries, including the United States, the patent term is generally 20 years from the earliest claimed filing date of a non-provisional patent application in the applicable country. In the United States, a patent’s term may, in certain cases, be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S. Patent and Trademark Office in examining and granting a patent, or may be shortened if a patent or patent application claims patentably indistinct subject matter as another commonly owned patent or patent application having an earlier expiration date and the patentee terminally disclaims the portion of the term beyond such earlier expiration date. The Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration date of a U.S. patent as partial compensation for the length of time a drug is undergoing clinical development or under regulatory review while the patent is in force. A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent applicable to each regulatory review period may be extended and only those claims covering the approved drug, a method for using it or a method for manufacturing it may be extended.

Similar provisions are available in the EPO Countries and certain other foreign jurisdictions to extend the term of a patent that covers an approved drug. In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those products, depending upon the length of the clinical trials for each drug and other factors. The expiration dates referred to above are without regard to any patent term adjustments or potential patent term extension or other market exclusivity that may be available to us. See "—Government Regulation and Product Approvals" below for a description of market exclusivity mechanisms that may be available to us.

We may rely, in some circumstances, upon trade secrets to protect our technology. However, trade secrets can be difficult to protect. We seek to protect our proprietary technology and processes, in part, by confidentiality agreements with our employees, consultants, scientific advisors and contractors. We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.

Licensing and Other Arrangements

We are party to a number of license, acquisition, option and other agreements that have granted us rights to develop our product candidates and conduct our research and development programs. These agreements generally impose license fee, milestone payment, royalty payment and diligence obligations on us. Our material in-license and acquisition agreements are described below.

In the future, we may enter into additional acquisition or license agreements, particularly if we choose to acquire or in-license additional product candidates or other technologies, including sustained release delivery technologies for ~~Zimura~~ACP, and further expand our product pipeline. We expect that any future acquisition or license agreements would impose similar obligations on us. In the future, we may ~~also~~seek ~~enter into agreements to out-license intellectual property to our~~ collaboration ~~and~~opportunities ~~research partners to assist in the development and, if approved, commercialization of our product candidates, including~~ for ~~the future development and potential commercialization of IC-100 and IC-200. We may out-license certain rights to any of~~ our product candidates if we believe the arrangement could assist us in the development or potential commercialization of such product candidate and would otherwise help us pursue our business plan and strategic goals.

~~Zimura~~ACP - Archemix C5 License Agreement

In September 2011, we entered into an amended and restated exclusive license agreement with Archemix relating to anti-C5 aptamers, which we refer to as the C5 License Agreement. The C5 License Agreement superseded a July 2007 agreement between us and Archemix. Under the C5 License Agreement, we hold exclusive worldwide licenses, subject to certain pre–existing rights, under specified patents and technology owned or controlled by Archemix to develop, make, use, sell, offer for sale, distribute for sale, import and export pharmaceutical products comprised of or derived from an anti-C5 aptamer for the prevention, treatment, cure or control of human indications, diseases, disorders or conditions of the eye, adnexa of the eye, orbit and optic nerve, other than certain expressly excluded applications.

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certain pre–existing rights, under specified patents and technology owned or controlled by Archemix to develop, make, use, sell, offer for sale, distribute for sale, import and export pharmaceutical products comprised of or derived from an anti-C5 aptamer for the prevention, treatment, cure or control of human indications, diseases, disorders or conditions of the eye, adnexa of the eye, orbit and optic nerve, other than certain expressly excluded applications.

Financial Terms

In connection with the C5 License Agreement, as amended, we paid Archemix an upfront licensing fee of $1.0 million and issued to Archemix an aggregate of 2,000,000 shares of our series A-1 preferred stock and 500,000 shares of our series B-1 preferred stock. We have paid Archemix an aggregate of $9.0 million in fees based on our achievement of specified clinical milestone events under the C5 License Agreement, including two milestone payments of $1.0 million and $6.0 million triggered by the positive 12-month data from, and by completion of, the GATHER1 trial, which we paid in March 2020 and October 2020, respectively.

Under the C5 License Agreement, for each anti-C5 aptamer product that we may develop under the agreement, including ~~Zimura~~ACP, we are obligated to make additional payments to Archemix of up to an aggregate of $50.5 million if we achieve specified development, clinical and regulatory milestones, with $24.5 million of such payments relating to a first indication, $23.5 million of such payments relating to second and third indications and $2.5 million of such payments relating to sustained delivery applications. Under the C5 License Agreement, we are also obligated to make additional payments to Archemix of up to an aggregate of $22.5 million if we achieve specified commercial milestones based on net product sales of all anti-C5 products licensed under the agreement. We are also obligated to pay Archemix a double-digit percentage of specified non-royalty payments we may receive from any sublicensee of our rights under the C5 License Agreement. We are not obligated to pay Archemix a running royalty based on net product sales in connection with the C5 License Agreement.

Diligence Obligations

We are required to exercise commercially reasonable efforts in developing and commercializing at least one anti-C5 aptamer product and in undertaking actions required to obtain regulatory approvals necessary to market such product in the United States, the European Union, and Japan, and in such other markets where we determine that it is commercially reasonable to do so.

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Term and Termination

Unless earlier terminated, the C5 License Agreement will expire upon the latest of 12 years after the first commercial sale in any country of the last licensed product, the expiration of the last-to-expire valid claim of the licensed patents that covers a licensed product, and the date on which no further payments of sublicensing income are to be received by us.

Either we or Archemix may terminate the C5 License Agreement if the other party materially breaches the agreement and the breach remains uncured for a specified period. Archemix may also terminate the C5 License Agreement, or may convert our exclusive license under the agreement to a non-exclusive license, if we challenge or assist a third party in challenging the validity or enforceability of any of the patents licensed under the agreement. We may terminate the agreement at any time and for any or no reason effective at the end of a specified period following our written notice of termination to Archemix.

ACP - DelSiTech License Agreement

In June 2022, we entered into the DelSiTech License Agreement with DelSiTech, under which DelSiTech granted us a worldwide, exclusive license under specified patent rights and know-how to develop, have developed, make, have made, use, offer to sell, sell, have sold, otherwise commercialize, export and import ACP using DelSiTech’s silica-based sustained release technology for the treatment of diseases of the eye in humans, which we refer to as the Licensed Product. We may grant sublicenses of the licensed patent rights and know-how without DelSiTech’s consent.

Diligence Obligations

As a condition to the ongoing effectiveness of DelSiTech’s grant of exclusive rights, (a) we would use commercially reasonable efforts to develop the Licensed Product and to seek regulatory approval for the Licensed Product in either the United States or the European Union and (b) we would use commercially reasonable efforts to commercialize the Licensed Product following receipt of regulatory approval in the United States, France, Germany, Italy, Spain or the United Kingdom, as applicable. We have sole discretion as to the use of commercially reasonable efforts for the above, and in the event that we choose not to or fail to use commercially reasonable efforts to develop or commercialize the Licensed Product, DelSiTech’s sole remedy for such failure is to convert the licenses granted to us under the DelSiTech License Agreement from exclusive to non-exclusive.

Financial Terms

In June 2022, we paid DelSiTech a €1.25 million upfront license fee, which we have recognized as a research and development expense. We further agreed to pay DelSiTech up to an aggregate of €35.0 million if we achieve specified clinical and development milestones with respect to the Licensed Product. In addition, we agreed to pay DelSiTech up to an aggregate of €60.0 million if we achieve specified commercial sales milestones with respect to worldwide net sales of the Licensed Product.

We are also obligated to pay DelSiTech royalties at a low single-digit percentage of net sales of the Licensed Product. The royalties payable by us are subject to reduction under specified circumstances. Our obligation to pay royalties under the

DelSiTech License Agreement will continue on a country-by-country basis until the later of: (a) the expiration of the last-to-expire licensed patent rights covering the Licensed Product in the country of sale, or (b) expiration of all regulatory exclusivity for the Licensed Product in the country of sale.

Term and Termination

The DelSiTech License Agreement also contains representations and warranties, covenants, indemnification and other negotiated provisions, including confidentiality obligations, customary for transactions of this nature. Unless earlier terminated by us or DelSiTech, the DelSiTech License Agreement will expire on a country-by-country basis upon the expiration of our obligation to pay royalties to DelSiTech on net sales of the Licensed Product. Upon expiration of the DelSiTech License Agreement, the licenses granted by DelSiTech to us will become fully paid up and irrevocable. We may terminate the DelSiTech License Agreement at any time for any reason upon 60 days’ prior written notice to DelSiTech. Either party may also terminate the DelSiTech License Agreement if the other party materially breaches the DelSiTech License Agreement and does not cure such breach within a specified cure period.

Following any termination of the DelSiTech License Agreement prior to expiration of the term of the DelSiTech License Agreement, all rights to the licensed patent rights and know-how that DelSiTech granted to us will revert to DelSiTech, subject to our right to sell off any Licensed Product in our inventory as of the effectiveness of such termination.

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IC-500 - Inception 4 Merger Agreement

In October 2018, we acquired IC-500 and a number of other HtrA1 inhibitors through our acquisition of Inception 4, Inc., or Inception 4, which was previously a privately held biotechnology company controlled by funds owned by Versant Ventures. We and Inception 4 entered into an agreement and plan of merger, which we refer to as the Inception 4 Merger Agreement, pursuant to which we acquired Inception 4 through a merger transaction, referred to as the Inception 4 Merger. Following the Inception 4 Merger, Inception 4 was merged into our wholly-owned subsidiary Orion, which currently owns the rights to IC-500 and the other HtrA1 inhibitors acquired in the Inception 4 Merger.

As upfront consideration for the Inception 4 Merger, the former equityholders of Inception 4 received 5,044,201 shares of our common stock, and in December 2018, they received an additional 130,526 shares of our common stock following finalization of customary post-closing adjustments. As part of the transaction, we received approximately $6.1 million in cash.

Contingent Consideration

In addition, pursuant to the Inception 4 Merger Agreement, the former equityholders of Inception 4 will be entitled to receive contingent future payments from us based on the achievement of certain clinical and regulatory milestones of up to an aggregate maximum amount of $105 million, with $45 million of such potential payments relating to GA and $60 million of such potential payments relating to wet AMD. These future milestone payments will be payable in the form of shares of our common stock, calculated based on the price of our common stock over a five-trading day period preceding the achievement of the relevant milestone, unless and until the issuance of such shares would, together with all other shares issued in connection with the Inception 4 Merger, exceed an overall maximum limit of approximately 7.2 million shares, which is equal to 19.9% of the number of issued and outstanding shares of our common stock as of the close of business on the business day prior to the closing date of the Inception 4 Merger, and will be payable in cash thereafter.

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aggregate maximum amount of $105 million, with $45 million of such potential payments relating to GA and $60 million of such potential payments relating to wet AMD. These future milestone payments will be payable in the form of shares of our common stock, calculated based on the price of our common stock over a five-trading day period preceding the achievement of the relevant milestone, unless and until the issuance of such shares would, together with all other shares issued in connection with the Inception 4 Merger, exceed an overall maximum limit of approximately 7.2 million shares, which is equal to 19.9% of the number of issued and outstanding shares of our common stock as of the close of business on the business day prior to the closing date of the Inception 4 Merger, and will be payable in cash thereafter.

Diligence Obligation

We agreed to use commercially reasonable efforts to perform the activities described in an agreed-upon development plan outlining certain activities for developing at least one HtrA1 inhibitor for the treatment of GA. Our maximum aggregate liability for any and all breaches of our obligation under the Inception 4 Merger Agreement to use commercially reasonable efforts to develop an HtrA1 inhibitor is limited to $5 million.

Other Terms and Conditions

The Inception 4 Merger Agreement contains customary representations, warranties and covenants for both Inception 4 and our company as the purchaser. The representations and warranties generally survived until the first anniversary of the closing date, with certain specified representations and warranties surviving to 30 months after the closing date and other specified representations and warranties surviving to the expiration of the applicable statute of limitations. The Inception 4 Merger Agreement also contains customary indemnification provisions whereby the former equityholders of Inception 4 will indemnify us and certain affiliated parties for any losses arising out of breaches of the representations, warranties and covenants of Inception 4 under the Inception 4 Merger Agreement; pre-closing tax matters; appraisal claims of former Inception 4 stockholders; any pre-closing indebtedness or expenses not previously adjusted for at the closing; fraud with respect to representations and warranties of Inception 4; and certain other matters.

License Agreement with UFRF and Penn for IC-100

In June 2018, we entered into an exclusive global license agreement with UFRF and Penn, which we refer to as the RHO-adRP License Agreement. Under the RHO-adRP License Agreement, UFRF and Penn granted us a worldwide, exclusive license under specified patent rights and a worldwide, non-exclusive license under specified know-how, including specified preclinical data, to manufacture, develop and commercialize certain AAV gene therapy products for the treatment of rhodopsin-mediated diseases. The rights granted under the RHO-adRP License Agreement included certain patent rights covering IC-100, our novel AAV gene therapy product candidate intended to treat RHO-adRP.

We may grant sublicenses of the licensed patent rights and know-how without the consent of the UFRF and Penn to certain affiliates and to biopharmaceutical companies that have a minimum market capitalization at the time such sublicense is granted and may otherwise grant sublicenses of the licensed patent rights and know-how with the consent of UFRF and Penn, not to be unreasonably withheld.

Diligence Obligations

We agreed to use commercially reasonable efforts to pursue an agreed-upon development plan with the intent to develop a licensed product for sale within at least the United States and two major European countries and, subject to obtaining marketing approval, to commercialize a licensed product in at least the United States and two major European countries. In addition, we agreed to meet specified development and commercial milestones with respect to a licensed product by specified dates, as the same may be extended under the terms of the RHO-adRP License Agreement.

Financial Terms

In June 2018, we paid a $0.5 million upfront license issuance fee in connection with entry into the agreement, as well as accrued patent prosecution expenses of approximately $30 thousand. Under the agreement, we agreed to pay an annual license maintenance fee in the low double-digit thousands of dollars, which will be payable on an annual basis until the first commercial sale of a licensed product. In addition, we agreed to reimburse UFRF for the costs and expenses of patent prosecution and maintenance related to the licensed patent rights.

We further agreed to pay UFRF, on behalf of both licensors, up to an aggregate of $23.5 million if we achieve specified clinical, marketing approval and reimbursement approval milestones with respect to a licensed product and additionally, up to an aggregate of $70.0 million if we achieve specified commercial sales milestones with respect to a licensed product.

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We are also obligated to pay UFRF, on behalf of both licensors, royalties at a low single-digit percentage of net sales of licensed products. Such royalties are subject to customary reductions for lack of patent coverage and loss of regulatory exclusivity. In addition, such royalties with respect to any licensed product in any country may be offset by a specified portion of any royalty payments actually paid by us with respect to such licensed product in such country under third-party licenses for patent rights or other intellectual property rights that are necessary to manufacture, develop and commercialize the licensed product in such country. Our obligation to pay royalties under the RHO-adRP License Agreement will continue on a licensed product-by-licensed product and country-by-country basis until the latest of:

•the expiration of the last-to-expire licensed patent rights covering a licensed product in the country of sale;

•the expiration of regulatory exclusivity covering a licensed product in the country of sale; and

•ten years from the first commercial sale of the applicable licensed product in the country of sale.

Beginning on the earlier of the calendar year following the first commercial sale of a licensed product and the first business day of 2031, we are also obligated to pay certain minimum royalties, not to exceed an amount in the low hundreds of thousands of dollars on an annual basis, which minimum royalties are creditable against our royalty obligation with respect to net sales of licensed products due for the year in which the minimum royalty is paid.

If we or an affiliate sublicenses any of the licensed patent rights to a third party, we will be obligated to pay UFRF, on behalf of both licensors, a low double-digit percentage of the consideration received in exchange for such sublicense, with the applicable percentage based upon the stage of development of the sublicensed product at the time we or the applicable affiliate enters into the sublicense.

If we receive a rare pediatric disease priority review voucher from the FDA in connection with obtaining marketing approval for a licensed product and we subsequently use such priority review voucher in connection with a different product candidate, we will be obligated to pay UFRF, on behalf of both licensors, aggregate payments in the low double-digit millions of dollars based on certain marketing approval and commercial sales milestones with respect to such other product candidate. In addition, if we sell such a priority review voucher to a third party, we will be obligated to pay UFRF, on behalf of both licensors, a low double-digit percentage of any consideration received from such third party in connection with such sale.

Term and Termination

Unless earlier terminated by us, the RHO-adRP License Agreement will expire upon the expiration of our obligation to pay royalties to UFRF on net sales of licensed products. We may terminate the agreement at any time for any reason upon prior written notice to UFRF. Penn or UFRF may terminate the agreement if we materially breach the agreement and do not cure such breach within a specified cure period, if we experience a specified insolvency event, if we cease to carry on the entirety of our business related to the licensed patent rights, if we cease for more than four consecutive quarters to make any payment of earned royalties on net sales of licensed products following the commencement of commercialization thereof, unless such cessation is based on safety concerns that we are actively attempting to address, or if we or an affiliate challenges or assists a third party in challenging the validity, scope, patentability, and/or enforceability of the licensed patent rights.

Following any termination of the agreement prior to expiration of the term of the agreement, all rights to the licensed patent rights and know-how granted to us will revert to UFRF and Penn.

License Agreement with Penn and UFRF for IC-200

In April 2019, we entered into an exclusive global license agreement, which we refer to as the BEST1 License Agreement, with Penn and UFRF. We entered into the BEST1 License Agreement by exercising our exclusive option rights under an option agreement that we previously entered into with Penn and UFRF in October 2018. Under the BEST1 License Agreement, Penn and UFRF granted us a worldwide, exclusive license under specified patent rights and specified know-how and a worldwide, non-exclusive license under other specified know-how to research, develop, manufacture and commercialize certain AAV gene therapy products, including IC-200, for the treatment of Best disease and other BEST1-related IRDs.

We have agreed to use commercially reasonable efforts to pursue an agreed-upon development plan with the intent to develop a licensed product for sale within at least the United States and two major European countries and, subject to obtaining marketing approval, to commercialize such product in at least the United States and two major European countries. In addition, we have agreed to meet specified development and regulatory milestones with respect to a licensed product by specified dates, as the same may be extended under the terms of the agreement.

We may grant sublicenses of the licensed patent rights and know-how, without the consent of Penn or UFRF, to certain affiliates and to biopharmaceutical companies that have a minimum market capitalization at the time such sublicense is

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granted, and may otherwise grant sublicenses to the licensed patent rights and know-how with the consent of Penn and UFRF, not to be unreasonably withheld.

Financial Terms

In May 2019, we paid Penn, for the benefit of Penn and UFRF, a $0.2 million upfront license issuance fee, which was recorded as a research and development expense, and we paid UFRF accrued patent prosecution expenses of approximately $18 thousand, which was recorded as a general and administrative expense. We have also agreed to pay Penn, for the benefit of Penn and UFRF, an annual license maintenance fee in the low double-digit thousands of dollars, which fee will be payable on an annual basis until the first commercial sale of a licensed product. In addition, we have agreed to pay Penn, for the benefit of Penn and UFRF, a one-time patent grant fee in the low triple-digit thousands of dollars, upon the issuance of a U.S. patent that claims inventions disclosed in the licensed patent rights or know-how or inventions generated under certain related sponsored research agreements with Penn or UFRF, and that is exclusively licensed to us. Furthermore, we have agreed to reimburse Penn and UFRF for the costs and expenses of patent prosecution and maintenance related to the licensed patent rights.

We have further agreed to pay Penn, for the benefit of Penn and UFRF, up to an aggregate of $15.7 million if we achieve specified clinical, marketing approval and reimbursement approval milestones with respect to one licensed product, and up to an aggregate of an additional $3.1 million if we achieve these same milestones with respect to a different licensed product. In addition, we have agreed to pay Penn, for the benefit of Penn and UFRF, up to an aggregate of $48.0 million if we achieve specified commercial sales milestones with respect to one licensed product, and up to an aggregate of an additional $9.6 million if we achieve these same milestones with respect to a different licensed product.

We are also obligated to pay Penn, for the benefit of Penn and UFRF, royalties at a low single-digit percentage of net sales of licensed products. Such royalties are subject to customary deductions, credits, and reductions for lack of patent coverage and loss of regulatory exclusivity. In addition, such royalties with respect to any licensed product in any country may be offset by a specified portion of any royalty payments actually paid by us with respect to such licensed product in such country under third-party licenses to patent rights or other intellectual property rights that are necessary to research, develop, manufacture and commercialize the licensed product in such country. Our obligation to pay royalties under the BEST1 License Agreement will continue on a licensed product-by-licensed product and country-by-country basis until the latest of:

•the expiration of the last-to-expire licensed patent rights covering the sale of the applicable licensed product in the country of sale;

•the expiration of regulatory exclusivity covering the applicable licensed product in the country of sale; and

•10 years from the first commercial sale of the applicable licensed product in the country of sale.

Beginning on the earlier of the calendar year following the first commercial sale of a licensed product and calendar year 2032, we are also obligated to pay certain minimum royalties, not to exceed an amount in the mid tens of thousands of dollars on an annual basis, which minimum royalties are creditable against our royalty obligation with respect to net sales of licensed products due in the year the minimum royalty is paid.

If we or any of our affiliates sublicense any of the licensed patent rights to a third party, we will be obligated to pay Penn, for the benefit of Penn and UFRF, a high single-digit to a mid ten's percentage of the consideration received in exchange for such sublicense, with the applicable percentage based upon the stage of development of the sublicensed product at the time we or the applicable affiliate enters into the sublicense.

If we receive a rare pediatric disease priority review voucher from the FDA in connection with obtaining marketing approval for a licensed product and we subsequently use such priority review voucher in connection with a different product candidate outside the scope of the BEST1 License Agreement, we will be obligated to pay Penn, for the benefit of Penn and UFRF, aggregate payments in the low double-digit millions of dollars based on certain approval and commercial sales milestones with respect to such other product candidate. In addition, if we sell such a priority review voucher to a third party, we will be obligated to pay Penn, for the benefit of Penn and UFRF, a high single-digit percentage of any consideration received from such third party in connection with such sale.

Term and Termination

The BEST1 License Agreement, unless earlier terminated by us or Penn or UFRF, will expire upon the expiration of our obligation to pay royalties to Penn, for the benefit of Penn and UFRF, on net sales of licensed products. Before the effectiveness of an IND for a licensed product, we may terminate the BEST1 License Agreement with respect to such licensed product or in its entirety, at any time for any reason upon prior written notice to Penn and UFRF. Following the effectiveness of an IND for a licensed product, we may terminate the BEST1 License Agreement with respect to such licensed product by

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providing Penn prior written notice and a certification that we are ceasing all use, research and development and commercialization of such licensed product, subject to certain limited exceptions. We may also terminate the BEST1 License Agreement if Penn or UFRF materially breaches the BEST1 License Agreement and does not cure such breach within a specified cure period.

Penn or UFRF may terminate the BEST1 License Agreement if we materially breach the BEST1 License Agreement and do not cure such breach within a specified cure period, if we experience a specified insolvency event, if we cease to carry on the entirety of our business related to the licensed patent rights, if we cease for more than four consecutive quarters to make any payment of earned royalties on net sales of licensed products following the commencement of commercialization thereof, unless such cessation is based on safety concerns that we are actively attempting to address, or if we, any of our affiliates or any of our sublicensees challenge or assist a third party in challenging the validity, scope, patentability, and/or enforceability of the licensed patent rights. If we materially breach certain diligence obligations under the BEST1 License Agreement with respect to only one licensed product, then Penn and UFRF may only terminate our rights and licenses under the BEST1 License Agreement for such licensed product, but not for other licensed products.

Following any termination of the BEST1 License Agreement prior to expiration of the term of the BEST1 License Agreement, all rights to the licensed patent rights and know-how that Penn and UFRF granted to us will revert to Penn and UFRF.

License Agreement with UMass for the miniCEP290 Program

In July 2019, we entered into an Exclusive License Agreement, which we refer to as the miniCEP290 License Agreement, with UMass. We entered into the miniCEP290 License Agreement by exercising our exclusive option rights under an option agreement and a sponsored research agreement that we previously entered into with UMass in February 2018. Under the miniCEP290 License Agreement, UMass granted us a worldwide, exclusive license under specified patent rights and specified biological materials and a non-exclusive license under specified know-how to make, have made, use, offer to sell, sell, have sold and import products for the treatment of diseases associated with mutations in the CEP290 gene, including LCA10. We may grant sublicenses of the licensed patent rights and know-how without the consent of UMass.

We have agreed to use diligent efforts to develop licensed products and to introduce such licensed products into the commercial market. Subject to obtaining marketing approval, we agreed to make any approved licensed product reasonably available to the public. In addition, we have agreed to meet specified development and regulatory milestones with respect to a licensed product by specified dates, as the same may be extended under the terms of the miniCEP290 License Agreement.

Financial Terms

In July 2019, we issued to UMass 75,000 shares of our common stock following execution of the miniCEP290 License Agreement pursuant to an exemption from registration afforded by Section 4(a)(2) of the Securities Act of 1933, as amended, or the Securities Act. In September 2019, we paid UMass a $0.4 million upfront license fee, which was recorded as a research and development expense, and we paid UMass accrued patent prosecution expenses of approximately $18 thousand, which was recorded as a general and administrative expense.

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the Securities Act. In September 2019, we paid UMass a $0.4 million upfront license fee, which was recorded as a research and development expense, and we paid UMass accrued patent prosecution expenses of approximately $18 thousand, which was recorded as a general and administrative expense.

We have also agreed to pay UMass an annual license maintenance fee in the low double-digit thousands of dollars, which fee will be payable on an annual basis until the expiration of the royalty term for the licensed products. Furthermore, we have agreed to reimburse UMass for the costs and expenses of patent prosecution and maintenance related to the licensed patent rights.

We have further agreed to pay UMass up to an aggregate of $14.75 million in cash and issue up to 75,000 shares of our common stock if we achieve specified clinical and regulatory milestones with respect to a licensed product. In addition, we have agreed to pay UMass up to an aggregate of $48.0 million if we achieve specified commercial sales milestones with respect to a licensed product.

We are also obligated to pay UMass royalties at a low single-digit percentage of net sales of licensed products. Our obligation to pay royalties under the miniCEP290 License Agreement will continue on a licensed product-by-licensed product and country-by-country basis until the later of: (a) the expiration of the last-to-expire licensed patent rights covering the sale of the applicable licensed product in the country of sale, or (b) 10 years from the first commercial sale of the applicable licensed product in the country of sale. Beginning with the calendar year following receipt of marketing approval for a licensed product, we are also obligated to pay certain minimum royalties, not to exceed an amount in the mid-double-digit thousands of dollars on an annual basis, which minimum royalties are creditable against our royalty obligation with respect to net sales of licensed products due in the year the minimum royalty is paid.

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If we or any of our affiliates sublicenses any of the licensed patent rights or know-how to a third party, we will be obligated to pay UMass a high single-digit to a mid-tens percentage of the consideration received in exchange for such sublicense, with the applicable percentage based upon the stage of development of the licensed products at the time we or the applicable affiliate enters into the sublicense.

If we receive a rare pediatric disease priority review voucher, or a priority review voucher, from the FDA in connection with obtaining marketing approval for a licensed product, and we subsequently use such priority review voucher in connection with a different product candidate outside the scope of the miniCEP290 License Agreement, we will be obligated to pay UMass a low-tens percentage of the fair market value of the priority review voucher at the time of approval of such product candidate and a low-twenties percentage of the fair market value of the priority review voucher at the time of achievement of a specified commercial sales milestone for such other product candidate. In addition, if we sell such a priority review voucher to a third party, we will be obligated to pay UMass a low-thirties percentage of any consideration received from such third party in connection with such sale.

Term and Termination

The miniCEP290 License Agreement, unless earlier terminated by us or UMass, will expire upon the expiration of our obligation to pay royalties to UMass on net sales of licensed products. We may terminate the miniCEP290 License Agreement at any time for any reason upon prior written notice to UMass. We may also terminate the miniCEP290 License Agreement if UMass materially breaches the miniCEP290 License Agreement and does not cure such breach within a specified cure period.

UMass may terminate the miniCEP290 License Agreement if we materially breach the miniCEP290 License Agreement and do not cure such breach within a specified cure period.

Following any termination of the miniCEP290 License Agreement prior to expiration of the term of the miniCEP290 License Agreement, all rights to the licensed patent rights and know-how that UMass granted to us will revert to UMass.

Government Regulation and Product Approvals

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the European Union, extensively regulate, among other things, the research, development, testing, manufacture, pricing, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products. The processes for obtaining marketing approvals in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other legal requirements of regulatory authorities, require the expenditure of substantial time and financial resources.

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Review and Approval of Drugs and Biologics in the United States

In the United States, the FDA approves and regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and implementing regulations. Biologic products, including gene therapy products, are licensed for marketing under the Public Health Service Act, or PHSA. A company, institution, or organization which takes responsibility for the initiation and management of a clinical development program for such products, and for their regulatory approval, is typically referred to as a sponsor. The failure to comply with requirements under the FDCA or PHSA and other applicable laws at any time during the product development process, approval process or after approval may subject an applicant and/or sponsor to a variety of administrative or judicial sanctions, including refusal by the FDA to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and other types of letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice or other governmental entities, including state agencies.

A drug candidate must be approved by the FDA through a new drug application, or NDA. A biologic candidate is licensed by the FDA through approval of a biologic license application, or BLA. A sponsor seeking approval to market and distribute a new product in the United States must typically undertake the following:

•completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or GLP, regulations;

•completion of the manufacture, under current Good Manufacturing Practices, or cGMP, conditions, of the drug substance and drug product that the sponsor intends to use in human clinical trials along with required analytical and stability testing;

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•design of a clinical trial protocol and submission to the FDA of an IND, which must take effect before human clinical trials may begin;

•approval by an independent institutional review board, or IRB, representing each clinical trial site before each clinical trial may be initiated at that clinical site;

•performance of adequate and well-controlled human clinical trials in accordance with good clinical practices, or GCP, to establish the safety and efficacy of the proposed drug product for each indication for which the sponsor is seeking approval and the safety, potency and purity of a candidate biologic product for each indication for which the sponsor is seeking approval;

•preparation and submission to the FDA of an application requesting marketing approval for one or more proposed indications;

•review by an FDA advisory committee, where appropriate or if applicable;

•satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with cGMP requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;

•satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;

•payment of user fees and securing FDA approval of the application; and

•compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy, or REMS, and the potential requirement to conduct post-approval studies.

Preclinical Studies

Before a sponsor begins testing a drug or biologic with potential therapeutic value in humans, the product candidate must undergo preclinical testing. Preclinical studies include laboratory evaluation of product chemistry, toxicity and formulation, and the purity and stability of the substance, as well as in vitro and animal studies to assess the potential safety and activity of the product candidate for initial testing in humans and to establish a rationale for therapeutic use. These studies are typically referred to as IND-enabling studies. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations and the United States Department of Agriculture’s Animal Welfare Act, if applicable.

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The IND and IRB Processes

An IND is an exemption from the FDCA that allows an unapproved product to be shipped in interstate commerce for use in an investigational clinical trial and a request for FDA authorization to administer an investigational product to humans. Such authorization must be secured prior to interstate shipment and administration of any product candidate that is not the subject of an approved application. In support of a request for an IND, sponsors must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND. In addition, the results of the preclinical tests, together with manufacturing information, analytical data and any available clinical data or literature and plans for clinical trials, among other things, are submitted to the FDA as part of an IND. The FDA requires a 30-day waiting period after the filing of each IND before clinical trials may begin. This waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks. At any time during this 30-day period, or thereafter, the FDA may raise concerns or questions about the conduct of the trials as outlined in the IND and impose a clinical hold or partial clinical hold. In this case, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin or re-commence.

In addition to the foregoing IND requirements, an IRB or ethics committee representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review and re-approve the study at least annually. The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects. An IRB must operate in compliance with FDA regulations. An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.

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it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.

Additionally, some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee, or DSMB. This group provides authorization as to whether or not a trial may move forward at designated check points based on certain available data from the study to which only the DSMB may access. Suspension or termination of development during any phase of clinical trials can occur if it is determined that the participants are being exposed to an unacceptable health risk. Other reasons for suspension or termination may be made by the sponsor based on evolving business objectives and/or competitive climate.

Human Clinical Trials in Support of an Application

Clinical trials involve the administration of an investigational product to human subjects under the supervision of qualified investigators in accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial. Clinical trials are conducted under written study protocols detailing, among other things, the inclusion and exclusion criteria, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

Human clinical trials are typically conducted in four sequential phases, which may overlap or be combined:

•Phase 1. The product candidate is initially introduced into a small number of healthy human subjects or, in certain indications, patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness and to determine optimal dosage.

•Phase 2. The product candidate is administered to a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage. Phase 2a clinical trials tend to be smaller pilot studies for the purpose of demonstrating biological activity and clinical "proof of concept." Phase 2b studies tend to be larger studies focused on finding the optimal dosage and may be controlled.

•Phase 3. These clinical trials are commonly referred to as “pivotal” studies, which denotes a study that presents the data that the FDA or other relevant regulatory agency will use to determine whether or not to approve a product candidate. The product candidate is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, identify adverse effects, establish the overall risk–benefit profile of the product and to provide adequate information for the labeling of the product.

•Phase 4. Post-approval studies may be required to be conducted after initial marketing approval. These studies are used to gain additional experience from the treatment of patients in the intended therapeutic indication.

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A clinical trial may combine the elements of more than one phase and the FDA often requires more than one Phase 3 trial to support marketing approval of a product candidate. A company’s designation of a clinical trial as being of a particular phase is not necessarily indicative that the study will be sufficient to satisfy the FDA requirements of that phase because this determination cannot be made until the protocol and data have been submitted to and reviewed by the FDA. Moreover, a pivotal trial is a clinical trial that is believed to satisfy FDA requirements for the evaluation of a product candidate’s safety and efficacy such that it can be used, alone or with other pivotal or non-pivotal trials, to support regulatory approval. Generally, pivotal trials are Phase 3 trials, but they may be Phase 2 trials if the design provides a well-controlled and reliable assessment of clinical benefit, particularly in an area of unmet medical need.

In December 2022, with the passage of Food and Drug Omnibus Reform Act, or FDORA, Congress required sponsors to develop and submit a diversity action plan for each phase 3 clinical trial or any other “pivotal study” of a new drug or biological product. These plans are meant to encourage the enrollment of more diverse patient populations in late-stage clinical trials of FDA-regulated products. Specifically, actions plans must include the sponsor’s goals for enrollment, the underlying rationale for those goals, and an explanation of how the sponsor intends to meet them. In addition to these requirements, the legislation directs the FDA to issue new guidance on diversity action plans.

Progress reports detailing the safety results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur. In addition, IND safety reports must be submitted to the FDA for any of the following: serious and unexpected suspected adverse reactions; findings from other studies or animal or in vitro testing that suggest a significant risk to humans exposed to the product candidate; and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The FDA, the sponsor or the DSMB may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk.

56Finally, sponsors of clinical trials are required to register and disclose certain clinical trial information on a public registry (clinicaltrials.gov) maintained by the U.S. National Institutes of Health, or NIH. In particular, information related to the product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the registration of the clinical trial. Both NIH and the FDA have recently signaled the government’s willingness to begin enforcing those requirements against non-compliant clinical trial sponsors. The failure to submit clinical trial information to clinicaltrials.gov, as required, is a prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to $10,000 for each day the violation continues. Although the FDA has historically not enforced these reporting requirements due to HHS’s long delay in issuing final implementing regulations, those regulations have now been issued and the FDA has issued several Notices of Noncompliance to manufacturers since April 2021.

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Finally, sponsors of clinical trials are required to register and disclose certain clinical trial information on a public registry (clinicaltrials.gov) maintained by the U.S. National Institutes of Health, or NIH. In particular, information related to the product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the registration of the clinical trial. Both NIH and the FDA have recently signaled the government’s willingness to begin enforcing those requirements against non-compliant clinical trial sponsors. The failure to submit clinical trial information to clinicaltrials.gov, as required, is a prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to $10,000 for each day the violation continues.

Expanded Access to an Investigational Drug for Treatment Use

Expanded access, sometimes called “compassionate use,” is the use of investigational new drug products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options. Expanded access allows a patient to obtain an investigational new drug when enrolling in a clinical trial for that drug is difficult or not feasible for the patient. FDA regulations allow access to investigational drugs under an IND by the sponsor or the treating physician for treatment purposes on a case-by-case basis in certain circumstances, subject to FDA approval. There is no obligation for a sponsor to make its drug products available for expanded access. In April 2020, we adopted an expanded access policy, which is, asavailable ~~required~~on byour website in accordance with the 21st Century Cures Act~~, or Cures Act, available on our website~~.

In addition, the Right to Try Act, signed into law in May 2018, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval. Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without needing FDA approval under the expanded access program. There is no obligation for a drug manufacturer to make its drug products available to eligible patients under the Right to Try Act.

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Manufacturing and Other Regulatory Requirements

Concurrent with clinical trials, sponsors usually complete additional animal safety studies, develop additional information about the chemistry and physical characteristics of the product candidate and finalize a process for manufacturing commercial quantities of the product candidate in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other criteria, the sponsor must develop methods for testing the identity, strength, quality, and purity of the finished product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

Specifically, the FDA’s regulations require that pharmaceutical products be manufactured in specific approved facilities and in accordance with cGMPs. The cGMP regulations include requirements relating to organization of personnel, buildings and facilities, equipment, control of components and product containers and closures, production and process controls, packaging and labeling controls, holding and distribution, laboratory controls, records and reports and returned or salvaged products. Manufacturers and other entities involved in the manufacture and distribution of approved pharmaceuticals are required to register their establishments with the FDA and some state agencies, and they are subject to periodic unannounced inspections by the FDA for compliance with cGMPs and other requirements. Inspections must follow a “risk-based schedule” that may result in certain establishments being inspected more frequently. Manufacturers may also have to provide, on request, electronic or physical records regarding their establishments. Delaying, denying, limiting, or refusing inspection by the FDA may lead to a product being deemed to be adulterated. Changes to the manufacturing process, specifications or container closure system for an approved product are strictly regulated and often require prior FDA approval before being implemented. The FDA’s regulations also require, among other things, the investigation and correction of any deviations from cGMP and the imposition of reporting and documentation requirements upon the sponsor and any third-party manufacturers involved in producing the approved product.

Special Regulations and Guidance Governing Gene Therapy Products

The FDA has defined a gene therapy product as one that mediates its effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome and which is administered as nucleic acids, viruses, or genetically engineered microorganisms. The products may be used to modify cells in vivo or transferred to cells ex vivo prior to administration to the recipient.

The FDA has issued various guidance documents regarding gene therapies, including final guidance documents released in January 2020 relating to chemistry, manufacturing and controls information for gene therapy INDs, long-term follow-up after the administration of gene therapy products, gene therapies for rare diseases and gene therapies for retinal disorders. Although the FDA has indicated that these and other guidance documents it previously issued are not legally binding, we believe that our compliance with them is likely necessary to gain approval for any gene therapy product candidate we may develop. The guidance documents provide additional factors that the FDA will consider at each of the above stages of development and relate to, among other things, the proper preclinical assessment of gene therapies; the proper design of tests to measure product potency in support of an IND or BLA application; and measures to observe delayed adverse effects in subjects who have been exposed to investigational gene therapies when the risk of such effects is high. Further, the FDA usually recommends that sponsors observe subjects for potential gene therapy-related delayed adverse events for a 15-year period, including a minimum of five years of annual examinations followed by 10 years of annual queries, either in person or by questionnaire. We expect the FDA to issue additional guidance on gene therapies.

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follow-up after the administration of gene therapy products, gene therapies for rare diseases and gene therapies for retinal disorders. Although the FDA has indicated that these and other guidance documents it previously issued are not legally binding, we believe that our compliance with them is likely necessary to gain approval for any gene therapy product candidate we may develop. The guidance documents provide additional factors that the FDA will consider at each of the above stages of development and relate to, among other things, the proper preclinical assessment of gene therapies; the proper design of tests to measure product potency in support of an IND or BLA application; and measures to observe delayed adverse effects in subjects who have been exposed to investigational gene therapies when the risk of such effects is high. Further, the FDA usually recommends that sponsors observe subjects for potential gene therapy-related delayed adverse events for a 15-year period, including a minimum of five years of annual examinations followed by 10 years of annual queries, either in person or by questionnaire. We expect the FDA to issue additional guidance on gene therapies.

Special Protocol Assessment Agreements

A Special Protocol Assessment, or SPA, agreement is an agreement between a drug manufacturer and the FDA on the design and size of studies and clinical trials that can be used for approval of a drug or biological product. The FDA’s guidance on such agreements states that an agreement may not be changed by the manufacturer or the agency unless through a written agreement of the two entities or if FDA determines a substantial scientific issue essential to determining the safety or effectiveness of the drug. The protocols that are eligible for SPA agreements are: animal carcinogenicity protocols, final product stability protocols and clinical protocols for Phase 3 trials whose data will form the primary basis for an efficacy claim.

The FDA may meet with sponsors, provided certain conditions are met, for the purpose of reaching an SPA agreement on the design and size of clinical trials intended to form the primary basis of an efficacy claim in a marketing application. If a sponsor makes a reasonable written request to meet with the FDA for the purpose of reaching agreement on the design and size of a clinical trial, then the FDA will meet with the sponsor. If an agreement is reached, the FDA will reduce the agreement to writing and make it part of the administrative record. An agreement may not be changed by the sponsor or FDA after the trial begins, except with the written agreement of the sponsor and FDA, or if the director of the FDA reviewing division determines that “a substantial scientific issue essential to determining the safety or effectiveness of the drug” was identified after the testing began. If a sponsor and the FDA meet regarding the design and size of a clinical trial and the parties cannot agree that the trial design is adequate to meet the goals of the sponsor, the FDA will clearly state the reasons for the disagreement in a letter to the sponsor.

~~Review of a Product Candidate by the FDA~~55

If clinical trials are successful, the next step in the development process is the preparation and submission to the FDA of an application for marketing approval. The application is the vehicle through which sponsors formally propose that the FDA approve a new drug for marketing and sale in the United States for one or more indications. The application must contain a description of the manufacturing process and quality control methods, as well as results of preclinical tests, toxicology studies, clinical trials and proposed labeling, among other things. Every new product must be the subject of an approved application before it may be commercialized in the United States. Under federal law, the submission of most applications is subject to an application user fee, which for federal fiscal year 2022 is $3,117,218 for an application requiring clinical data. The sponsor of an approved application is also subject to an annual program fee, which for fiscal year 2022 is $369,413. Certain exceptions and waivers are available for some of these fees, such as an exception from the application fee for products with orphan designation and a waiver for certain small businesses.

Following submission of an application, the FDA conducts a preliminary review of an application within 60 calendar days of its receipt and must inform the sponsor by that time or before whether the application is sufficiently complete to permit substantive review. In the event that FDA determines that an application does not satisfy this standard, it will issue a Refuse to File, or RTF, determination to the sponsor. The FDA may request additional information rather than accept an application for filing. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in depth substantive review. Under the Prescription Drug User Fee Act, or PDUFA, the FDA has agreed to specified performance goals and timelines in the review process of applications, which goals and timelines depend on the type of product candidate for which review is sought and whether the sponsor has applied for and received from the FDA any special review status for the particular product candidate allowing for expedited review. Special review status is available for certain products that are intended to address an unmet medical need in the treatment of a serious or life–threatening disease or condition under one of the following FDA-designations: fast track designation, breakthrough therapy designation, priority review designation and regenerative medicine advanced therapy designation. The review process and the PDUFA goal date may be extended by the FDA for three additional months to consider new information or clarification provided by the sponsor to address an outstanding deficiency identified by the FDA following the original submission.

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Inbegan. ~~connection~~If ~~with~~a ~~its~~sponsor ~~review~~and ~~of an application,~~ the FDA ~~typically~~meet ~~will~~regarding ~~inspect~~ the ~~facility~~design ~~or facilities where the product is or will be manufactured, stored, packaged~~ and ~~tested.~~size ~~These~~of ~~pre–approval~~a ~~inspections~~clinical ~~may~~trial ~~cover all facilities associated with an application submission, including component manufacturing (e.g., active pharmaceutical ingredients), finished product manufacturing,~~ and ~~control~~the ~~testing~~parties ~~laboratories.~~cannot ~~The~~agree ~~FDA will not approve an application unless it determines~~ that the ~~manufacturing~~trial ~~processes~~design ~~and~~is ~~facilities are in compliance with cGMP requirements and~~ adequate to ~~assure~~meet ~~consistent~~the ~~production~~goals of the ~~product within required specifications. Additionally~~sponsor, ~~before approving an application,~~ the FDA will ~~typically~~clearly ~~inspect~~state ~~one~~the orreasons ~~more~~for ~~clinical~~the ~~sites~~disagreement toin ~~assure~~a ~~compliance~~letter ~~with~~to ~~GCP and~~ the ~~integrity of the clinical data submitted~~sponsor.

Review of a Product Candidate by the FDA

If clinical trials are successful, the next step in the development process is the preparation and submission to the FDA of an application for marketing approval. The application is the vehicle through which sponsors formally propose that the FDA approve a new drug for marketing and sale in the United States for one or more indications. The application must contain a description of the manufacturing process and quality control methods, as well as results of preclinical tests, toxicology studies, clinical trials and proposed labeling, among other things. Every new product must be the subject of an approved application before it may be commercialized in the United States. Under federal law, the submission of most applications is subject to an application user fee, which for federal fiscal year 2023 is $3,242,026 for an application requiring clinical data. The sponsor of an approved application is also subject to an annual program fee, which for fiscal year 2023 is $393,933. Certain exceptions and waivers are available for some of these fees, such as an exception from the application fee for products with orphan designation and a waiver for certain small businesses.

Following submission of an application, the FDA conducts a preliminary review of an application within 60 calendar days of its receipt and must inform the sponsor by that time or before whether the application is sufficiently complete to permit substantive review. In the event that FDA determines that an application does not satisfy this standard, it will issue a Refuse to File, or RTF, determination to the sponsor. The FDA may request additional information rather than accept an application for filing. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in depth substantive review. Under the Prescription Drug User Fee Act, or PDUFA, the FDA has agreed to specified performance goals and timelines in the review process of applications, which goals and timelines depend on the type of product candidate for which review is sought and whether the sponsor has applied for and received from the FDA any special review status for the particular product candidate allowing for expedited review. Special review status is available for certain products that are intended to address an unmet medical need in the treatment of a serious or life–threatening disease or condition under one of the following FDA-designations: fast track designation, breakthrough therapy designation, priority review designation and regenerative medicine advanced therapy designation. The review process and the PDUFA target action date may be extended by the FDA for three additional months to consider new information or clarification provided by the sponsor to address an outstanding deficiency identified by the FDA following the original submission.

In connection with its review of an application, the FDA typically will inspect the facility or facilities where the product is or will be manufactured, stored, packaged and tested. These pre–approval inspections may cover all facilities associated with an application submission, including component manufacturing (e.g., active pharmaceutical ingredients), finished product manufacturing, and control testing laboratories. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving an application, the FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted. With passage of FDORA, Congress clarified the FDA’s authority to conduct inspections by expressly permitting inspection of facilities involved in the preparation, conduct, or analysis of clinical and non-clinical studies submitted to the FDA as well as other persons holding study records or involved in the study process.

In addition, as a condition of approval, the FDA may require a sponsor to develop a REMS. REMS use risk minimization strategies beyond the professional labeling to ensure that the benefits of the product outweigh the potential risks. To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected benefit of the product, expected duration of treatment, seriousness of known or potential adverse events, and whether the product is a New Molecular Entity.

The FDA is required to refer an application for a novel product candidate to an advisory committee or explain why such referral was not made. Typically, an advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides 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.

Under the Pediatric Research Equity Act, or PREA, an application or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. With enactment of the Food and Drug Administration Safety and Innovation Act, or FDASIA, in 2012, sponsors must also submit pediatric study plans prior to the submission of the assessment data required under PREA. These plans are subject to FDA review before beginning the pediatric study. Product candidates that have received orphan designation are generally exempt from the requirements of PREA. In addition, a sponsor may apply for a waiver of the PREA requirements, which the FDA has indicated it will automatically grant for certain diseases that do not affect pediatric populations, including AMD.

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exempt from the requirements of PREA. In addition, a sponsor may apply for a waiver of the PREA requirements, which the FDA has indicated it will automatically grant for certain diseases that do not affect pediatric populations, including AMD.

The FDA’s Decision on an Application

The FDA reviews an application to determine, among other things, whether the product is safe and whether it is effective for its intended use(s), with the latter determination being made on the basis of substantial evidence. The FDA has interpreted this evidentiary standard to require at least two adequate and well-controlled clinical investigations to establish effectiveness of a new product. Under certain circumstances, however, the FDA has indicated that a single trial with certain characteristics and additional information may satisfy this standard.

After evaluating the application and all related information, including the advisory committee recommendations, if any, and inspection reports of manufacturing facilities and clinical trial sites, the FDA will issue either a Complete Response Letter, or CRL, or an approval letter. To reach this determination, the FDA must determine that the expected benefits of the proposed product outweigh its potential risks to patients. This “benefit-risk” assessment is informed by the extensive body of evidence about the product’s safety and efficacy in the NDA or potency, purity and safety in a BLA.

A CRL generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application. If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the application, the FDA will issue an approval letter. The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included. Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. If a CRL is issued, the sponsor will have one year to respond to the deficiencies identified by the FDA, at which time the FDA can deem the application withdrawn or, in its discretion, grant the sponsor an additional six month extension to respond.

If the FDA approves a product, it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess the product’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, which can materially affect the potential market and profitability of the product. The FDA may prevent or limit further marketing of a product based on the results of post–market studies or surveillance programs.

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Fast Track, Breakthrough Therapy, Priority Review and Regenerative Advanced Therapy Designations and Accelerated Approval; Rare Pediatric Disease Priority Review Voucher Program

The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment of a serious or life–threatening disease or condition. These programs are fast track designation, breakthrough therapy designation, priority review designation and regenerative advanced therapy designation. The FDA may also approve certain products based on an accelerated basis. None of these expedited programs changes the standards for approval, but each may help expedite the development or approval process governing product candidates.

Specifically, the FDA may designate a product for fast track review if it is intended, whether alone or in combination with one or more other products, for the treatment of a serious or life–threatening disease or condition, and if the product demonstrates the potential to address unmet medical needs for such a disease or condition. For fast track products, sponsors may have greater interactions with the FDA and the FDA may initiate review of sections of a fast track product’s application before the application is complete. This rolling review may be available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast track product may be effective. The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information. However, the FDA’s time period goal for reviewing a fast track application does not begin until the last section of the application is submitted. In addition, the fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process. In April 2020, the FDA granted fast track designation to ~~Zimura~~ACP for the treatment of GA secondary to dry AMD.

FDASIA established a new regulatory scheme allowing for expedited review of products designated as “breakthrough therapies.” A product may be designated as a breakthrough therapy if it is intended, either alone or in combination with one or more other products, to treat a serious or life–threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process; providing timely advice to the product sponsor regarding development and approval; involving more senior staff in the review process; assigning ~~a cross–disciplinary project lead for the review team; and taking other steps to design the clinical trials in an efficient manner.~~

The FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. The FDA determines, on a case by case basis, whether the proposed product represents a significant improvement when compared with other available therapies. Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment–limiting product reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation. A priority designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months.57

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a cross–disciplinary project lead for the review team; and taking other steps to design the clinical trials in an efficient manner. In November 2022, the FDA granted breakthrough therapy designation to ACP for GA secondary to AMD.

With passage of the Cures Act, Congress authorized the FDA to accelerate review and approval of products designated as regenerative advanced therapies. A product is eligible for this designation if it is a regenerative medicine therapy that is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product candidate has the potential to address unmet medical needs for such disease or condition. The benefits of a regenerative advanced therapy designation include early interactions with the FDA to expedite development and review, benefits available to breakthrough therapies, and potential eligibility for priority review and accelerated approval based on surrogate or intermediate endpoints.

The FDA may grant accelerated approval to a product for a serious or life–threatening condition that provides meaningful therapeutic advantage to patients over existing treatments based upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The FDA may also grant accelerated approval for such a condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality and that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. Products granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.

The FDA may award priority review vouchers, or PRVs, to sponsors of rare pediatric disease product applications that meet certain criteria. A rare pediatric disease is a rare disease where the disease is serious or life-threatening with the serious or life-threatening manifestations primarily affecting individuals from age zero to 18. A sponsor who receives approval for a drug or biologic for a rare pediatric disease may qualify for a PRV, which the sponsor may redeem to receive priority review of a subsequent marketing application for a different product. In lieu of using the PRV for one of its own product candidates, a sponsor may sell that voucher for use by a third party. Current prices for these PRVs range in the hundreds of millions of dollars. The current rare pediatric disease priority review voucher program will expire on September 30, 2024, although a drug designated as a rare pediatric disease treatment by September 30, 2024, can still receive a priority review voucher but no later than September 30, 2026.

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subsequent marketing application for a different product. In lieu of using the PRV for one of its own product candidates, a sponsor may sell that voucher for use by a third party. Current prices for these PRVs range in the hundreds of millions of dollars. The current rare pediatric disease priority review voucher program will expire on September 30, 2024, although a drug designated as a rare pediatric disease treatment by September 30, 2024 can still receive a priority review voucher but no later than September 30, 2026.

Post-Approval Requirements

Products manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product. After approval, most changes to the approved product, such as adding new indications or other label changes, or changing the manufacturing process for the approved product, are subject to additional testing and/or FDA review and approval.

In addition, manufacturers and other entities involved in the manufacture and distribution of approved products are required to register their establishments with the FDA and state agencies, and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements upon the sponsor and any third–party manufacturers that the sponsor may decide to use. Accordingly, sponsors and manufacturers must continue to spend time, money, and effort in the area of production and quality control to maintain cGMP compliance. Further, the FDA will conduct laboratory research related to the safety, purity, potency and effectiveness of pharmaceutical products.

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

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add new safety information; imposition of post-market studies or clinical trials to assess new safety risks; or imposition of distribution or other restrictions under a REMS program. Other potential consequences include, among other things:

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

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

•injunctions or the imposition of civil or criminal penalties.

The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market. Products may be promoted only for the approved indications and in accordance with the provisions of the approved label. Although health care providers may prescribe products for off-label uses in their professional judgment, manufacturers are prohibited from soliciting, encouraging or promoting unapproved uses of a product. It may be permissible, under very specific, narrow conditions, for a manufacturer to engage in nonpromotional, non-misleading communication regarding off-label information, such as distributing scientific or medical journal information. Moreover, with passage of the Pre-Approval Information Exchange Act in December 2022, sponsors of products that have not been approved may proactively communicate to payors certain information about products in development to help expedite patient access upon product approval. Previously, such communications were permitted under FDA guidance but the new legislation explicitly provides protection to sponsors who convey certain information about products in development to payors, including unapproved uses of approved products.

Generic Drugs and Exclusivity

Under the Hatch-Waxman Amendments to the FDCA, the FDA is authorized to approve generic drugs that are shown to contain the same active ingredients as, and is bioequivalent to, drugs previously approved by the FDA pursuant to NDAs, which are also known as reference listed drugs, or RLDs. To obtain approval of a generic drug, a sponsor must submit an abbreviated new drug application, or ANDA, to the FDA. An ANDA sponsor does not generally rely on its own preclinical or clinical data to demonstrate safety and effectiveness but instead can rely on preclinical and clinical testing previously conducted by the sponsor of the RLD. The ANDA sponsor must show that the generic version is identical to the RLD with respect to a number of factors, including the active ingredient, and that the generic version is "bioequivalent" to the RLD. Physicians, pharmacists and third-party payors generally consider an approved generic drug to be fully substitutable for the RLD.

The FDA is also authorized to approve an alternative type of NDA under Section 505(b)(2) of the FDCA. This type of application allows the sponsor to rely, in part, on the FDA’s previous findings of safety and efficacy for a similar product, or published literature. Specifically, Section 505(b)(2) applies to NDAs for a drug for which the investigations made to show whether or not the drug is safe for use and effective in use and relied upon by the sponsor for approval of the application “were not conducted by or for the sponsor and for which the sponsor has not obtained a right of reference or use from the person by or for whom the investigations were conducted.”

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Sponsors of RLDs are required to list in the FDA's Orange Book each patent with claims covering the RLD or approved methods of using the RLD. An ANDA sponsor is required to certify to the FDA concerning any such patents, which may be a certification that the listed patent is invalid, unenforceable or will not be infringed by the new product, which is known as a Paragraph IV certification. An ANDA sponsor that makes a Paragraph IV certification must notify the sponsor of the RLD, who may then initiate a patent infringement lawsuit in response to the notice of Paragraph IV certification. The filing of a lawsuit within 45 days of receipt of a Paragraph IV certification notice prevents the FDA from approving the ANDA until the earliest of 30 months after receipt of the Paragraph IV certification, expiration of the patent or a decision in the infringement case that is favorable to the ANDA sponsor.

Market and data exclusivity provisions under the FDCA can delay the submission or the approval of certain drug applications for competing products, including generic drugs. The FDCA provides a five-year period of non-patent data exclusivity within the United States to the first sponsor to gain 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 responsible for the pharmacological activity of the drug substance. This interpretation was confirmed with enactment of the Ensuring Innovation Act in April 2021. We expect ACP to be eligible for the five-year period of data exclusivity, if approved. During the exclusivity period, the FDA may not accept for review an ANDA or an NDA under Section 505(b)(2) of the FDCA, or an 505(b)(2) NDA, submitted by another company that references the previously approved drug. However, an ANDA or 505(b)(2) NDA may be submitted after four years if it contains a Paragraph IV certification.

The FDCA also provides three years of marketing exclusivity for an NDA, 505(b)(2) NDA, or supplement to an existing NDA or 505(b)(2) NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the sponsor, are deemed by the FDA to be essential to the approval of the application or supplement. Three-year exclusivity may be awarded for changes to a previously approved drug product, such as new indications, dosages, strengths or dosage forms of an existing drug. This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and, as a general matter, does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for generic versions of the original, unmodified drug product. The five-year and three-year exclusivities will not delay the submission or approval of a full NDA; however, a sponsor submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

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investigations and, as a general matter, does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for generic versions of the original, unmodified drug product. The five-year and three-year exclusivities will not delay the submission or approval of a full NDA; however, a sponsor submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Biosimilars and Exclusivity

The Patient Protection and Affordable Care Act, or ACA, included a subtitle called the Biologics Price Competition and Innovation Act of 2009, or BPCIA. The BPCIA established a regulatory scheme authorizing the FDA to approve biosimilars and interchangeable biosimilars. A biosimilar is a biological product that is highly similar to an existing FDA-licensed "reference product." To date, the FDA has approved a number of biosimilars and the first interchangeable biosimilar product was approved on July 30, 2021, and a second product previously approved as a biosimilar was designated as interchangeable in October 2021. The FDA has also issued numerous guidance documents outlining its approach reviewing and licensing biosimilars and interchangeable biosimilars under the PHSA.

Under the BPCIA, a manufacturer may submit an application for licensure of a biologic product that is biosimilar to a reference product. In order for the FDA to approve a biosimilar product, it must find that there are no clinically meaningful differences between the reference product and proposed biosimilar product in terms of safety, purity and potency. For the FDA to approve a biosimilar product as "interchangeable" with a reference product, the agency must find that the biosimilar product can be expected to produce the same clinical results as the reference product, and for products administered multiple times, that the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date of approval of the reference product. The FDA may not approve a biosimilar product until 12 years from the date on which the reference product was approved. Even if a product is considered to be a reference product eligible for exclusivity, another company could market a competing version of that product if the FDA approves a full BLA for such product containing the sponsor’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of their product. The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products. Since the passage of the BPCIA, there have been recent government proposals to reduce the 12-year reference product exclusivity period, but none has been enacted to date. At the same time, many states have passed laws or amendments to laws, including laws governing pharmacy practices, which are state-regulated, involving biosimilars.

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Patent Term Extension

A patent claiming a new drug product, its method of use or its method of manufacture may be eligible for a limited patent term extension, also known as patent term restoration, under the Hatch-Waxman Amendments, which permits a patent restoration of up to five years for patent term lost during product development and FDA regulatory review. Patent term extension is generally available only for drug products whose active ingredient has not previously been approved by the FDA. The restoration period granted is typically one-half the time between the effective date of an IND and the submission date of a marketing approval application, plus the time between the submission date of a marketing approval application and the ultimate approval date. Patent term extension cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date. Only one patent applicable to an approved drug product is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent in question. A patent that covers multiple drugs for which approval is sought can only be extended in connection with one of the approvals. The United States Patent and Trademark Office (USPTO) reviews and approves the application for any patent term extension in consultation with the FDA.

Orphan Drug Designation and Exclusivity

Under the Orphan Drug Act, the FDA may designate a product as an “orphan drug” if it is intended to treat a rare disease or condition, generally meaning that it affects fewer than 200,000 individuals in the United States, or more in cases in which there is no reasonable expectation that the cost of developing and making a product available in the United States for treatment of the disease or condition will be recovered from sales of the product. A company must request orphan drug designation before submitting an application for the product and the rare disease or condition. If the request is granted, the FDA will disclose the identity of the therapeutic agent and its potential use. Orphan drug designation does not shorten the PDUFA ~~goal~~target action dates for the regulatory review and approval process, although it does convey certain advantages such as tax benefits and exemption from the PDUFA application fee.

If a product with orphan designation receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease or condition for which it was designated, the product generally will receive orphan drug exclusivity. Orphan drug exclusivity means that the FDA may not approve another sponsor’s marketing application for the same product for the same indication for seven years, except in certain limited circumstances. Orphan exclusivity does not block the approval of a different product for the same rare disease or condition, nor does it block the approval of the same product for different indications. In September 2021, the FDA issued final guidance describing its current thinking on when a gene therapy product is the “same” as another product for purposes of orphan exclusivity. Under the guidance, if either the transgene or vector differs between two gene therapy products in a manner that does not reflect “minor” differences, the two products would be considered different drugs for orphan drug exclusivity purposes. The FDA indicated that it will determine whether two vectors from the same viral class are the same on a case-by-case basis and may consider additional key features in assessing sameness. If a product designated as an orphan drug ultimately receives marketing approval for an indication broader than what was designated in its orphan drug application, it may not be entitled to exclusivity.

Orphan drug exclusivity will not bar approval of another product under certain circumstances, including if a subsequent product for the same indication is shown to be clinically superior to the approved product on the basis of greater efficacy or safety or provides a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand. In September 2021, the Court of Appeals for the 11th Circuit held that, for the purpose of determining the scope of market exclusivity, the term “same disease or condition” in the statute means the designated “rare disease or condition” and could not be interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” It is unclear how this court decision will be implemented by the FDA.60

Pediatric Exclusivity

Pediatric exclusivity is another type of non-patent exclusivity in the United States and, if granted, provides for an additional six months of regulatory exclusivity. For drug products, the six month exclusivity may be attached to the term of any existing patent or regulatory exclusivity, including orphan drug exclusivity and regulatory exclusivities available under the Hatch-Waxman provisions of the FDCA. For biologic products, the six month period may be attached to any existing regulatory exclusivities but not to any patent terms. This six-month exclusivity may be granted if an application sponsor submits pediatric data that fairly respond to a written request from the FDA for such data. The data do not need to show that the product is effective in the pediatric population studied; rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted. If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patent protection covering the product are extended by six months. This is not a patent term extension, but it effectively extends the regulatory period during which the

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~~FDA~~marketing ~~cannot~~application ~~approve~~for anthe ~~ANDA~~same product for the same indication for seven years, except in certain limited circumstances. Orphan exclusivity does not block the approval of a different product for the same rare disease or ~~505(b)(2)~~condition, ~~NDA~~nor ~~that~~does ~~references~~it block the approval of the same product. ~~With~~for ~~regard~~different toindications. In ~~patents~~September 2021, the ~~six-month~~FDA ~~pediatric~~issued ~~exclusivity~~final ~~period~~guidance ~~will~~describing ~~not~~its ~~attach~~current tothinking ~~any~~on ~~patents~~when a gene therapy product is the “same” as another product for ~~which~~purposes anof ~~ANDA~~orphan exclusivity. Under the guidance, if either the transgene or ~~505(b)(2)~~vector ~~sponsor~~differs ~~submitted~~between two gene therapy products in a ~~paragraph IV~~manner ~~certification,~~that ~~unless~~does not reflect “minor” differences, the ~~NDA~~two ~~sponsor~~products orwould ~~patent~~be ~~owner~~considered ~~first~~different ~~obtains~~drugs afor ~~court~~orphan ~~determination~~drug exclusivity purposes. The FDA indicated that it will determine whether two vectors from the ~~patent~~same isviral ~~valid~~class ~~and~~are ~~infringed~~the same on a case-by-case ~~the~~basis ~~proposed~~and ~~ANDA~~may orconsider ~~505(b)(2)~~additional key features in assessing sameness. If a product designated as an orphan drug ultimately receives marketing approval for an indication broader than what was designated in its orphan drug application, it may not be entitled to exclusivity.

Orphan drug exclusivity will not bar approval of another product under certain circumstances, including if a subsequent product for the same indication is shown to be clinically superior to the approved product on the basis of greater efficacy or safety or provides a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand. In September 2021, the Court of Appeals for the 11th Circuit held that, for the purpose of determining the scope of market exclusivity, the term “same disease or condition” in the statute means the designated “rare disease or condition” and could not be interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” Although there have been legislative proposals to overrule this decision, they have not been enacted into law. On January 23, 2023, the FDA announced that, in matters beyond the scope of that court order, the FDA will continue to apply its existing regulations tying orphan-drug exclusivity to the uses or indications for which the orphan drug was approved.

Pediatric Exclusivity

Review and Approval of Products in Europe and other Foreign Jurisdictions

In addition to regulations in the United States, a manufacturer is subject to a variety of regulations in foreign jurisdictions to the extent it chooses to conduct clinical trials or sell any products in those foreign countries. Even if a manufacturer obtains FDA approval of a product, it must still obtain the requisite approvals from regulatory authorities in foreign countries before beginning clinical trials or marketing the product in those countries. To obtain regulatory approval of an investigational product in the European Union, a manufacturer must submit a marketing authorization application, or MAA, to the EMA. For other countries outside of the European Union, such as the United Kingdom or countries in Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country. In all cases, clinical trials are to be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

Clinical Trial Approval in the European Union

On January 31, 2022, the new Clinical Trials Regulation (EU) No 536/2014 became effective in the European Union and replaced the prior Clinical Trials Directive 2001/20/EC. The new regulation aims at simplifying and streamlining the authorization, conduct and transparency of clinical trials in the European Union. Under the new coordinated procedure for the approval of clinical trials, the sponsor of a clinical trial to be conducted in more than one Member State of the European Union, or EU Member State, will only be required to submit a single application for approval. The submission will be made through the Clinical Trials Information System, a new clinical trials portal overseen by the EMA and available to clinical trial sponsors, competent authorities of the EU Member States and the public.

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Beyond streamlining the process, the new Regulation includes a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors, and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts. Part I is assessed by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned). Part II is assessed separately by each Member State concerned. Strict deadlines have been established for the assessment of clinical trial applications. The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the concerned EU Member State. However, overall related timelines will be defined by the Clinical Trials Regulation.

The new regulation did not change the preexisting requirement that a sponsor must obtain prior approval from the competent national authority of the EU Member State in which the clinical trial is to be conducted. If the clinical trial is conducted in different EU Member States, the competent authorities in each of these EU Member States must provide their approval for the conduct of the clinical trial. Furthermore, the sponsor may only start a clinical trial at a specific study site after the applicable ethics committee has issued a favorable opinion.

Parties conducting certain clinical trials must, as in the United States, post clinical trial information in the EU at the EudraCT website.

Marketing Authorization

In the European Union, marketing authorizations for medicinal products may be obtained through different procedures founded on the same basic regulatory process. A marketing authorization may be granted only to a sponsor established in the European Union. As in the United States, marketing authorization holders and manufacturers of approved medicinal products are subject to comprehensive regulatory oversight by the EMA and the competent authorities of the individual EU Member States both before and after grant of marketing authorizations.

Centralized Procedure. The centralized procedure provides for the grant of a single marketing authorization by the European Commission that is valid across the European Economic Area, i.e., the European Union as well as Iceland, Liechtenstein and Norway. The centralized procedure is compulsory for medicinal products produced by certain biotechnological processes, products designated as orphan medicinal products, and products with a new active substance indicated for the treatment of certain diseases. It is optional for those products that are highly innovative or for which a centralized process is not in the interest of patients. Manufacturers must demonstrate the quality, safety, and efficacy of their products to the EMA, which provides an opinion regarding the MAA. The European Commission grants or refuses marketing authorization in light of the opinion delivered by the EMA.

Specialized Procedures for Gene Therapies. The grant of marketing authorization in the European Union for gene therapy products is governed by Regulation 1394/2007/EC on advanced therapy medicinal products, read in combination with Directive 2001/83/EC of the European Parliament and of the Council, commonly known as the Community code on medicinal products for human use. Regulation 1394/2007/EC includes specific rules concerning the authorization, supervision, and pharmacovigilance of gene therapy medicinal products. All advanced therapy medicinal products are approved centrally through the EMA. The EMA's Committee for Advanced Therapies reviews and provides an opinion regarding each advanced therapy MAA for potential final approval by the European Commission.

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through the EMA. The EMA's Committee for Advanced Therapies reviews and provides an opinion regarding each advanced therapy MAA for potential final approval by the European Commission.

Decentralized Procedure. The decentralized procedure provides for approval by one or more other concerned EU Member States of an assessment of an MAA conducted by one EU Member State, known as the reference EU Member State. In accordance with this procedure, a sponsor submits an MAA to the reference EU Member State and the concerned EU Member States. This application is identical to the application that would be submitted to the EMA for authorization through the centralized procedure. Following receipt of a valid application, the reference EU Member State prepares a draft assessment and drafts of the related materials. The resulting assessment report is submitted to the concerned EU Member States which must decide whether to approve the assessment report and related materials.

If a concerned EU Member State cannot approve the assessment report and related materials due to concerns relating to a potential serious risk to public health, disputed elements may be referred to the European Commission, whose decision is binding on all EU Member States. Authorization in accordance with the decentralized procedure will result in authorization of the medicinal product only in the reference EU Member State and in the other concerned EU Member States.

Mutual Recognition Procedure. In accordance with the mutual recognition procedure, the sponsor applies for national marketing authorization in one EU Member State. Upon receipt of this authorization the sponsor can then seek the recognition of this authorization by other EU Member States.

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PRIME Designation

In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist. The PRIority MEdicines, or PRIME, scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation. Products from small- and medium-sized enterprises, or SMEs, may qualify for earlier entry into the PRIME scheme than larger companies. Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated marketing authorization application assessment once a dossier has been submitted. Importantly, a dedicated agency contact and rapporteur from the CHMP or Committee for Advanced Therapies are appointed early in the PRIME scheme, facilitating increased understanding of the product at EMA’s Committee level.

Periods of Authorization and Renewals in the European Union

A marketing authorization is valid for five years, in principle, and it may be renewed after five years on the basis of a reevaluation of the risk-benefit balance by the EMA or by the relevant EU Member State. To seek renewal, at least six months prior to expiration of the marketing authorization, the holder must provide the EMA or the EU Member State with a consolidated version of the file detailing the continued quality, safety and efficacy of the product, including all variations introduced since the marketing authorization was granted. Once renewed, the marketing authorization is valid for an unlimited period, unless the European Commission or the relevant competent authority of the EU Member State decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal period. Any marketing authorization that is not followed by the marketing of the medicinal product on the European Union market, in the case of the centralized procedure, or in the market of the EU Member State which delivered the marketing authorization, in the case of the decentralized procedure, within three years after authorization ceases to be valid.

Patent Term Extensions in the European Union and Other Jurisdictions

The European Union also provides for patent term extension through Supplementary Protection Certificates, or SPCs. The rules and requirements for obtaining a SPC are similar to those in the United States. An SPC may extend the term of a patent for up to five years after its originally scheduled expiration date and can provide up to a maximum of fifteen years of marketing exclusivity for a drug. These periods can be extended for six additional months if pediatric exclusivity is obtained, which is described in detail below. Although SPCs are available throughout the European Union, sponsors must apply on a country-by-country basis. Similar patent term extension rights exist in certain other foreign jurisdictions outside the European Union.

Regulatory Data Exclusivity in the European Union

In the European Union, innovative medicinal products approved on the basis of a complete independent data package qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity. We expect ACP to be eligible for the eight years of data exclusivity and two additional years of market exclusivity, if approved. Data exclusivity prevents sponsors for authorization of generics of these innovative products from referencing the innovator’s data in a generic (abridged) application for a period of eight years. During an additional two-year period of market exclusivity, a generic MAA can be submitted and authorized, and the innovator’s data may be referenced, but no generic medicinal product can be placed on the European Union market until the expiration of the market exclusivity. The overall ten-year period will be extended to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications that are shown, during the scientific evaluation prior to authorization, to bring a significant clinical benefit in comparison with existing therapies. Even if a compound is considered to be an innovative medicinal product so that the innovator gains the additional prescribed period of marketing exclusivity, another company nevertheless could also market another version of the product if such company obtained marketing authorization based on an MAA with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials.

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can be placed on the European Union market until the expiration of the market exclusivity. The overall ten-year period will be extended to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications that are shown, during the scientific evaluation prior to authorization, to bring a significant clinical benefit in comparison with existing therapies. Even if a compound is considered to be an innovative medicinal product so that the innovator gains the additional prescribed period of marketing exclusivity, another company nevertheless could also market another version of the product if such company obtained marketing authorization based on an MAA with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials.

Orphan Drug Designation and Exclusivity in the European Union

Regulation (EC) No 141/2000 and Regulation (EC) No. 847/2000 provide that a product can be designated as an orphan medicinal product by the European Commission if its sponsor can establish that the product is intended for the diagnosis, prevention or treatment of: (1) a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the European Union when the application is made, or (2) a life-threatening, seriously debilitating or serious and chronic condition in the European Union and that without incentives the medicinal product is unlikely to be developed. For either of these conditions, the sponsor must demonstrate that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the European Union or, if such method exists, the medicinal product will be of significant benefit to those affected by that condition.

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Once authorized, orphan medicinal products are entitled to ten years of market exclusivity in all EU Member States and, in addition, a range of other benefits during the development and regulatory review process, including scientific assistance for study protocols, authorization through the centralized marketing authorization procedure and a reduction or elimination of registration and marketing authorization fees. The market exclusivity period can be extended by two years following completion of an agreed upon pediatric investigation plan. However, marketing authorization may be granted to a similar medicinal product with the same orphan indication during the ten year period with the consent of the marketing authorization holder for the original orphan medicinal product or if the manufacturer of the original orphan medicinal product is unable to supply sufficient quantities. Marketing authorization may also be granted to a similar medicinal product with the same orphan indication if the new product is safer, more effective or otherwise clinically superior to the original orphan medicinal product. The period of market exclusivity may, in addition, be reduced to six years if it can be demonstrated on the basis of available evidence that the original orphan medicinal product is sufficiently profitable to not justify maintenance of market exclusivity.

Pediatric Studies and Exclusivity

Before obtaining a marketing authorization in the European Union, sponsors must demonstrate compliance with all measures included in an EMA-approved Pediatric Investigation Plan, or PIP, approved by the Pediatric Committee of the EMA, or PDCO, covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, a class waiver, or a deferral for one or more of the measures included in the PIP. This requirement also applies when a company wants to add a new indication, pharmaceutical form or route of administration for a medicine that is already authorized. The PDCO may grant deferrals for some medicines, allowing a company to delay development of the medicine for children until there is enough information to demonstrate its effectiveness and safety in adults. The PDCO may also grant waivers when development of a medicine for children is not needed or is not appropriate, such as for diseases that only affect the elderly population. Before an MAA can be filed, or an existing marketing authorization can be amended, the EMA must determine that the sponsor actually complied with the agreed studies and measures listed in each relevant PIP. If a sponsor obtains a marketing authorization in all EU Member States, or a marketing authorization granted via the centralized procedure by the European Commission, and the study results for the pediatric population are included in the product information, even when negative, the medicine is then eligible for an additional six-month period of qualifying patent protection through extension of the term of the SPC or alternatively a one year extension of the regulatory market exclusivity from ten to eleven years, as selected by the marketing authorization holder.

Brexit and the Regulatory Framework in the United Kingdom

The United Kingdom’s withdrawal from the EU took place on January 31, 2020. As ~~The~~of EUJanuary ~~and~~1, 2021, the ~~U.K.~~Medicines ~~reached~~and anHealthcare ~~agreement~~products onRegulatory ~~their~~Agency, ~~new~~or ~~partnership in~~ the ~~Trade and Cooperation Agreement~~MHRA, orbecame ~~the~~responsible ~~Trade~~for ~~Agreement,~~supervising ~~which~~medicines ~~was~~and ~~applied~~medical ~~provisionally~~devices ~~beginning~~in onGreat ~~January~~Britain, 1comprising England, ~~2021~~Scotland and ~~which~~Wales ~~entered~~under ~~into~~domestic ~~force~~law onwhereas ~~May~~Northern 1,Ireland ~~2021.~~continues ~~The~~to ~~Trade~~be ~~Agreement~~subject ~~focuses~~to ~~primarily~~EU onrules ~~free~~under ~~trade~~the byNorthern ~~ensuring~~Ireland noProtocol. ~~tariffs~~The orMHRA ~~quotas~~will rely on ~~trade~~the inHuman ~~goods,~~Medicines ~~including~~Regulations ~~healthcare~~2012 ~~products~~(SI ~~such~~2012/1916) (as ~~medicinal products. Thereafter~~amended), or the EUHMR, ~~and~~as the ~~U.K.~~basis ~~will~~for ~~form~~regulating ~~two~~medicines. ~~separate~~The ~~markets~~HMR ~~governed~~has byincorporated ~~two~~into ~~distinct~~the ~~regulatory~~domestic ~~and~~law ~~legal~~of ~~regimes~~the U.K. ~~As such,~~ the ~~Trade~~body ~~Agreement~~of ~~seeks~~EU tolaw ~~minimize~~governing ~~barriers~~medicinal toproducts ~~trade in goods while accepting~~ that ~~border~~pre-existed ~~checks~~prior ~~will~~to ~~become inevitable as a consequence that~~ the U.K.’s iswithdrawal nofrom ~~longer part of~~ the ~~single market~~EU. ~~As of January 1, 2021, the Medicines~~

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and Healthcare products Regulatory Agency, or the MHRA, became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law whereas Northern Ireland continues to be subject to EU rules under the Northern Ireland Protocol. The MHRA will rely on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended), or the HMR, as the basis for regulating medicines. The HMR has incorporated into the domestic law of the U.K. the body of EU law governing medicinal products that pre-existed prior to the U.K.’s withdrawal from the EU.

Pharmaceutical Insurance Coverage, Pricing and Reimbursement

In the United States and markets in many other countries, patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on third-party payors to reimburse all or part of the associated healthcare costs. Significant uncertainty exists as to the coverage and reimbursement status of products approved by the FDA and other government authorities. Thus, even if a product candidate is approved, sales of the product will depend, in part, on the extent to which third-party payors, including government health programs in the United States such as Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage, and establish adequate reimbursement levels, for the product. Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. Third-party payors may limit coverage for a particular indication to specific products on an approved list, also known as a formulary, which might not include all of the approved products for such indication.

In order to secure coverage and reimbursement for any product that might be approved for sale, a company may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the product, in addition to the studies required to obtain FDA or other comparable marketing approvals. Nonetheless, product candidates may not be considered medically necessary or cost effective by the payors. A payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved. Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage and reimbursement for the product, and the level of coverage and reimbursement can differ significantly from payor to payor. Moreover, coverage policies and third-party reimbursement rates may change at any time.

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The containment of healthcare costs also has become a priority of federal, state and foreign governments and the prices of pharmaceutical products have been a focus in this effort. Governments have shown significant interest in implementing cost-containment programs, including rebate programs, price controls, restrictions on reimbursement and requirements for substitution of generic products. Efforts to control drug pricing have garnered bipartisan support in the U.S. Congress. Under both the previous Trump Administration and the current Biden Administration, various U.S. government agencies, including the FDA and the Center for Medicare & Medicaid Services, or CMS, proposed a number of rules intended to curb drug prices. For example, in October 2020, the Department of Health and Human Services, or HHS, and the FDA published a final rule allowing states and other entities to develop a Section 804 Importation Program, or SIP, to import certain prescription drugs from Canada into the United States. The final rule is currently the subject of ongoing litigation, but at least six states (Vermont, Colorado, Florida, Maine, New Mexico, and New Hampshire) have passed laws allowing for the importation of drugs from Canada with the intent of developing SIPs for review and approval by the FDA.

Further, on July 9, 2021, President Biden signed Executive Order 14063, which focuses on, among other things, the price of pharmaceuticals. The executive order directs HHS to create a plan within 45 days to combat “excessive pricing of prescription pharmaceuticals and enhance domestic pharmaceutical supply chains, to reduce the prices paid by the federal government for such pharmaceuticals, and to address the recurrent problem of price gouging.” On September 9, 2021, HHS released its plan to reduce pharmaceutical prices. The key features of that plan are to: (a) make pharmaceutical prices more affordable and equitable for all consumers and throughout the health care system by supporting pharmaceutical price negotiations with manufacturers; (b) improve and promote competition throughout the prescription pharmaceutical industry by supporting market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase transparency; and (c) foster scientific innovation to promote better healthcare and improve health by supporting public and private research and making sure that market incentives promote discovery of valuable and accessible new treatments.

AtMore ~~the~~recently, ~~state~~on ~~level~~August 16, ~~individual~~2022, ~~states~~the ~~are~~Inflation ~~increasingly~~Reduction ~~aggressive~~Act inof ~~passing~~2022, ~~legislation~~or ~~and~~IRA, ~~implementing~~was ~~regulations~~signed ~~designed~~into tolaw ~~control~~by ~~pharmaceutical~~President ~~and~~Biden. ~~biological~~The ~~product~~new ~~pricing,~~legislation ~~including~~has ~~price~~implications orfor ~~patient~~Medicare ~~reimbursement~~Part ~~constraints~~D, ~~discounts,~~which ~~restrictions~~is ona ~~access~~program available to ~~certain~~individuals ~~products,~~who ~~and~~are ~~marketing~~entitled ~~cost~~to ~~disclosure~~Medicare ~~and~~Part ~~transparency~~A ~~measures,~~or ~~and,~~enrolled in ~~some~~Medicare ~~cases,~~Part ~~measures~~B ~~designed~~ to ~~encourage~~give ~~importation~~them ~~from~~the ~~other~~option ~~countries~~of ~~and~~paying ~~bulk~~a ~~purchasing.~~monthly Apremium ~~number~~for ofoutpatient ~~states,~~prescription ~~for~~drug ~~example~~coverage. Among other things, ~~require~~the ~~drug~~IRA requires manufacturers ~~and~~of ~~other~~certain ~~entities~~drugs to engage in ~~the~~price negotiations ~~drug~~with ~~supply~~Medicare ~~chain~~(beginning in 2026), ~~including~~with ~~health~~prices ~~carriers,~~that ~~pharmacy~~can ~~benefit~~be ~~managers,~~negotiated subject to a cap; imposes rebates under Medicare Part and ~~wholesale~~Medicare ~~distributors,~~Part D to ~~disclose~~penalize ~~information~~price ~~about~~increases ~~pricing~~that ofoutpace ~~pharmaceuticals.~~inflation In(first ~~addition,~~due ~~regional~~in ~~healthcare~~2023); ~~organizations~~ and ~~individual~~replaces ~~hospitals~~the ~~are~~Part ~~increasingly~~D ~~using~~coverage ~~bidding~~gap ~~procedures~~discount toprogram ~~determine~~with ~~which~~a ~~pharmaceutical~~new ~~products~~discounting ~~and~~program ~~which~~(beginning ~~suppliers~~in ~~will~~2025). beThe ~~included~~IRA inpermits ~~their~~the ~~prescription~~Secretary ~~drug~~of ~~and~~the ~~other~~HHS ~~healthcare~~to ~~programs.~~implement ~~These~~many ~~measures~~of ~~could~~these ~~reduce~~provisions through guidance, as opposed to regulation, for the initial years.

67Specifically, with respect to price negotiations, Congress authorized Medicare to negotiate lower prices for certain costly single-source drug and biologic products that do not have competing generics or biosimilars and are reimbursed under Medicare Part B and Part D. CMS may negotiate prices for ten high-cost drugs paid for by Medicare Part D starting in 2026,

~~Table~~followed ofby ~~Contents~~ 15 Part D drugs in 2027, 15 Part B or Part D drugs in 2028, and 20 Part B or Part D drugs in 2029 and beyond.

~~ultimate~~This ~~demand~~provision ~~for~~applies ~~our~~to drug products, ifthat ~~and~~have ~~once~~been approved, orfor ~~put~~at ~~pressure~~least on9 ~~our~~years ~~product pricing. We expect that additional state~~ and ~~federal~~biologics ~~healthcare reform measures will be adopted in the future, any of which could limit the amounts~~ that ~~federal~~have ~~and~~been ~~state~~licensed ~~governments will pay~~ for ~~healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.~~13

years, but it does not apply to drugs and biologics that have been approved for a single rare disease or condition. Further, the

legislation subjects drug manufacturers to civil monetary penalties and a potential excise tax for failing to comply with the

legislation by offering a price that is not equal to or less than the negotiated “maximum fair price” under the law or for taking

price increases that exceed inflation. The legislation also requires manufacturers to pay rebates for drugs in Medicare Part D

whose price increases exceed inflation. The new law also caps Medicare out-of-pocket drug costs at an estimated $4,000 a year

in 2024 and, thereafter beginning in 2025, at $2,000 a year. At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on access to certain products, and marketing cost disclosure and transparency measures, and, in some cases, measures designed to encourage importation from other countries and bulk purchasing. A number of states, for example, require drug manufacturers and other entities in the drug supply chain, including health carriers, pharmacy benefit managers, and wholesale distributors, to disclose information about pricing of pharmaceuticals. In addition, regional healthcare organizations and individual hospitals are increasingly using bidding procedures to determine which pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs. These measures could reduce the ultimate demand for our products, if and once approved, or put pressure on our product pricing. We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.

Outside the United States, ensuring adequate coverage and payment for a product also involves challenges. Pricing of prescription pharmaceuticals is subject to governmental control in many countries. Pricing negotiations with governmental authorities can extend well beyond the receipt of regulatory marketing approval for a product and may require a clinical trial that compares the cost effectiveness of a product to other available therapies. The conduct of such a clinical trial could be expensive and result in delays in commercialization.

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In the European Union, pricing and reimbursement schemes vary widely from country to country. Some countries provide that products may be marketed only after a reimbursement price has been agreed. Some countries may require the completion of additional cost effectiveness clinical studies. EU Member States may approve a specific price for a product or any of them may instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market. Other member states allow companies to fix their own prices for products, but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions. Over the past decade, many EU Member States have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to manage healthcare expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the European Union over the past decade. Reference pricing used by various EU Member States, and parallel trade, i.e., arbitrage between low-priced and high-priced member states, can further reduce prices.

In addition to initiatives specifically directed at lowering or containing prescription drug prices, legislative action in the United States at the national level has resulted in reduced funding levels for Medicare. For example, the Budget Control Act of 2011, or BCA, led to aggregate reductions in Medicare payments to providers of up to 2% per fiscal year from 2013 through 2031, and the American Taxpayer Relief Act of 2012 reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. We expect that ~~Zimura~~ACP, if approved for GA, would be reimbursed by the Medicare Part B "buy and bill" reimbursement model, under which physicians purchase ~~Zimura~~ACP from us or a wholesaler/distributor, and then bill Medicare for their costs following administration. Medicare Part B currently provides for reimbursement to the physicians at a rate equal to the average sales price for the product plus a six percent markup. The BCA has reduced the effective rate of that markup to 4.3%. Any further reduction in healthcare, including Medicare, funding may affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

Moreover, the number of individuals covered by health insurance has a direct impact on the potential market for our product candidates, if approved. The ACA, passed in 2010, included the "individual mandate," which required most Americans to carry a minimal level of health insurance. Individuals who did not obtain required coverage were subject to a penalty. The individual mandate was repealed as part of the Tax Cuts and Jobs Act of 2017, or TCJA, with the repeal becoming effective on January 1, 2019. According to the Congressional Budget Office, the repeal of the individual mandate will cause 13 million fewer Americans to be insured in 2027 and premiums in insurance markets may rise. In addition, since passage of the ACA, there have been several lawsuits challenging the ACA, and we expect additional lawsuits may be filed.

Despite those developments, we expect the 117th Congress and the Biden Administration to support and expand on the ACA. For example, on January 28, 2021, President Biden issued an executive order directing federal agencies to review all existing regulations, policies and a variety of other guidance that limit Americans’ access to high-quality healthcare and to

consider actions that will protect and strengthen Medicaid, the ACA and, more generally, access to affordable healthcare for Americans. Under this order, federal agencies are to advance President Biden’s overall access policy and make determinations as to whether additional actions are necessary. Specifically, the agencies must examine, among other things, policies that undermine protections for people with pre-existing conditions, including complications related to COVID-19, and policies that undermine the health insurance marketplace or other markets for health insurance.

Healthcare Law and Regulation

Healthcare providers and third-party payors play a primary role in the recommendation and prescription of products that are granted marketing approval. Arrangements with providers, consultants, third-party payors and customers are subject to broadly applicable fraud and abuse, anti-kickback, false claims, reporting of payments to physicians and patient privacy laws and regulations and other healthcare laws and regulations that may constrain business and/or financial arrangements. Restrictions under applicable federal and state healthcare laws and regulations include the following:

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•the federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, paying, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid;

•federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalties laws, which prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false, fictitious or fraudulent or knowingly making, using or causing to made or used a false record or statement to avoid, decrease or conceal an obligation to pay money to the federal government;

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•the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which, among other things, prohibits knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;

•HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and their respective implementing regulations, which impose obligations, including mandatory contractual terms, relating to safeguarding the privacy, security and transmission of individually identifiable health information by certain covered entities and their business associates;

•the federal false statements statute, which prohibits knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services;

•the federal Foreign Corrupt Practices Act, which, among other things, prohibits providing or offering to provide money or anything of value to a foreign government body, government official, or political candidate for the improper purpose of obtaining or keeping business;

•federal transparency requirements such as the federal Physician Payments Sunshine Act, created under the ACA, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to CMS information related to payments and other transfers of value made by that entity to physicians, other healthcare providers and teaching hospitals, as well as ownership and investment interests held by physicians, ~~other healthcare providers~~ and their immediate family members; and

•analogous state and foreign laws and regulations, such as state anti–kickback and false claims laws, state pharmaceutical sales representative listing requirements and other consumer protection laws, which may apply to healthcare items or services that are reimbursed by private insurers.

•Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government in addition to requiring manufacturers to report information related to payments to physicians and other health care providers or marketing expenditures. State and foreign laws, such as the European Union's General Data Protection Regulation, also govern the privacy and security of, and require the notification of any breaches of, health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

•State and foreign laws, such as the European Union's General Data Protection Regulation, also govern the privacy and security of, and require the notification of any breaches of, health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

Our Corporate Information

Our principal executive offices are located at 8 Sylvan Way, Parsippany, New Jersey, 07054, and our telephone number is (609) 474-6755. Our Internet website is http://www.ivericbio.com.

Available Information

We make available free of charge through our website our Annual Report on Form 10–K, Quarterly Reports on Form 10–Q, Current Reports on Form 8–K and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act. We make these reports available through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the SEC. You can find, copy and inspect information we file at the SEC’s public reference room. You can review our electronically filed reports and other information that we file with the SEC on the SEC’s web site at http://www.sec.gov. We also make available, free of charge on our website, the reports filed with the SEC by our executive officers, directors and 10% stockholders pursuant to Section 16 under the Exchange Act as soon as reasonably practicable after copies of those filings are provided to us by those persons. The information contained on, or that can be accessed through, our website is not a part of or incorporated by reference in this Annual Report on Form 10–K.

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free of charge on our website, the reports filed with the SEC by our executive officers, directors and 10% stockholders pursuant to Section 16 under the Exchange Act as soon as reasonably practicable after copies of those filings are provided to us by those persons. The information contained on, or that can be accessed through, our website is not a part of or incorporated by reference in this Annual Report on Form 10–K.

Item 1A. Risk Factors.

The following risk factors and other information included in this Annual Report on Form 10-K should be carefully considered. The risks and uncertainties described below are not the only risks and uncertainties we face. Additional risks and uncertainties not presently known to us or that we presently deem less significant may also impair our business operations. Please see page 1 of this Annual Report on Form 10-K for a discussion of some of the forward-looking statements that are qualified by these risk factors. If any of the following risks occur, our business, financial condition, results of operations and future growth prospects could be materially and adversely affected.

Risks Related to Our Business Plan, Financial Position and Need for Additional Capital

We are a development-stage company without any commercial products. The value of our company, ~~therefore,~~ is highly dependent on the success and potential commercialization of ~~Zimura~~ACP and our other research and development efforts and the amount of our available cash. Our research and development programs, which are focused on novel therapies and technologies, carry significant scientific and other risks. If any of these programs are not successful, the value of your investment may decline.

We are a development-stage company without any approved products. Our growth prospects and the future value of our company are ~~highly~~ dependent on the progress of our research and development programs, including our ongoing and any future clinical trials for ~~Zimura~~ACP, our preclinical development program for IC-500, and our gene therapy research programs. In particular, we are highly dependent on the success of ~~Zimura~~ACP, and any delays or issues with its ~~further development, its~~ potential marketing approval, or its potential commercialization will likely cause the value of your investment to decline significantly. Drug development is a highly uncertain undertaking and carries significant scientific and other risks.

We may encounter unforeseen difficulties, complications, delays, expenses and other known and unknown factors. We may never be successful in developing or commercializing any of our product candidates or other programs. There is a high rate of failure in pharmaceutical research and development. Even if we have promising preclinical or clinical candidates, their development could fail at any time. Our failure could be due to unexpected scientific, safety or efficacy issues with our product candidates and other programs, invalid hypotheses regarding the molecular targets and mechanisms of action we choose to pursue or unexpected delays in our research and development programs resulting from applying the wrong criteria or experimental systems and procedures to our programs or lack of experience or other factors, ~~including disruptions resulting from the COVID-19 pandemic,~~ with the possible result that none of our product candidates or other programs result in the development of marketable products. WeAlthough we have ~~not~~results ~~yet~~from ~~demonstrated~~two ~~our ability to successfully complete the development of a pharmaceutical product, including completion of~~ large-scale, pivotal clinical trials (GATHER1 and GATHER2) with safety and efficacy data that we believe are sufficient to seek and obtain marketing approval orfor ~~activities~~ACP ~~necessary~~for GA secondary to ~~apply~~AMD, ~~for~~we ~~and~~need to complete activities necessary to obtain marketing approval, including the qualification of aone or more commercial ~~manufacturer~~manufacturers through a pre-approval ~~inspection~~inspections with regulatory authorities. IfWe ~~successful~~are inworking ~~developing and obtaining marketing approval of one of our product candidates, we would need~~ to transition from a company having a product development focus to a company capable of commercializing pharmaceutical products. At this time, we are ~~beginning~~continuing to hire commercialization personnel and build a commercial infrastructure for the potential commercialization of ~~Zimura~~ACP, if approved. We may not be successful in such a transition, as our company has never conducted the sales, marketing, manufacturing and distribution activities necessary for successful product commercialization.

Because the value of our company is largely based on the prospects for our research and development programs and their potential to result in therapies capable of achieving marketing approval and generating future revenues, any failure, delay or setback for these programs will likely have a negative impact on the value of your investment. In addition, even if we are successful in advancing the development of IC-500, which is currently in preclinical development, the value of our common stock may not rise in a meaningful way. As we continue to invest in our research and development programs to generate data to support further development or applications to obtain marketing approval for commercialization, the amount of our available cash will continue to decline until we raise additional finances.

WeCompanies ~~have~~in aour ~~history~~industry offace ~~significant~~a ~~operating~~wide ~~losses.~~range Weof ~~expect~~challenging toactivities, ~~continue~~each toof ~~incur~~which ~~losses~~entails ~~until such time~~separate, ~~if ever, that we successfully commercialize our product candidates~~ and ~~may~~in ~~never~~many ~~achieve~~cases orsubstantial, ~~maintain profitability~~risk.

~~Since~~The ~~inception,~~long-term wesuccess ~~have~~of ~~experienced significant cash outflows in funding~~ our ~~operations. To date~~company, ~~we have not generated any revenues from commercial product sales~~ and ~~have financed~~ our ~~operations~~ability ~~primarily~~to ~~through~~become ~~private~~profitable ~~placements~~as ofa ~~our~~biopharmaceutical ~~common stock and preferred stock~~company, ~~venture~~will ~~debt~~require ~~borrowings,~~us ~~funds~~to ~~received~~be ~~under~~successful ~~our~~in ~~prior~~a ~~Fovista~~range ~~royalty~~of ~~purchase~~challenging ~~and sale agreement with Novo Holdings A/S~~activities, ~~our initial public offering, which we closed in September 2013, funds we received under~~ including:

70•designing, conducting and successfully completing preclinical research and development activities, including preclinical efficacy and IND-enabling studies, for our product candidates;

•making arrangements with third-party manufacturers and providers of starting materials for our product candidates, and having those manufacturers successfully develop manufacturing processes for drug substance and drug product and provide adequate amounts of drug product for preclinical and clinical activities in accordance with our expectations and regulatory requirements;

•designing, conducting and completing clinical trials for our product candidates;

•obtaining favorable results from required clinical trials, including for each ophthalmic product candidate, favorable results from two adequate and well-controlled pivotal clinical trials in the relevant indication;

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~~our~~•applying ~~prior~~for ~~Fovista licensing~~ and ~~commercialization~~receiving ~~agreement~~marketing ~~with~~approvals ~~Novartis~~from ~~Pharma~~applicable ~~AG,~~regulatory ~~funds~~authorities we received in connection with our acquisition of Inception 4 in October 2018, and our follow-on public offerings, which we closed in February 2014, December 2019, June 2020, July 2021 and October 2021. As of December 31, 2021, we had an accumulated deficit of $679.6 million. Our net loss was $114.5 million for the ~~year~~ ~~ended December 31,~~marketing ~~2021~~ and wesale ~~expect~~of toour ~~continue~~product ~~to incur significant operating losses for the foreseeable future.~~candidates;

~~Zimura~~•making isarrangements inwith ~~clinical development, IC~~third-~~500~~party ismanufacturers infor preclinical development, and we are advancing multiple gene therapy research programs. We expect our research and development expenses to increase as we pursue these programs as currently planned. We could incur additional research and development expenses if we modify or further expand the scope of our clinical trials, our preclinical development programs or our gene therapy research programs, or if we inscale-~~license~~up ~~or acquire,~~ and ~~undertake~~commercial ~~development of~~manufacturing, ~~additional~~validating ~~product candidates~~ and ~~technologies,~~receiving including sustained release delivery technologies for Zimura and any promising product candidates that emerge from our gene therapy research programs. We could also incur additional research and development expenses if, for example, we are required by the FDA, the EMA or regulatory ~~authorities~~approval in other jurisdictions, or if we otherwise decide, to perform clinical trials and/or nonclinical or other studies in addition to those we currently expect to conduct. If we experience delays or disruptions to our research and development programs, including delays in patient enrollment or issues with patient retention or patients missing scheduled visits and treatments, if we experience issues with our preclinical development programs, such as unfavorable toxicology or other preclinical data, if we experience issues with the manufacture and supply of ~~product candidates for~~ our ~~development programs, including issues with process development or~~ manufacturing ~~scale-up~~processes ~~activities, whether such delays or disruptions are due to the COVID-19 pandemic or other reasons, we could incur additional~~ and ~~unexpected expenses as a result of such delays or disruptions and~~ our ~~business~~third-party ~~and~~manufacturers’ ~~financial~~facilities ~~results may be materially impacted. Furthermore, if we successfully develop~~ and ~~expect~~ensuring toadequate ~~obtain~~supply ~~marketing approval for any~~ of ~~our~~drug ~~product candidates~~substance, wedrug ~~expect to incur significant commercialization expenses related to~~ product ~~sales, marketing, distribution~~ and ~~manufacturing.~~starting Wematerials ~~expect~~used ~~to start incurring these expenses as we prepare~~ for the ~~potential~~manufacture ~~commercialization~~ of ~~Zimura.~~drug Wesubstance ~~are party to agreements with Archemix with respect to Zimura, the former equityholders of Inception 4 with respect to IC-500, the University of Florida Research Foundation, Incorporated, or UFRF,~~ and ~~Penn,~~drug ~~with respect to IC-100 and IC-200, and UMass with respect to any potential~~ product candidates from our miniCEP290 program, in each case, that impose significant milestone payment obligations on us if we or a potential collaborator achieves specified clinical, regulatory and commercial milestones with respect to these product candidates, as well as certain royalties on net sales with respect to IC-100, IC-200 and any product candidates we choose to develop from our miniCEP290 program. It is likely that any future in-licensing or acquisition agreements that we enter into with respect to additional product candidates or technologies would include similar obligations.;

•establishing sales, marketing and distribution capabilities, either internally or through collaborations or other arrangements, to effectively market and sell our product candidates, if and when approved;

•achieving acceptance of the product candidate, if and when approved, by patients, the medical community and third-party payors;

•if our product candidates are approved, obtaining from governmental and third-party payors adequate coverage and reimbursement for our product candidates and, to the extent applicable, associated injection procedures conducted by treating physicians;

•effectively competing with other therapies, including the existing standard of care, and other forms of drug delivery;

•maintaining a continued acceptable safety profile of the product candidate during development and following approval;

•obtaining and maintaining patent and trade secret protection and regulatory exclusivity, including under the Hatch-Waxman Amendments to the Federal Food, Drug and Cosmetic Act, or FDCA, or the Orphan Drug Act if we choose to seek such protections for any of our product candidates;

•protecting and enforcing our rights in our intellectual property portfolio; and

•complying with all applicable regulatory requirements, including Good Laboratory Practices, or GLP, Good Clinical Practices, or GCP, current Good Manufacturing Practices, or cGMP, and standards, rules and regulations governing promotional and other marketing activities.

Each of these activities has associated risks, many of which are detailed below and throughout this “Risk Factors” section. We may never succeed in these activities and, even if we do, may never generate revenues from product sales that are significant enough to achieve commercial success and profitability. Our failure to be commercially successful and profitable would decrease the value of our company and could impair our ability to raise capital, expand our business, maintain our research and development efforts, diversify our product offerings or continue our operations. A decrease in the value of our company would also cause our stockholders to lose all or part of their investment.

We have a history of significant operating losses. We expect to continue to incur losses until such time, if ever, that we successfully commercialize one or more of our product candidates and may never achieve or maintain profitability.

Since inception, we have experienced significant cash outflows in funding our operations. To date, we have not generated any revenues from commercial product sales and have financed our operations primarily through private placements of our common stock and preferred stock, venture debt borrowings, funds received under our prior Fovista royalty purchase and sale agreement with Novo Holdings A/S, our initial public offering, which we closed in September 2013, funds we received under our prior Fovista licensing and commercialization agreement with Novartis Pharma AG, funds we received in connection with our acquisition of Inception 4 in October 2018, our follow-on public offerings, which we closed in February 2014, December 2019, June 2020, July 2021, October 2021 and December 2022 and borrowings under the 2022 Term Loan Facility, pursuant to the Loan Agreement with Hercules and SVB. As of December 31, 2022, we had an accumulated deficit of $864.8 million. Our net loss was $185.2 million for the twelve months ended December 31, 2022, and we expect to continue to incur significant operating losses for the foreseeable future.

ACP is in clinical development, IC-500 is in preclinical development, and we are exploring multiple sustained release delivery technologies for ACP and advancing multiple gene therapy research programs. We expect our research and development expenses to increase as we pursue these programs as currently planned. We could incur additional research and development expenses if we modify or further expand the scope of our clinical trials, such as our initiation of the OLE study for ACP in GA secondary to AMD, our preclinical development programs or our gene therapy research programs, or if we in-license or acquire, and undertake development of, additional product candidates and technologies, including additional sustained release delivery technologies for ACP and any promising product candidates that emerge from our gene therapy research programs. We could also incur additional research and development expenses if, for example, we are required by the

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FDA, the EMA or regulatory authorities in other jurisdictions, or if we otherwise decide, to perform clinical trials and/or nonclinical or other studies in addition to those we currently expect to conduct. If we experience delays or disruptions to our research and development programs, including delays in patient enrollment or issues with patient retention or patients missing scheduled visits and treatments, if we experience issues with our preclinical development programs, such as unfavorable toxicology or other preclinical data, if we experience issues with the manufacture and supply of product candidates, including issues with process development or manufacturing scale-up activities, whether such delays or disruptions are due to the COVID-19 pandemic or other reasons, we could incur additional and unexpected expenses as a result of such delays or disruptions and our business and financial results may be materially impacted. Furthermore, if we successfully develop and expect to obtain marketing approval for any of our product candidates, we expect to incur significant commercialization expenses related to product sales, marketing, distribution and manufacturing. We have started incurring these expenses as we prepare for the potential commercialization of ACP. We are party to agreements with Archemix with respect to ACP, DelSiTech with respect to formulations of ACP with DelSiTech’s silica-based sustained release delivery technology, the former equityholders of Inception 4 with respect to IC-500, and UMass with respect to any potential product candidates from our miniCEP290 program, in each case, that impose significant milestone payment obligations on us if we or a potential collaborator achieves specified clinical, regulatory and commercial milestones with respect to these product candidates, as well as certain royalties on net sales with respect to formulations of ACP with DelSiTech’s silica-based sustained release delivery technology and any product candidates we choose to develop from our miniCEP290 program. It is likely that any future in-licensing or acquisition agreements that we enter into with respect to additional product candidates or technologies would include similar obligations.

We expect that we will continue to incur significant expenses as we:

•~~continue~~build ~~the~~our ~~development~~commercial ofoperations ~~Zimura in GA~~ and ~~STGD1~~sales, ~~and~~marketing ~~initiate development of Zimura in intermediate AMD~~ and ~~potentially~~distribution ~~other~~capabilities ~~indications~~for ACP;

•expand our outsourced manufacturing capabilities for ~~Zimura~~ACP and IC-500 ~~and begin to establish commercial operations and sales, marketing and distribution capabilities for Zimura~~;

•~~prepare~~continue anthe ~~NDA~~development ~~and~~of anACP ~~MAA~~in ~~for~~GA, ~~Zimura~~STGD1 and ~~seek~~potentially ~~marketing~~other ~~approval for any product candidates that successfully complete clinical trials~~indications;

•~~in-license~~seek ormarketing ~~acquire~~approval ~~the~~for ~~rights~~ACP ~~to,~~ and ~~pursue~~any ~~the development of,~~ other product candidates orthat ~~technologies~~successfully ~~for~~complete ~~retinal~~clinical ~~diseases, such as sustained release delivery technologies for Zimura~~trials;

•in-license or acquire the rights to, and pursue the development of, other product candidates or technologies for retinal diseases, such as sustained release delivery technologies for ACP;

•continue the development of IC-500 and pursue our gene therapy research programs;

•maintain, expand and protect our intellectual property portfolio;

•hire additional ~~clinical,~~ commercial, medical affairs, clinical, regulatory, pharmacovigilance, manufacturing, quality control, quality assurance and scientific personnel; and

•expand our general and administrative functions to support our future growth.

Our ability to become and remain profitable depends on our ability to generate revenues in excess of our expenses. Our ability to generate revenues from product sales is dependent on our obtaining marketing approval for and commercializing our product candidates or any product candidates we may in-license or acquire. We may be unsuccessful in our efforts to develop and commercialize product candidates or in our efforts to in-license or acquire additional product candidates. Even if we succeed in developing and commercializing one or more of our product candidates, we may never achieve sufficient sales revenue to achieve or maintain profitability. See “—Risks Related to Product Development and Commercialization” for a further discussion of the risks we face in successfully developing and commercializing our product candidates and achieving profitability.

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WeAlthough ~~expect~~we believe we ~~will~~have ~~require~~sufficient ~~substantial,~~cash ~~additional~~resources ~~funding~~to inlaunch ~~order~~ACP for GA secondary to ~~complete~~AMD in the ~~activities~~United ~~necessary~~States, toif ~~develop~~approved ~~and~~based ~~commercialize~~on ~~Zimura~~our orexpectations, ~~any~~we ofmay ~~our~~require ~~other~~additional ~~product~~funding ~~candidates.~~beyond what we currently expect or sooner than we currently expect. If we are unable to raise capital when needed, we could be forced to delay, reduce or eliminate one or more of our product development programs or commercialization efforts. ~~We may require additional funding beyond what we currently expect or sooner than we currently expect.~~

As of December 31, ~~2021~~2022, we had ~~cash,~~approximately ~~cash equivalents and available-for-sale securities of~~ $~~381~~646.78 million. Wein ~~estimate that our year-end 2022~~ cash, cash equivalents and available-for-sale securities ~~will range between $215 million and $225 million~~. We ~~also~~ estimate that our cash, cash equivalents, ~~and~~ available- for- sale securities and committed loan facilities will be sufficient to fund our planned capital expenditure requirements, debt service obligations and operating expenses through at least ~~mid-2024. These estimates are based on our current business plan, which includes~~ the ~~continuation~~next oftwelve ~~our~~months. ~~ongoing~~These ~~clinical~~estimates ~~development~~do ~~programs~~not ~~for~~include ~~Zimura~~any inpotential GAnew ~~and~~borrowings ~~STGD1~~under ~~and~~ the ~~initiation~~2022 ofTerm anLoan ~~intermediate~~Facility ~~AMD~~with ~~clinical~~Hercules ~~trial, preparation~~ and ~~potential~~SVB ~~filing~~beyond ~~of an NDA and a MAA for Zimura in GA, continuing preparations for a potential commercial launch of Zimura in GA, investing in sustained release delivery technologies for Zimura, and~~ the ~~advancement of our IC-500 development program~~$25.0 ~~Excluded~~million ~~from~~that ~~these~~we ~~estimates~~plan ~~are any potential approval or sales milestones payable~~ to ~~Archemix~~borrow orduring ~~any~~2023 ~~potential~~based ~~expenses~~on ~~for~~our ~~actual~~achievement ~~commercial launch~~ of ~~Zimura,~~the ~~such~~performance asmilestone ~~sales force expenses, any additional expenditures~~ related to ~~potentially studying Zimura in indications outside of GA, STGD1 and intermediate AMD, or resulting from~~ the ~~potential~~FDA's ~~in-licensing~~acceptance ~~or acquisition~~ of ~~additional product candidates or technologies, or any associated development we may pursue. We have based these estimates on assumptions that may prove to be wrong, and we could use~~ our ~~available~~NDA ~~capital~~for ~~resources sooner than we currently expect~~filing.

~~We expect the development of our product candidates will continue for at least the next several years.~~ Although we believe we have sufficient financial resources ~~for~~to ~~the~~launch ~~activities~~ACP ~~necessary~~for toGA ~~complete~~secondary ~~development~~to ~~of,~~AMD ~~including~~in ~~manufacturing~~the ~~scale-up~~United ~~and validation activities~~States, ~~and~~if ~~potentially~~approved ~~seek~~based ~~marketing~~on ~~approval~~our ~~of Zimura in GA~~expectations, we ~~expect~~may weneed ~~will require~~ additional funding into ~~order~~continue to ~~launch and~~ commercialize ~~Zimura~~ACP infor GA, if approved. We ~~also~~ expect we will require substantial, additional funding in order to complete the activities necessary to develop and commercialize ~~Zimura~~ACP for other indications, a sustained release delivery technology for ACP or any of our other product candidates. At this time, we cannot reasonably estimate the total remaining costs necessary to complete development, to complete process development and manufacturing scale-up and validation activities and to potentially seek marketing approval for ~~Zimura~~ACP for any other indication, a sustained release delivery technology for ACP or for any of our other product candidates.

Our future capital requirements will depend on many factors, including:

•the ~~scope~~costs, ~~progress,~~timing ~~costs~~ and ~~results~~outcome of ~~our~~regulatory ~~current~~filings and ~~future~~reviews ~~Zimura~~of ~~clinical~~our ~~programs~~product ~~and~~candidates, ~~any~~including ~~further~~regulatory ~~development~~review weof ~~may~~our ~~undertake~~filed toNDA ~~enable~~and usthe toplanned ~~file~~submission anof ~~NDA~~MAAs ~~and an MAA~~ for ~~Zimura~~ACP in ~~one~~GA orsecondary ~~more~~to ~~indications~~AMD;

•the ~~scope~~timing, ~~progress,~~scope ~~costs~~ and ~~results~~costs of ~~process~~establishing ~~development,~~a ~~manufacturing~~commercial ~~scale-up~~infrastructure ~~and~~for ~~validation~~potential ~~activities,~~commercialization ~~analytical~~of ~~method~~ACP, ~~development~~including ~~and~~the ~~qualification,~~hiring and ~~stability~~deployment ~~studies~~of ~~associated~~a ~~with~~sales ~~Zimura~~force and ~~our~~the ~~other~~establishment ~~product~~of ~~candidates;~~sales, marketing and distribution capabilities;

• the ~~timing~~scope, ~~scope~~progress, costs and ~~costs~~results of ~~establishing~~process adevelopment, ~~commercial~~manufacturing ~~infrastructure~~scale-up ~~for~~and ~~potential~~validation ~~commercialization~~activities, ofanalytical ~~Zimura~~method development and ~~for~~qualification, ~~any~~and ~~other~~stability ~~product~~studies ~~candidates~~associated ~~for~~with ~~which~~ACP weand ~~receive,~~our orother ~~expect~~product ~~to receive, marketing approval~~candidates;

•the ~~costs~~scope, ~~timing~~progress, ~~and~~costs ~~outcome of regulatory filings~~ and ~~reviews~~results of our ~~product~~current ~~candidates, including the potential submission~~ and ~~regulatory~~future ~~review~~ACP ofclinical anprograms ~~NDA~~ and anany ~~MAA~~further ~~for~~development ~~Zimura~~we inmay GAundertake;

•our ability to establish collaborations on favorable terms, if at all, if we choose to do so, including a potential collaboration for the further development and potential commercialization of ~~Zimura~~ACP in one or more territories outside the United States ~~and a collaboration or out-license for the further development and potential commercialization of IC-100 and IC-200~~;

•the extent to which we in-license or acquire rights to, and undertake research or development of, additional product candidates or technologies, including sustained release delivery technologies for ~~Zimura~~ACP;

•the ~~scope,~~extent ~~progress,~~of ~~costs~~our ~~and~~debt ~~results~~service ofobligations and our ~~efforts~~ability, toif ~~develop IC-500~~desired, ~~including activities~~ to ~~establish~~refinance ~~manufacturing~~any ~~capabilities~~of ~~and~~our ~~other~~existing ~~preclinical~~debt ~~development~~on ~~activities~~terms tothat ~~enable~~are usmore favorable to ~~file an IND for this product candidate~~us;

•the scope, progress, costs and results of our efforts to develop IC-500, including activities to establish manufacturing capabilities and other preclinical development activities to enable us to submit an IND for this product candidate;

•the scope, progress, costs and results from our gene therapy research programs, including costs related to the in-license and future development of any promising product candidates and technologies that emerge from these programs;

•the timing and extent of delays or disruptions to our research and development programs as a result of the COVID-19 pandemic and other macro-economic events;

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•the costs of preparing, filing and prosecuting patent applications, maintaining and protecting our intellectual property rights and defending intellectual property-related claims; and

•subject to receipt of marketing approval, net revenue received from commercial sales of any of our product candidates, after milestone payments and royalty payments that we would be obligated to make.

We do not have any committed external source of funds. Our ability to raise adequate additional financing when needed, and on terms acceptable to us, will depend on many factors. These factors include investors' perceptions of the potential success of our ongoing business, including the development of our product candidates and other programs, and the potential future growth of our business. Additionally, these factors include general market conditions that also affect other companies. For example, the COVID-19 pandemic and governmental responses to the pandemic have caused volatility and uncertainty in the financial markets as well as additional volatility in the price of our stock, which may result in prospective investors being less likely to invest new capital. These factors may make raising capital difficult, and may result in us accepting terms that are unfavorable to us, especially if we are in need of financing at the particular time. Although we were successful in raising approximately $162.6 million in net proceeds in an underwritten public offering of our common stock in October 2021, we may not be able to successfully raise additional capital in the future. The size of our company and our status as a company listed on The Nasdaq Global Select Market, or Nasdaq, may also limit our ability to raise financing. For example, our ability to raise adequate financing through a public offering may be limited by market conditions and SEC rules based on our current market capitalization. Nasdaq listing rules also generally limit the number of shares we may issue in a private placement to a number less than 20% of the number of shares of our common stock outstanding immediately prior to the transaction, unless we issue such shares at a premium, which investors may be unwilling to accept, or unless we obtain shareholder approval, which can be expensive and time-consuming and can add risk to our ability to complete the financing transaction. If we are unable to raise additional funds when needed, we may be required to delay, limit, reduce or terminate the development of one or more of our product candidates, our gene therapy research programs, or our future commercialization efforts.71

WeTable may require additional funding beyond what we currently expect due to unforeseen or other reasons. Our costs may exceed our expectations if we experience an issue in our clinical trials, such as issues with patient enrollment, the retention of enrolled patients, enrolled patients maintaining scheduled visits and receiving scheduled treatments, or the availability of drug supply, if we experience an issue with manufacturing, such as issues with process development, scale-up and validation, or establishing and qualifying second source suppliers and ensuring adequate inventory for our expected needs, if we experience an issue in our preclinical development programs, such as unfavorable toxicology or other preclinical data, or if we modify or further expand the scope of our clinical trials, preclinical development programs or gene therapy research programs. Our costs may also exceed our expectations for other reasons, for example, if we are required by the FDA, the EMA, or regulatory authorities in other jurisdictions to perform clinical trials or nonclinical or other studies in addition to those we currently expect to conduct. For example, we are conducting the GATHER2 trial with the expectation that data collected from such trial, if it is positive, together with other available data, will be sufficient to support an application for marketing approval in the United States and the European Union and we may subsequently decide to, or be required by regulatory authorities to, enroll additional patients in the GATHER2 trial, or conduct additional clinical trials or nonclinical studies of Zimura in order to seek or maintain marketing approval or qualify for reimbursement approval. In addition, the COVID-19 pandemic may result in disruptions to the progress of the GATHER2 or STAR trials, including slowing patient enrollment in STAR or causing enrolled patients in either trial to miss their scheduled visits or drop out in greater numbers than we expect, or disruptions to our other research and development programs, which could cause us to continue to expend our cash resources while not progressing our research and development programs as expeditiously as we would have had the pandemic not occurred or persisted. As a result of any of the above, we may need or may seek to obtain additional funding for our continuing operations sooner or in greater amounts than expected.Contents

Our ~~need~~ability ~~for~~to raise adequate additional financing ~~may~~when ~~continue~~needed, ~~even~~and ifon weterms ~~are~~acceptable ~~able~~ to ~~successfully~~us, ~~develop~~will ~~one~~depend oron ~~more~~many factors. These factors include investors' perceptions of the potential success of our ongoing business, including the development of our product candidates. ~~Our~~and other programs, and the potential future ~~commercial~~growth ~~revenues~~of our business. Additionally, ifthese ~~any~~factors include general market conditions that also affect other companies. For example, ~~will~~the beCOVID-19 ~~derived~~pandemic ~~from~~and ~~sales~~other ofmacro-economic events, such ~~product~~as ~~candidates~~the current high levels of inflation, and governmental responses to those events have caused volatility and uncertainty in the financial markets as well as additional volatility in the price of our stock, which may ~~not~~result bein ~~available~~prospective ~~for~~investors atbeing ~~least~~less ~~several~~likely ~~years~~to ~~following~~invest ~~completion~~new ofcapital. ~~successful~~These ~~product~~factors ~~development~~may make raising capital difficult, ifand atmay ~~all.~~result Inin ~~addition~~us accepting terms that are unfavorable to us, especially if ~~approved,~~we ~~our~~are ~~product~~in ~~candidates~~need ~~may~~of ~~not~~financing ~~achieve~~at ~~commercial~~the ~~success~~particular time. ~~Even~~Although ifwe ~~those~~were ~~products~~successful ~~are~~in ~~successful~~raising ~~and~~approximately we$324.3 domillion ~~achieve~~in ~~profitability~~net proceeds in an underwritten public offering of our common stock in December 2022, we may not be able to ~~sustain~~successfully orraise ~~increase~~additional ~~profitability~~capital onin the future. The size of our company and our status as a ~~quarterly~~company listed on The Nasdaq Global Select Market, or ~~annual~~Nasdaq, ~~basis~~may also limit our ability to raise financing. ~~Under~~For ~~most~~example, ifNasdaq ~~not~~listing ~~all,~~rules generally limit the number of shares we may issue in a private placement to a number less than 20% of the ~~foregoing~~number ~~circumstances~~of shares of our common stock outstanding immediately prior to the transaction, unless we issue such shares at a premium, which investors may ~~need~~be unwilling to accept, or unless we obtain ~~substantial~~shareholder ~~additional~~approval, which can be expensive and time-consuming and can add risk to our ability to complete the financing transaction. If we are unable to ~~achieve~~raise additional funds when needed, we may be required to delay or reduce our ~~business~~future ~~objectives~~commercialization efforts, or delay, reduce or terminate the development of one or more of our product candidates.

We may require additional funding beyond what we currently expect due to unforeseen or other reasons. Our costs may exceed our expectations if the timeline for potential commercial launch of ACP is accelerated, if we need to establish commercial infrastructure or capabilities, including hiring additional personnel or conducting additional disease-state awareness activities, to a greater extent than we have planned, or if we choose not to or are unable to find a collaborator for commercialization of ACP in one or more territories outside the United States. Our costs may also exceed our expectations if we experience an issue with manufacturing, such as issues with process development, scale-up and validation, or establishing and qualifying second source suppliers and ensuring adequate inventory for our expected needs, including potential launch of ACP; if we experience an issue in our clinical trials, such as issues with patient enrollment, the retention of enrolled patients, enrolled patients maintaining scheduled visits and receiving scheduled treatments, or the availability of drug supply; if we experience an issue in our preclinical development programs, such as unfavorable toxicology or other preclinical data; or if we modify or further expand the scope of our clinical trials, preclinical development programs or gene therapy research programs. Our costs may also exceed our expectations for other reasons, for example, if we are required by the FDA, the EMA, or regulatory authorities in other jurisdictions to perform clinical trials or nonclinical or other studies in addition to those we currently expect to conduct. For example, we believe that the data from the GATHER2 trial, together with other available data, are sufficient to support applications for marketing approval in the United States, the European Union and the United Kingdom. We may subsequently decide to, or be required by regulatory authorities to, conduct additional clinical trials or nonclinical studies of ACP in order to seek or maintain marketing approval or qualify for reimbursement approval. In addition, the COVID-19 pandemic and other macroeconomic events may result in disruptions to the progress of the GATHER2 or STAR trials or the OLE study, including slowing patient enrollment in STAR or causing enrolled patients in either trial to miss their scheduled visits or drop out in greater numbers than we expect, or disruptions to our other research and development programs, which could cause us to continue to expend our cash resources while not progressing our research and development programs as expeditiously as we would have had the pandemic not occurred or persisted. As a result of any of the above, we may need or may seek to obtain additional funding for our continuing operations sooner or in greater amounts than expected.

Our need for additional financing may continue even if we are able to successfully obtain regulatory approval and launch ACP in GA secondary to AMD. Our future commercial revenues, if any, will be derived from product sales, which may not be available or become substantial for a period of time following launch. In addition, if approved, our products may not achieve commercial success. Even if those products are successful and we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. Under most, if not all, of the foregoing circumstances, we may need to obtain substantial additional financing to achieve our business objectives.

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

Until such time, if ever, when we can generate substantial product revenues, we may need or may seek to finance our operations through a combination of equity offerings, debt financings, collaborations, strategic alliances and marketing, distribution or licensing arrangements. InFor ~~addition~~example, wein ~~may~~July ~~seek~~2022, ~~additional~~we ~~capital~~entered ~~due~~into tothe ~~favorable~~Loan ~~market~~Agreement ~~conditions~~with orHercules ~~strategic~~and ~~considerations~~SVB, ~~even~~providing iffor wethe ~~believe~~2022 ~~that~~Term Loan Facility, pursuant to which we have ~~sufficient~~total ~~funds~~borrowing ~~for~~capacity ~~our~~under ~~current~~several ortranches ~~future~~of ~~operating~~up ~~plans~~to $250.0 million Toin aggregate principal amount, of which (i) $50.0 million was drawn in July 2022 upon execution of the ~~extent~~Loan Agreement and an additional $50.0 million was drawn in December 2022 after our achievement of a specified performance milestone relating to the GATHER2 trial data we obtained for ACP in September 2022, (ii) an additional tranche of $25.0 million is available to be drawn at our option anytime through September 30, 2023 which we plan to draw in 2023, (iii) an

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additional tranche of $75.0 million may be drawn at our option at any time after our achievement of a specified performance milestone relating to the approval of the NDA by the FDA through the earlier of 90 days after achievement or September 30, 2024 and (iv) an additional $50.0 million is available subject to approval of the lenders’ investment committee in its discretion. However, if we do not satisfy the remaining specified performance milestone or the lenders do not otherwise approve additional borrowings, we will not have access to the remaining amounts of the 2022 Term Loan Facility. In addition, we may seek additional capital due to favorable market conditions or strategic considerations, even if we believe that we have sufficient funds for our current or future operating plans. To the extent that we raise additional capital through the sale of equity or convertible debt securities, our existing stockholders' ownership interests would be diluted, and the terms of these new securities may include liquidation or other preferences that adversely affect our existing stockholders' rights as common stockholders. The dilutive effect of future equity issuances may be substantial, depending on the price of our common stock at the time of such capital raise, with a lower stock price translating to greater dilution for existing stockholders. Debt financing and preferred equity financing, if available, would involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures, declaring dividends, making certain investments or entering into certain other transactions. For example, the covenants under the Loan Agreement include limitations on our ability to obtain additional financing, to make certain investments and to enter into certain other transactions.

In addition, we have issued, and may in the future issue additional, equity securities as consideration for business development transactions, which may also dilute our existing stockholders' ownership interests. For example, under the agreement and plan of merger pursuant to which we acquired IC-500, or the Inception 4 Merger Agreement, we issued an aggregate of 5,174,727 shares of our common stock as up-front consideration to the former equityholders of Inception 4. The Inception 4 Merger Agreement also requires us to make payments to the former equityholders of Inception 4 upon the achievement of certain clinical and regulatory milestones, subject to the terms and conditions set forth in the Inception 4 Merger Agreement. Those milestone payments will be in the form of shares of our common stock, calculated based on the price of our common stock over a five-trading day period preceding the achievement of the relevant milestone, unless and until the issuance of such shares would, together with all other shares issued under the Inception 4 Merger Agreement, exceed an overall maximum limit of approximately 7.2 million shares, which is equal to 19.9% of the number of issued and outstanding shares of our common stock as of the close of business on the business day prior to the closing date of our acquisition of Inception 4, and will be payable in cash thereafter. In July 2019, we also issued 75,000 shares of our common stock to UMass as partial upfront consideration for the in-license of our miniCEP290 program, and are obligated to issue up to 75,000 additional shares to UMass upon the achievement of a development milestone.

In March 2021, we filed a shelf registration statement on Form S-3, or the March 2021 Shelf Registration, pursuant to which we may offer and sell shares of common stock, debt securities and other securities for aggregate gross sale proceeds of up to $300.0 million, of which we may offer and sell up to $100.0 million from time to time pursuant to an “at-the-market” sales agreement, or the ATM Agreement, we entered into in March 2021 with Cowen and Company, LLC, or Cowen, as agent, subject to the terms and conditions described in the ATM Agreement and SEC rules and regulations. In July 2021, we issued and sold 13,397,500 shares of our common stock in an underwritten public offering under the March 2021 Shelf Registration. We have not yet issued and sold any shares of common stock under our “at-the-market” offering program. In addition, in October 2021, we filed an automatically effective shelf registration statement, or the October 2021 Shelf Registration, under which we may issue an indeterminate amount of shares of common stock, debt securities and other securities. In October 2021 and December 2022, we issued and sold 10,350,000 shares of our common stock and 15,352,500 shares of our common stock, respectively, in two underwritten public offerings under the October 2021 Shelf Registration. If we make further sales under the March 2021 Shelf Registration or the October 2021 Shelf Registration or if we make sales under our “at-the-market” offering program, the sales could dilute our stockholders, reduce the trading price of our common stock or impede our ability to raise future capital.

If we raise additional funds through collaborations, royalty transactions, strategic alliances or marketing, distribution or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, products or product candidates or grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to grant rights to develop and market products or product candidates that we would otherwise prefer to develop and market ourselves.

Our operating activities may be restricted as a result of covenants related to the outstanding indebtedness under our Loan Agreement with Hercules and SVB and we may be required to repay the outstanding indebtedness in an event of default, which could have a materially adverse effect on our business.

As more fully described in “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Contractual Obligations and Commitments”, in July 2022, we entered into the 2022 Term Loan Facility. The 2022 Term Loan Facility is secured by a lien on substantially all of our assets, including intellectual property, with certain limited exceptions set forth in the Loan Agreement. The Loan Agreement contains various covenants that limit our ability to engage in specified types of transactions. These covenants limit our ability to, among other things, sell, transfer, lease or dispose of certain

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~~that~~assets; weincur ~~raise~~indebtedness; ~~additional~~encumber ~~capital through the sale of equity~~ or ~~convertible~~permit ~~debt~~liens ~~securities,~~on ~~our~~certain ~~existing~~assets; ~~stockholders'~~make ~~ownership~~certain ~~interests~~investments ~~would be diluted,~~ and ~~the~~acquisitions; ~~terms~~make ofcertain ~~these~~restricted ~~new~~payments, ~~securities~~including ~~may~~paying ~~include~~dividends ~~liquidation~~on, or ~~other~~repurchasing ~~preferences~~or ~~that~~making ~~adversely~~distributions ~~affect~~with ~~our~~respect ~~existing stockholders' rights as common stockholders. The dilutive effect of future equity issuances may be substantial~~to, ~~depending on the price of~~ our common stock; atand ~~the~~enter ~~time~~into ofcertain ~~such capital raise, with a lower stock price translating to greater dilution for existing stockholders~~transactions. ~~Debt~~Our ~~financing~~business ~~and preferred equity financing, if available,~~ may ~~involve~~be ~~agreements~~adversely ~~that~~affected ~~include~~by ~~covenants~~these ~~limiting~~restrictions oron ~~restricting~~ our ability to ~~take~~operate ~~specific~~our ~~actions, such as incurring additional debt, making capital expenditures, declaring dividends or entering into certain investments or transactions~~business.

InThe ~~addition,~~covenants weunder ~~have issued, and may in~~ the ~~future~~2022 ~~issue~~Term ~~additional,~~Loan ~~equity~~Facility ~~securities as consideration for business development transactions, which may~~ also ~~dilute~~include ~~our~~a ~~existing~~requirement ~~stockholders' ownership interests. For example, under the agreement and plan of merger pursuant~~ to ~~which we acquired Inception 4~~maintain, orduring the ~~Inception~~period 4commencing ~~Merger~~on ~~Agreement,~~May ~~we issued an aggregate of 5~~15,~~174,727~~ shares of our common stock as up-front consideration to the former equityholders of Inception 4. The Inception 4 Merger Agreement also requires us to make payments to the former equityholders of Inception 4 upon the achievement of certain clinical and regulatory milestones2023, ~~subject to the terms~~ and ~~conditions~~ending ~~set forth in the Inception 4 Merger Agreement. Those milestone payments will be in the form of shares of our common stock, calculated based~~ on ~~the~~August ~~price of our common stock over a five-trading day period preceding the achievement of the relevant milestone~~14, ~~unless and until the issuance of such shares would~~2024, ~~together~~certain ~~with~~minimum ~~all~~levels ~~other shares issued under the Inception 4 Merger Agreement, exceed an overall maximum limit~~ of ~~approximately~~cash ~~7.2~~in ~~million~~accounts ~~shares,~~subject ~~which is equal~~ to ~~19.9%~~a ofcontrol ~~the~~agreement ~~number~~in offavor ~~issued and outstanding shares~~ of ~~our~~Hercules ~~common stock~~ as ~~of the close of business on the business day prior to the closing date of our acquisition of Inception 4~~agent, ~~and~~which ~~will be payable in cash thereafter. In July 2019,~~ we ~~also~~refer ~~issued 75,000 shares of our common stock~~ to ~~UMass~~ as ~~partial~~Qualified ~~upfront consideration for the in-license of our miniCEP290 program, and are obligated to issue up to 75,000 additional shares to UMass upon the achievement of a development milestone~~Cash.

~~In March 2021~~Further, westarting ~~filed a shelf registration statement~~ on ~~Form~~August ~~S-3~~15, or2024, ~~the~~we ~~March~~will ~~2021~~be ~~Shelf~~required ~~Registration, pursuant~~ to ~~which~~maintain wea ~~may~~certain ~~offer~~minimum ~~and~~amount ~~sell shares~~ of ~~common~~trailing ~~stock,~~six-month ~~debt~~net ~~securities~~product ~~and~~revenue ~~other~~from ~~securities~~sales ~~for aggregate gross sale proceeds~~ of ~~up to $300.0 million~~ACP, oftested ~~which~~on wea ~~may~~quarterly ~~offer and sell up to $100~~basis.0 ~~million~~However, ~~from~~this ~~time~~revenue tocovenant ~~time~~will ~~pursuant~~be towaived anduring ~~“at-the-market”~~periods ~~sales~~in ~~agreement,~~which ~~or the ATM Agreement,~~ we ~~entered~~(x) ~~into~~(i) inmaintain ~~March~~a ~~2021~~market ~~with~~capitalization ~~Cowen and Company, LLC, or Cowen, as agent, subject to the terms and conditions described~~ in ~~the~~excess ~~ATM~~of ~~Agreement and SEC rules and regulations~~$600.0 Inmillion ~~July 2021, we issued~~ and ~~sold~~(ii) ~~13,397,500~~maintain ~~shares~~Qualified ofCash ~~our common stock~~ in an ~~underwritten~~amount ~~public~~greater ~~offering~~than ~~under~~or ~~the~~equal ~~March~~to ~~2021~~fifty ~~Shelf~~percent ~~Registration.~~(50%) Weof ~~have~~the ~~not~~outstanding ~~yet~~term ~~issued~~loan ~~and~~advances ~~sold~~made ~~any shares of common stock~~ under ~~our “at-~~the~~-market”~~ ~~offering~~2022 ~~program.~~Term InLoan ~~addition,~~Facility inat ~~October~~such ~~2021,~~time ~~we filed an automatically effective shelf registration statement,~~ or ~~the~~(y) ~~October~~maintain ~~2021~~Qualified ~~Shelf~~Cash ~~Registration,~~in ~~under which we may issue~~ an ~~indeterminate~~ amount ofgreater ~~shares~~than ofor ~~common~~equal ~~stock,~~to ~~debt~~ninety ~~securities~~percent ~~and~~(90%) ~~other securities. In October 2021, we issued and sold 10,350,000 shares~~ of ~~our common stock in an underwritten public offering under~~ the ~~October~~outstanding ~~2021~~term ~~Shelf~~loan ~~Registration.~~advances Ifmade ~~we make further sales~~ under the ~~March~~2022 ~~2021~~Term ~~Shelf~~Loan ~~Registration~~Facility ~~or the October 2021 Shelf Registration or if we make sales under our “~~at~~-the-market”~~ ~~offering~~such ~~program, the sales could dilute our stockholders, reduce the trading price of our common stock or impede our ability to raise future capital~~time.

IfA webreach ~~raise~~of ~~additional~~any ~~funds~~of ~~through~~the ~~collaborations,~~covenants ~~royalty~~under ~~transactions,~~the ~~strategic~~Loan ~~alliances~~Agreement orcould ~~marketing,~~result ~~distribution~~in ora ~~licensing~~default ~~arrangements~~under ~~with~~the ~~third~~2022 ~~parties,~~Term weLoan ~~may~~Facility. ~~have~~If toan ~~relinquish~~event ~~valuable~~of ~~rights~~default tounder ~~our~~the ~~technologies,~~2022 ~~future~~Term ~~revenue~~Loan ~~streams~~Facility occurs, ~~products~~including ora ~~product~~material ~~candidates~~adverse oreffect, ~~grant~~subject ~~licenses~~to oncertain ~~terms~~exceptions, ~~that~~on ~~may~~our ~~not~~business, beoperations, ~~favorable~~properties, toassets ~~us.~~or Iffinancial wecondition, ~~choose~~the tolenders ~~pursue~~could aelect ~~collaboration~~to ~~for~~declare ~~any~~all ofamounts ~~our~~outstanding, ~~product~~if ~~candidates~~any, weto ~~may~~ be ~~required~~immediately todue ~~relinquish~~and ~~certain~~payable ~~valuable~~and ~~rights~~terminate ~~depending~~all oncommitments ~~the~~to ~~terms~~extend offurther ~~such a transaction~~credit. If wethere are ~~unable~~any toamounts ~~raise~~outstanding ~~additional~~that ~~funds through equity or debt financings when needed,~~ we ~~may~~are beunable ~~required~~ to ~~grant~~repay, ~~rights~~the tolenders ~~develop~~could ~~and~~proceed ~~market~~against ~~products~~the orcollateral ~~product~~granted ~~candidates~~to ~~that~~them ~~we would otherwise prefer~~ to ~~develop~~secure ~~and~~such ~~market ourselves~~indebtedness.

The COVID-19 pandemic, which is a fluid and evolving situation, has adversely affected and may continue to negatively affect our business and operations in a number of ways, and its long-term effects are uncertain. In addition, ~~the~~our ~~pandemic~~outstanding ~~has~~debt ~~caused~~combined ~~substantial~~with ~~disruptions~~our inother ~~the~~ financial ~~markets~~obligations and ~~economies~~contractual commitments, ~~which~~ could ~~adversely~~have ~~affect~~significant ~~our~~adverse ~~business~~consequences, ~~and operations.~~including:

~~The~~•requiring ~~COVID-19~~us ~~pandemic,~~to ~~which~~dedicate ~~began~~a insubstantial ~~December~~portion ~~2019, has spread worldwide. A majority~~ of ~~the~~cash, ~~world's~~cash ~~population~~equivalents ~~has~~and ~~been~~available ~~affected~~for bysale ~~government~~securities ~~efforts~~ to ~~slow~~ the ~~spread~~payment of ~~the~~interest ~~outbreak through stay-at-home and social distancing orders~~on, ~~shutdowns of businesses~~ and ~~public~~principal ~~places~~of, ~~heightened~~our ~~border security~~debt, ~~travel~~which ~~restrictions,~~would ~~quarantines~~reduce ~~and~~the ~~other~~amounts ~~measures.~~available ~~The~~to ~~COVID-19~~fund ~~pandemic~~working ~~and government measures taken in response have had a significant impact~~capital, ~~both~~commercialization ~~direct and indirect~~expenditures, onproduct ~~businesses~~development ~~and~~efforts ~~commerce, as a substantial number of people have been required to stay~~ and work from home; worker shortages have occurred; supply chains have been disrupted; facilities and production have been suspended; and demand for certain goods and services, such as medical services and supplies, has spiked, while demand for other ~~goods~~general ~~and~~corporate ~~services, such as travel and conferences, has fallen.~~purposes;

~~Beginning~~•limiting our flexibility in ~~March~~planning ~~2020~~for, ~~the~~or ~~COVID-19~~reacting ~~pandemic and measures taken~~ to, ~~contain~~changes itin ~~have affected~~ our business and ~~operations~~our inindustry; ~~a number of ways. These include, but are not limited to, the following:~~and

•placing us at a competitive disadvantage compared to our competitors that have less debt or better debt servicing options.

We intend to satisfy our current and future debt service obligations with our existing cash, cash equivalents and available for sale securities, potential future product revenues and funds from external sources. However, we may not have sufficient funds or may be unable to arrange for additional financing to pay the amounts due under the 2022 Term Loan Facility. Funds from external sources may not be available on acceptable terms, if at all.

The COVID-19 pandemic, which is a fluid situation, has adversely affected and may continue to negatively affect our business and operations in a number of ways, and its long-term effects are uncertain. In addition, the pandemic and other macroeconomic events have caused substantial disruptions in the financial markets and economies, which could adversely affect our business and operations.

Since March 2020, the COVID-19 pandemic and measures taken to contain it have affected our business and operations in a number of ways. These include, but are not limited to, the following:

•Clinical Trial Operations. The pandemic has affected how we conduct our clinical trials, including patient recruitment and efforts to support patient visits to our clinical trial sites. Although the pandemic did not materially affect our clinical trials in 2022, we do not know if and how the pandemic may affect the continued progress of our ongoing clinical trials or any future clinical trials we may conduct. For a more detailed discussion of the impact of the COVID-19 pandemic on our clinical trial operations, please see the Risk Factor titled, “The COVID-19 pandemic has affected and may continue to affect the initiation and conduct of our clinical trials, including the retention of patients for our GATHER2 clinical trial and patient recruitment and retention for our STAR clinical trial and the OLE study. It may have long-lasting effects on the conduct of clinical trials, which can make our ongoing and any future trials more difficult, costly or time consuming.”

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•~~Clinical~~Third-Party ~~Trial~~Collaborators ~~Operations~~and Vendors. InThe ~~March~~pandemic ~~2020,~~has wecaused ~~decided~~many ~~to delay the initiation~~ of ~~patient enrollment in~~ our ~~GATHER2~~third-party ~~trial.~~contract ~~As we initiated patient enrollment in June 2020~~manufacturers, wecontract ~~and~~research ~~our~~organizations ~~clinical trial sites implemented new health~~ and ~~safety~~other ~~practices~~vendors to ~~mitigate~~limit ~~the~~their ~~effects~~operations ~~of the COVID-19 pandemic~~ and ~~to support patients and site~~ staff~~. In addition~~, wewhich ~~added~~resulted ~~more than 30 new sites to the GATHER2 trial to help with patient recruitment. Although we have since completed patient enrollment~~ in ~~GATHER2,~~delays ~~we may face difficulties in retaining patients or maintaining scheduled visits~~ to ~~the~~some ~~extent patients are affected by the virus or lockdown measures or are fearful~~ of ~~visiting or traveling to~~ our ~~clinical~~manufacturing ~~trial~~and ~~sites~~research ~~because~~and ofdevelopment ~~the pandemic~~activities. We ~~are~~Over ~~aware~~the ~~that~~past atwo ~~number~~years, several of ~~patients~~our ~~initially~~vendors ~~enrolled~~have inbeen ~~the~~facing ~~STAR~~backlogs ~~trial~~due ~~missed~~to ~~consecutive~~work ~~visits~~and ~~during~~demands ~~the~~from ~~early~~other ~~months of the pandemic~~clients, ~~and~~including ~~that~~those awho ~~number~~were ofdeveloping ~~patients~~vaccines inor ~~our~~medicines ~~Latin America sites~~ for ~~GATHER2 missed visits because of~~ the COVID-19 pandemic~~. We~~, dowhich ~~not~~limited ~~yet~~their ~~know~~availability ~~whether~~to ~~the~~perform ~~number~~work offor ~~missed~~us. ~~visits~~In ~~will increase or decrease in the GATHER2 or STAR trials~~addition, orseveral ~~what the impact~~ of ~~missed~~our ~~visits~~vendors ~~may~~have beexperienced onhigh ~~patient~~levels ~~retention~~of inabsenteeism ~~those~~due ~~trials or the trial results, especially because we are masked~~ to ~~the~~variants ~~treatment~~ of ~~patients during~~ the ~~conduct~~virus ~~of the trials. We have been~~ and ~~continue~~as ~~to monitor the situation closely. For~~ a ~~more~~result ~~detailed~~scaled ~~discussion~~back oftheir ~~the impact of the COVID-19 pandemic on our clinical trial~~ operations,. ~~please~~At ~~see~~this ~~the Risk Factor titled~~time, ~~“The~~we ~~COVID-19~~do ~~pandemic~~not ~~has~~know ~~affected~~whether ~~and~~there ~~may~~will ~~continue~~be tofurther ~~affect~~impact ~~the~~on ~~initiation and conduct of our clinical trials, including~~ the ~~retention~~work of ~~patients for~~ our ~~GATHER2~~third-party ~~clinical~~vendors ~~trial~~ and ~~patient~~collaborators ~~recruitment~~due ~~and~~to ~~retention~~the ~~for our STAR clinical trial. It may have long~~COVID-~~lasting~~19 ~~effects on the conduct of clinical trials, which can make our ongoing and any future trials more difficult, costly or time consuming”~~pandemic.

•~~Third-Party~~Supply ~~Collaborators~~Chain and ~~Vendors~~Materials. ~~Many~~The ofpandemic ~~our~~has ~~third-party~~caused ~~contract manufacturers~~shortages, ~~academic~~delays ~~research collaborators~~ and ~~contract~~disruptions ~~research~~in ~~organizations limited their operations and staff during~~ the ~~COVID-19~~global ~~pandemic~~supply chain, ~~which~~including ~~resulted in delays to some of~~ our ~~manufacturing~~contract ~~and~~manufacturers' ~~research and development activities and limited our~~ ability to beprocure ~~on site to oversee these activities. For example~~items, ~~the~~such ~~closure~~as ofraw ~~animal research laboratories at UMMS for several months during 2020 caused delays to the progress of~~materials, ~~and~~that toare ~~our~~essential ~~timelines~~ for ~~receipt of data from, our minigene research programs. Over~~ the ~~past~~manufacture ~~year, several~~ of our ~~vendors~~product have been facing backlogs due to work and demands from other clients, including those who are developing vaccines or medicines for the COVID-19 pandemic, which has limited their availability to perform work for uscandidates. For example, ~~we anticipate that~~ the ~~start~~new ofmanufacturer ~~the IND-enabling toxicology studies for IC-500 will be later than what~~ we ~~originally~~are ~~planned,~~working ~~primarily~~with ~~due~~as toa ~~the~~second ~~limited~~source ~~availability~~ of ~~study~~supply ~~slots at CROs attributable to rising demand~~ for ~~their~~ACP ~~services~~drug assubstance ~~well~~has asexperienced ~~increased~~issues ~~absenteeism~~with ofprocuring ~~staff~~a atnumber ~~those CROs in wake~~ of ~~the~~raw ~~COVID-19~~materials ~~pandemic and the recent Omicron variant. We are also aware that some of our third-party contract manufacturers and storage vendors have experienced high levels of absenteeism~~ due to ~~the~~supply ~~Omicron~~chain ~~variant~~interruptions, ~~and~~which ascaused aseveral ~~result~~delays ~~started~~ to ~~limit their operations and on-site activities. These operational and staffing limitations may cause further delays for~~ our ~~development and~~ manufacturing ~~activities.~~timelines Atwith this ~~time,~~manufacturer. weWe docontinue ~~not~~to ~~know~~monitor ~~whether there will be further impact on the work of~~ our ~~third-party~~supply ~~vendors~~chain ~~and collaborators due to the COVID-19 pandemic~~closely.

~~•Supply~~The ~~Chain~~progression ~~and~~of ~~Materials. Shortages, delays and governmental restrictions arising from~~ the COVID-19 pandemic ~~have~~remains ~~disrupted~~fluid and ~~may~~its ~~continue~~impact toon ~~disrupt~~our ~~the~~business ~~ability~~and ofoperations ~~our~~remains ~~contract~~uncertain. ~~manufacturers~~Many tocompanies ~~procure~~have ~~items,~~been ~~such~~using asforce ~~raw~~majeure ~~materials,~~clauses ~~that~~in ~~are~~their ~~essential~~contracts ~~for~~to ~~the~~excuse ~~manufacture~~or ofdelay ~~our~~performing ~~product~~under ~~candidates.~~their ~~For example~~contracts, ~~during~~including ~~2020,~~as ~~our contract manufacturer for IC-500 drug substance experienced~~ a ~~shortage~~result ~~in obtaining one~~ of ~~the~~supply ~~raw~~chain ~~materials~~interruptions. ~~that~~Our ~~was~~contract ~~sourced from China~~manufacturers, ~~which~~contract ~~was~~research ~~caused~~organizations ~~by the shutdown of local suppliers~~ and ~~the~~other ~~slowdown~~third inparties ~~trade~~on ~~due~~whom towe ~~the~~rely ~~COVID-19 pandemic. This shortage delayed our process development activities~~ for ~~the~~goods ~~drug~~or ~~substance~~services ~~for~~may ~~IC-500~~make bysimilar ~~a number of months~~claims. InIf ~~addition,~~any ~~since~~such ~~2020,~~force ~~there~~majeure ~~have~~claims ~~been~~were ~~shortages~~successful, ofthen ~~various~~not ~~animals~~only ~~used~~would inour ~~research~~timelines ~~studies,~~be ~~such~~delayed asbut ~~several~~also ~~types~~our ofright ~~non-human~~to ~~primates,~~recover ~~which~~for ~~are~~any ~~typically~~economic ~~sourced~~damages ~~from China,~~ due to the ~~COVID-19~~delay ~~pandemic~~would ~~and~~be ~~disruptions to the global supply chain~~limited. ~~Although~~Because ~~our development programs have not yet been affected by these shortages,~~ we ~~are~~rely ~~continuing~~on tomany ~~monitor~~single-source ~~the situation. Furthermore~~suppliers, inany ~~October~~such ~~2021~~claims wefrom ~~learned~~them ~~that the new manufacturer we~~ are ~~working~~likely ~~with for second source supply of Zimura drug substance was experiencing issues with procuring an important raw material common~~ to ~~many~~result ~~manufacturing~~in ~~processes,~~a ~~which~~delay ~~occurred due~~ to ~~recent~~our ~~supply~~timelines ~~chain~~or ~~interruptions~~otherwise ~~and~~adversely ~~caused~~affect ~~a slight delay to~~ our ~~manufacturing~~operations ~~timelines~~or ~~with~~financial ~~this contract manufacturer~~position.

~~•Remote~~The ~~Working.~~full Weextent ~~instituted~~to ~~company~~which the COVID-~~wide~~19 ~~remote~~pandemic ~~working~~and ~~starting~~other inmacroeconomic ~~March~~events, ~~2020.~~including Inthe ~~2021,~~ongoing wemilitary ~~began~~conflict ~~permitting~~between ~~employees~~Russia toand ~~return~~Ukraine, towill directly or indirectly impact our ~~offices~~business, results of operations and financial condition will depend on adevelopments ~~voluntary~~that ~~basis~~are inuncertain ~~compliance~~and ~~with~~cannot be accurately predicted, including new ~~health~~information that may emerge concerning COVID-19 and ~~safety~~new ~~policies~~variants weand ~~implemented~~subvariants of the virus, ~~including~~the aactions ~~vaccination~~taken ~~policy~~to ~~for~~contain ~~employees~~it ~~working~~or inlessen ~~our~~its ~~offices~~impact, and the economic impact on local, regional, national and international markets. We ~~expect~~may experience additional disruptions to ~~operate~~our ~~under~~clinical atrials ~~hybrid~~or ~~(partially~~supply ~~remote~~chains, and ~~partially~~reduced operations at third-party facilities, such as our clinical trial sites and suppliers, and delays in ~~office)~~interactions ~~working~~with ~~model~~regulatory ~~for~~agencies ~~the~~or ~~foreseeable~~obtaining ~~near~~approvals ~~future~~for our product candidates. WeAlthough ~~are~~the ~~continuing~~current tomilitary ~~monitor~~conflict between Russia and ~~support~~Ukraine ~~the~~has not materially affected our business or operations, other geopolitical events and public health crises and ~~well-being~~natural disasters, such as future epidemics or pandemics or those resulting from the effects of ~~our~~climate ~~employees~~change, may arise in the future. Any of these events may materially and ~~their~~adversely ~~productivity~~affect asour ~~remote~~business ~~working~~operations ~~continues~~and financial condition.

~~The~~Our ~~progression~~strategy of ~~the~~obtaining ~~COVID-19~~additional ~~pandemic~~rights ~~remains~~to ~~fluid~~products, ~~and~~product ~~its~~candidates ~~impact~~or ontechnologies ~~our~~for ~~business and operations remains uncertain. Throughout~~ the ~~course~~treatment of ~~the~~retinal ~~pandemic~~diseases ~~thus~~may ~~far,~~not ~~many~~be ~~countries~~successful. ~~and~~Although ~~regions,~~we ~~including~~entered ~~many~~into ~~states~~a inlicense ~~the~~agreement ~~United~~with ~~States,~~DelSiTech ~~have~~for ~~experienced~~its ~~surges~~sustained inrelease ~~the~~delivery ~~number of new cases~~technology, ~~including~~that astechnology amay ~~result~~not ofbe ~~new~~successful ~~variants~~and/or towe ~~the~~may ~~SARS-COV-2~~not ~~virus,~~be ~~such~~successful asin ~~the~~obtaining ~~recently~~rights ~~emerged Omicron variant, which have caused public health authorities~~ to ~~reimpose~~and ~~restrictive~~developing ~~measures.~~other Insustained ~~addition,~~release ~~although~~delivery ~~the~~technologies ~~FDA has fully approved three vaccines as well as vaccine booster shots~~ for ~~certain~~ACP. ~~individuals, there continue to be challenges with increasing the percentage of vaccinated individuals among the general population, and the long-~~

An element of our strategy over the past few years has been to expand our pipeline through in-licensing or acquiring the rights to products, product candidates or technologies that would complement our strategic goals as well as other compelling retina opportunities. Since early 2018, we have completed multiple acquisition, in-license, exclusive option and sponsored research arrangements for product candidates and other technologies intended to treat retinal diseases. For example, in June 2022, we entered into a license agreement, or the DelSiTech License Agreement, with DelSiTech Ltd., or DelSiTech, pursuant to which we obtained a worldwide, exclusive license under specified patent rights and know-how to develop and commercialize new formulations of ACP using DelSiTech’s silica-based sustained release technology for treating diseases of the human eye. We plan to continue to evaluate additional opportunities to in-license or acquire products, product candidates and technologies on a selective and targeted basis, with a focus on potential additional sustained release delivery technologies for ACP that are promising and meet our criteria. We may also continue to consider other alternatives, including mergers, acquisitions, asset purchases or sales and/or other transactions involving our company as a whole or other collaboration transactions, including potential collaboration opportunities for further development and potential commercialization of ACP in one or more territories outside the United States. In December 2022, Opus acquired our rights, title and interests in and to our assets primarily related to our former product candidates IC-100 and IC-200. Our business development efforts may fail to result in our acquiring rights to additional products, product candidates or technologies, or may result in our consummating transactions with which you do not agree.

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~~term~~typically ~~safety~~involves ~~and~~conducting ~~efficacy~~a ~~and~~feasibility ~~ability~~study of ~~these~~ACP ~~vaccines~~formulated towith ~~slow~~the ~~transmission,~~sustained ~~including~~release ~~against~~delivery ~~new~~technology ~~variants~~and ofanalyzing the ~~virus~~resulting formulation, ~~are~~which ~~largely~~can ~~unknown.~~be ~~In the United States and some other countries~~time-consuming, ~~vaccine~~costly ~~mandates remain controversial~~ and ~~the~~uncertain ~~reluctance~~in ofoutcome. ~~many~~If ~~individuals~~a toformulation ~~get~~is ~~COVID-19~~promising ~~vaccines~~based ~~may~~on ~~affect~~ the ~~work~~analytical ~~of our vendors and other third parties providing services for us. As a result~~results, ~~governments~~we ~~may~~could ~~continue~~then toproceed ~~deploy measures~~ to ~~contain~~negotiate ~~the pandemic for~~ a ~~prolonged~~longer ~~period~~term ~~of time~~collaboration. ~~The~~For ~~full~~example, ~~extent~~we toin-licensed ~~which~~DelSiTech’s ~~the COVID~~silica-19based ~~pandemic~~sustained ~~will~~release ~~directly~~delivery ortechnology ~~indirectly~~after ~~impact~~reviewing ~~our~~feasibility ~~business,~~ results ofthat ~~operations~~we ~~and~~believe ~~financial~~are ~~condition~~promising; ~~will~~however, ~~depend~~further ontesting ~~developments~~and ~~that~~studies ~~are~~may ~~highly~~undermine ~~uncertain~~our ~~and~~belief. ~~cannot~~The beprocess ~~accurately~~of ~~predicted~~proposing, ~~including~~negotiating ~~new~~and ~~information~~implementing ~~that~~a ~~may~~license ~~emerge~~or ~~concerning~~acquisition ~~COVID-19 and new variants~~ of ~~the~~a ~~virus,~~product ~~the~~candidate ~~actions~~or ~~taken~~technology tois ~~contain~~lengthy itand orcomplex. ~~lessen~~With ~~its~~respect ~~impact,~~to ~~including~~potential ~~the~~product ~~availability,~~candidates ~~effectiveness~~or ~~and~~technologies ~~administration~~for ofwhich ~~vaccines,~~we ~~and~~have ~~the~~entered ~~economic~~into ~~impact~~option ~~on local~~agreements, ~~regional,~~our ~~national~~agreements ~~and~~generally ~~international~~do ~~markets.~~not Ifhave ~~the~~fixed ~~delays~~economic ~~and~~or other ~~disruptions~~key ~~due~~terms tofor ~~the~~definitive ~~pandemic become prolonged or more extensive~~agreements, ~~then~~and we may ~~experience~~not ~~further~~obtain ~~delays~~favorable orterms ~~disruptions~~if toand ~~our~~when ~~research~~we ~~and~~choose ~~development~~to ~~programs~~exercise ~~and~~ our ~~financial~~option ~~position,~~to ~~results~~acquire ~~of operations~~ or ~~cash~~in-license ~~flows~~any ~~for~~product ~~future~~candidates ~~periods~~or ~~may be materially affected~~technologies.

InThe ~~addition~~in-licensing and acquisition of pharmaceutical products is an area characterized by intense competition, ~~many~~and a number of companies ~~have~~(both ~~been~~more ~~using~~established ~~force~~and ~~majeure~~early ~~clauses~~stage inbiotechnology ~~their~~companies) ~~contracts~~are also pursuing strategies to ~~excuse~~in-license or ~~delay~~acquire ~~performing~~product ~~under~~candidates ~~their~~or ~~contracts~~technologies that we may consider attractive. ~~Our~~More ~~contract~~established ~~manufacturers,~~companies ~~academic~~may ~~research~~have ~~collaborators~~a competitive advantage over us due to their size, ~~contract~~cash resources and greater research, ~~organizations~~preclinical ~~and~~or ~~other~~clinical ~~third~~development, ~~parties~~manufacturing onor ~~whom~~commercialization wecapabilities, ~~rely~~while ~~for~~earlier ~~goods~~stage companies may be more aggressive or ~~services~~have ~~may~~a ~~make~~higher ~~similar~~risk ~~claims~~tolerance. IfIn ~~any~~addition, ~~such~~companies ~~force~~that ~~majeure~~perceive ~~claims~~us ~~were~~to ~~successful,~~be ~~then~~a ~~not~~competitor ~~only~~may ~~would~~be ~~our~~unwilling ~~timelines~~to assign or license rights to us. Other sustained release delivery technology companies that we are working with may be ~~delayed~~less ~~but~~willing ~~also~~to enter into long-term license or collaborations with us in light of our ~~right~~DelSiTech tolicense. ~~recover~~We ~~for~~also ~~any~~may ~~economic~~be ~~damages~~unable ~~due~~to in-license or acquire the rights to the ~~delay~~relevant product candidate or technology on terms that would beallow ~~limited.~~us ~~Because~~to wemake ~~rely~~an appropriate return on ~~many~~our ~~single-source~~investment. ~~suppliers~~Moreover, ~~any~~we ~~such~~may ~~claims~~devote ~~from~~resources ~~them~~to potential acquisitions or in-licensing opportunities that are ~~likely~~never tocompleted, ~~result~~or inwe amay ~~delay~~fail to ~~our~~realize ~~timelines~~the anticipated benefits of such efforts or ~~otherwise~~we ~~adversely~~may ~~affect~~incorrectly ~~our~~judge ~~operations~~the value of an acquired or ~~financial~~in-licensed ~~position~~product candidate or technology.

WeFurther, ~~cannot~~any ~~foresee~~product ifcandidate ~~and~~that ~~when~~we ~~the~~acquire ~~COVID~~or in-19license ~~pandemic~~would ~~will~~most belikely ~~effectively~~require ~~contained,~~additional ~~nor~~development ~~can~~efforts weprior ~~predict~~to ~~the~~commercial ~~severity~~sale, ~~and~~including ~~duration~~extensive ofclinical ~~the~~testing ~~impact~~and ofapproval by the ~~pandemic~~FDA onand ~~our~~applicable ~~financial~~foreign ~~condition~~regulatory ~~or operations~~authorities. WeFor ~~may~~potential ~~experience~~sustained ~~additional~~release ~~disruptions~~delivery totechnologies ~~our~~with ~~clinical~~ACP, ~~trials~~we orexpect ~~supply~~any ~~chains~~promising technologies, ~~and~~including ~~closures~~our ofin-licensed ~~facilities,~~DelSiTech’s ~~such~~silica-based assustained ~~clinical~~release ~~trial~~delivery ~~sites~~technology, ~~academic~~would ~~research~~require ~~centers~~extensive preclinical and ~~suppliers,~~clinical ~~including~~testing ~~single source suppliers,~~ and ~~delays~~investment in ~~interactions~~manufacturing ~~with~~before ~~regulatory~~any ~~agencies~~potential orapproval ~~obtaining~~by ~~approvals for our product candidates. In addition,~~ the ~~effects~~FDA ofor ~~COVID-19~~other onregulatory ~~the~~authorities. ~~financial~~All ~~markets~~product ~~could~~candidates ~~hamper~~are ~~our~~prone ~~ability~~ to ~~raise~~risks ~~additional~~of ~~finances.~~failure ~~Additional~~typical ~~public~~of ~~health~~pharmaceutical ~~crises~~product ~~and natural disasters~~development, ~~such~~including ~~as future epidemics or pandemics or those resulting from~~ the ~~effects~~possibility ofthat ~~climate~~a ~~change,~~product ~~may~~candidate ~~arise~~would innot ~~the~~be ~~future.~~shown ~~Any~~to ofbe ~~these~~sufficiently ~~events~~safe ~~may materially~~ and ~~adversely~~effective ~~affect~~for ~~our~~approval ~~business~~by ~~operations~~regulatory ~~and financial condition~~authorities.

Our strategy of obtaining additional rights to products, product candidates or technologies for the treatment of retinal diseases may not be successful. We may not be successful in obtaining rights to and developing a sustained release delivery technology for Zimura. We may not be successful in finding a collaborator for IC-100 and/or IC-200.

An element of our strategy over the past few years has been to expand our pipeline through in-licensing or acquiring the rights to products, product candidates or technologies that would complement our strategic goals as well as other compelling retina opportunities. Since early 2018, we have completed multiple acquisition, in-license, exclusive option and sponsored research arrangements for product candidates and other technologies intended to treat retinal diseases. We plan to continue to evaluate additional opportunities to in-license or acquire products, product candidates and technologies on a selective and targeted basis, with a focus on sustained release delivery technologies for Zimura. We may also continue to consider other alternatives, including mergers, acquisitions, asset purchases or sales and/or other transactions involving our company as a whole or other collaboration transactions, including potential collaboration or out-license opportunities for further development and potential commercialization of Zimura in one or more territories outside the United States and collaboration opportunities for further development and potential commercialization of IC-100 and/or IC-200. Our business development efforts may fail to result in our acquiring rights to additional products, product candidates or technologies, or may result in our consummating transactions with which you do not agree.

We may be unable to in-license or acquire the rights to any such products, product candidates or technologies from third parties for several reasons. The success of this strategy depends partly upon our ability to identify, select and acquire or in-license promising product candidates and technologies. For potential sustained release delivery technologies, that process typically involves conducting a feasibility study of Zimura formulated with the sustained release delivery technology and analyzing the resulting formulation, which can be time-consuming, costly and uncertain in outcome. If a formulation is promising based on the analytical results, we could then proceed to negotiate a longer term collaboration. The process of proposing, negotiating and implementing a license or acquisition of a product candidate or technology is lengthy and complex. With respect to potential product candidates or technologies for which we have entered into option agreements or sponsored research agreements for which we have option rights, our agreements generally do not have fixed economic or other key terms for definitive agreements, and we may not obtain favorable terms if and when we choose to exercise our option to acquire or in-license any product candidates or technologies.

The in-licensing and acquisition of pharmaceutical products is an area characterized by intense competition, and a number of companies (both more established and early stage biotechnology companies) are also pursuing strategies to in-license or acquire product candidates or technologies that we may consider attractive. More established companies may have a competitive advantage over us due to their size, cash resources and greater research, preclinical or clinical development,

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manufacturing or commercialization capabilities, while earlier stage companies may be more aggressive or have a higher risk tolerance. In addition, companies that perceive us to be a competitor may be unwilling to assign or license rights to us. We also may be unable to in-license or acquire the rights to the relevant product candidate or technology on terms that would allow us to make an appropriate return on our investment. Moreover, we may devote resources to potential acquisitions or in-licensing opportunities that are never completed, or we may fail to realize the anticipated benefits of such efforts or we may incorrectly judge the value of an acquired or in-licensed product candidate or technology.

Further, any product candidate that we acquire or in-license would most likely require additional development efforts prior to commercial sale, including extensive clinical testing and approval by the FDA and applicable foreign regulatory authorities. For potential sustained release delivery technologies with Zimura, we expect any promising technologies would require extensive preclinical and clinical testing and investment in manufacturing before any potential approval by the FDA or other regulatory authorities. All product candidates are prone to risks of failure typical of pharmaceutical product development, including the possibility that a product candidate would not be shown to be sufficiently safe and effective for approval by regulatory authorities.

If we are unable to successfully obtain rights to suitable product candidates or technologies, our business, financial condition and prospects for growth could suffer. In addition, acquisitions and in-licensing arrangements for product candidates and technologies are inherently risky, and ultimately, if we do not complete an announced acquisition or license transaction or integrate an acquired or licensed product candidate or technology successfully and in a timely manner, we may not realize the benefits of the acquisition or license to the extent anticipated and the perception of the effectiveness of our management team and our company may suffer in the marketplace. In addition, even if we are able to successfully identify, negotiate and execute one or more transactions to acquire or in-license new product candidates or technologies, our expenses and short-term costs may increase materially and adversely affect our liquidity.

In addition, acquisitions and in-licenses may entail numerous operational, financial, regulatory and legal risks, including:

•exposure to known and unknown liabilities, including possible intellectual property infringement claims, violations of laws, tax liabilities and commercial disputes;

•incurrence of substantial debt, dilutive issuances of securities or depletion of cash to pay for acquisitions or in-licensing transactions;

•inability to receive regulatory clearance from government agencies, such as the Federal Trade Commission, to close transactions after announcement;

•higher than expected acquisition and integration costs;

•difficulty in combining the operations and personnel of any acquired businesses with our operations and personnel;

•inability to maintain uniform standards, controls, procedures and policies;

•restructuring charges related to eliminating redundancies or disposing of assets as part of any such combination;

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•large write-offs and difficulties in assessing the relative percentages of in-process research and development expense that can be immediately written off as compared to the amount that must be amortized over the appropriate life of the asset;

•increased amortization expenses or, in the event that we write-down the value of acquired assets, impairment losses;

•impairment of relationships with key suppliers or customers of any acquired businesses due to changes in management and ownership;

•inability to retain personnel, key customers, distributors, vendors and other business collaborators integral to an in-licensed or acquired product candidate or technology;

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•potential failure of the due diligence process to identify significant problems, liabilities or other shortcomings or challenges of an acquired or licensed product candidate or technology, including problems, liabilities or other shortcomings or challenges with respect to intellectual property, data or product quality, revenue recognition or other accounting practices, partner disputes or issues and other legal and financial contingencies and known and unknown liabilities; and

•entry into therapeutic approaches, indications or markets in which we have no or limited direct prior development or commercial experience and where competitors in such markets have stronger market positions.

WeRisks ~~and~~Related ~~certain~~to ofRegulatory ~~our~~Approval ~~current and former board members and executive officers were named as defendants in lawsuits that could result in substantial costs and divert management’s attention. We are in the process~~ of ~~settling~~Our ~~those lawsuits, but the settlements are not yet final.~~ Products

WeEven ~~and~~if ~~certain of our current and former executive officers were named as defendants in a purported consolidated putative class action lawsuit initiated in 2017 that generally alleges that~~ we ~~and~~complete ~~certain of our officers violated Sections 10(b) and/or 20(a) of~~ the ~~Exchange~~necessary ~~Act~~preclinical ~~and~~studies ~~Rule 10b-5 promulgated thereunder by making allegedly false~~ and~~/or~~ ~~misleading~~clinical ~~statements concerning the results of our Phase 2b trial and the prospects of our Phase 3~~ trials, ~~for our prior product candidate Fovista in combination with anti-VEGF agents for~~ the ~~treatment~~marketing ofapproval ~~wet~~process ~~AMD.~~is Certain current and former members of our board of directors and current and former officers were also named as defendants in two shareholder derivative actions initiated in August 2018 and May 2021 respectivelyexpensive, ~~which~~time-consuming ~~generally allege that the defendants breached their fiduciary duties to our company by failing to oversee our business during the period of the Phase 2b~~ and ~~Phase~~uncertain ~~3 clinical trials of Fovista. These complaints seek equitable~~ and~~/or~~ ~~injunctive~~may ~~relief,~~prevent ~~unspecified~~us ~~damages,~~from ~~attorneys’~~obtaining ~~fees,~~approvals ~~and other costs. On September 8, 2021, the parties in the class action executed a settlement agreement, which has been submitted to the court~~ for ~~approval. We expect our directors’ and officers’ liability insurance to cover~~ the ~~costs~~commercialization of ~~the~~some ~~settlement,~~or ~~including~~all ~~plaintiff counsel’s fees. The shareholder derivative actions were stayed while a special litigation committee~~ of our ~~board~~product ~~of directors, or the SLC, investigated the allegations contained in the complaints~~candidates. OnIf ~~October~~we ~~18,~~are ~~2021,~~not ~~the~~able ~~parties notified the court overseeing the Pacheco matter that they had reached an agreement in principle~~ to ~~settle the action. On January 27~~obtain, ~~2022,~~or ~~the~~if ~~parties~~there ~~executed~~are adelays ~~settlement~~in ~~agreement~~obtaining, ~~which~~required ~~has~~regulatory ~~been submitted to the court for approval. We are unable~~approvals, ~~however, to predict the outcome of these matters at this time. Moreover, any conclusion of these matters in a manner adverse to us and for which~~ we ~~incur~~will ~~substantial costs or damages~~ not ~~covered~~be byable ~~our directors’ and officers’ liability insurance could have a material adverse effect on our financial condition and business. In addition, the litigation, including in responding~~ to ~~discovery~~commercialize ~~requests, caused~~ our ~~management~~product ~~and board of directors to divert time and attention to the litigation and could adversely impact our reputation~~candidates, and ~~if the litigation remains protracted, could further divert management and~~ our ~~board of directors’ attention and resources from other priorities, including the execution of our business plan and strategies that are important to our~~ ability to ~~grow~~generate ~~our~~revenue ~~business,~~would ~~any of which could have a material adverse effect on our business. Regardless of whether these lawsuits are finally settled, additional lawsuits may~~ be ~~filed~~materially ~~against us~~impaired.

~~Risks~~Our ~~Related~~product candidates and the activities associated with their development and commercialization, including their design, testing, manufacture, safety, recordkeeping, labeling, storage, advertising, promotion, sale and distribution and import and export, are subject to ~~Product~~comprehensive ~~Development~~regulation by the FDA, the EMA and ~~Commercialization~~comparable regulatory agencies in other countries.

~~Companies~~In ingeneral, ~~our~~the ~~industry~~FDA ~~face~~and similar regulatory authorities outside the United States require two adequate and well-controlled clinical trials demonstrating safety and effectiveness for marketing approval for an ophthalmic pharmaceutical product. Failure to obtain marketing approval for a ~~wide~~product ~~range~~candidate will prevent us from commercializing the product candidate. We have not received approval to market any of ~~challenging~~our ~~activities~~product candidates from regulatory authorities in any jurisdiction. Securing marketing approval requires obtaining positive safety and efficacy data from required clinical trials, as well as the submission of extensive preclinical and clinical data and supporting information to regulatory authorities for each indication to establish the product candidate’s safety and efficacy. Securing marketing approval also requires the submission of ~~which~~information ~~entails~~about ~~separate~~the product's manufacturing processes to, and ininspection ~~many~~of ~~cases~~manufacturing ~~substantial~~facilities by, ~~risk~~the relevant regulatory authorities. The FDA or other regulatory authorities may determine that a product candidate that we may develop is not effective, is only moderately effective or has undesirable or unintended side effects, toxicities or other characteristics that preclude our obtaining marketing approval or prevent or limit commercial use.

The ~~long~~FDA issued guidance in March 2022 stating that it would treat co-~~term~~packaged ~~success~~ophthalmic products, which generally consist of ~~our~~a ~~company,~~drug ~~and~~component ~~our~~that ~~ability~~provides tothe ~~become~~primary ~~profitable~~active pharmaceutical ingredient along with device components such as aneedles ~~biopharmaceutical~~or ~~company~~syringes, ~~will~~as ~~require~~a uscombination toproduct. We expect that our planned finished form of ACP drug product will be ~~successful~~treated inby the FDA as a ~~range~~combination product. We do not believe that this guidance has affected our strategy for obtaining FDA approval of ~~challenging~~ACP ~~activities,~~for ~~including:~~the treatment of GA secondary to AMD.

~~•designing~~The process of obtaining marketing approvals, ~~conducting~~both in the United States and ~~successfully~~abroad, ~~completing~~is ~~preclinical~~expensive, ~~research~~may take many years, if approval is obtained at all, and ~~development~~can ~~activities~~vary substantially based upon a variety of factors, including ~~preclinical~~the ~~efficacy~~type, complexity and ~~IND-enabling~~novelty ~~studies~~of the product candidates involved and information concerning similar product candidates as our product candidates. Changes in marketing approval policies during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application. Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application or may decide that our data are insufficient for approval and require additional nonclinical, clinical or other studies. In addition, varying interpretations of the data obtained from preclinical and clinical testing could delay, limit or prevent marketing approval of a product ~~candidates;~~candidate. Any marketing approval we ultimately obtain may be limited or subject to restrictions or post-approval commitments that render the approved product not commercially viable.

~~•designing,~~Table ~~conducting~~of ~~and completing clinical trials for our product candidates;~~Contents

~~•obtaining~~Marketing ~~favorable~~approval ~~results~~of ~~from~~novel ~~required~~product ~~clinical trials~~candidates, ~~including~~ for ~~each~~example ~~ophthalmic~~aptamers ~~product~~such ~~candidate~~as ACP, ~~favorable~~manufactured ~~results~~using ~~from~~specialized

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