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 | ||||||||
| 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
(Exact name of registrant as specified in its charter)
(State or other jurisdiction of incorporation or organization) | (I.R.S. Employer Identification No.) | ||||||||||
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| (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 | ||||||
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.
| ☒ | 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
If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to § 240.10D-1(b) ☐
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
TABLE OF CONTENTS
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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 various stages of age-related macular degeneration (AMD);
•our expectations regarding the impact of results from GATHER1, our completed Phase 3 clinical trial evaluating 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 submit marketing authorization applications to 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, including expectations regarding patient retention and the safety profile of ACP, including from our open-label extension study for patients who completed the GATHER2 trial, and expectations regarding the potential for ACP to receive regulatory approval for the treatment of GA based on the clinical trial results we have received to date;
•our plans and strategy for the potential commercialization of ACP, including hiring of medical affairs and commercialization personnel, building a commercialization infrastructure, including sales, marketing and distribution capabilities, and our expectations regarding the market dynamics for treatments for GA and other commercial matters;
•our ability to establish and maintain capabilities and capacity for the manufacture of ACP and our other product candidates, including scale up and validation of the manufacturing process for ACP drug substance and drug product, and securing the supply of the polyethylene glycol (PEG) starting material and other materials for our expected manufacturing needs and securing the supply of ACP drug substance, drug product and finished goods for our expected needs;
•our plans for evaluating, obtaining rights to, developing and potentially commercializing new formulations of ACP with the silica-based sustained release technology we in-licensed from DelSiTech Ltd. (DelSiTech) and other sustained release delivery technologies for ACP;
•the timing, costs, conduct and outcome of STAR, our ongoing Phase 2b screening trial evaluating 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 ACP outside the United States; 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 ACP;
•our estimates regarding expenses, future revenues and debt service obligations, the sufficiency of our cash resources and our capital requirements and need for, and ability to obtain, additional financing;
•our plans to raise additional capital, including through equity offerings, debt financings, collaborations, strategic alliances, licensing arrangements, royalty agreements and marketing and distribution arrangements;
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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.
1.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.
2.We have a history of 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.
3.We may need additional financing in order to commence, if approved, and continue commercializing ACP, or continue developing our other product candidates. Securing financing may be challenging and/or dilutive to our shareholders, and if we are unable to secure financing when needed, we may need to curtail our development programs or planned commercialization activities.
4.The covenants in our Loan and Security Agreement with Hercules Capital, Inc. and Silicon Valley Bank may limit and restrict from us from pursuing certain operating activities. If we are in default under that agreement, we may need to repay all existing indebtedness under that term loan facility.
5.We need to satisfy numerous regulatory requirements in order to secure marketing approval and reimbursement approval, if applicable, for ACP and other product candidates. These requirements differ across jurisdictions. Failure to satisfy and maintain those requirements can preclude us from commercializing our products.
6.Regulatory authorities, including the FDA and EMA, may disagree with our analyses or conclusions from our clinical trials of ACP in GA secondary to 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 ACP in GA and the EMA and other regulatory authorities may disagree with the requirements of the FDA. We may need to conduct additional clinical trials or nonclinical studies for ACP in order to obtain marketing approval or reimbursement approval.
7.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 able to secure adequate supply of PEG starting material, ACP drug substance, ACP drug product or ACP finished goods for our future needs, including potential commercial launch. Issues with manufacturing can derail the further development or commercialization of our product candidates.
8.To commercialize any of our product candidates, if approved, we will need to set up a sales and marketing infrastructure. We are continuing to hire 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 patients, the medical community and payors.
9.We face substantial competition from large pharmaceutical companies, smaller biotech companies and others.
10.Drug development is inherently risky with numerous scientific, technical, regulatory and other challenges. A promising drug candidate can fail at any time and for any number of reasons.
11.We are pursuing the development of our product candidates using novel mechanisms of action targeting indications for which there are few or no approved products. These include, for example, complement 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. These approaches carry numerous scientific, regulatory and other risks.
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12.The 12-month results of GATHER2 may not be replicated by the 24-month results from the trial, which may not replicate the results of the GATHER1 trial. We may discover safety issues with our product candidates due to known and currently unknown factors, which could hamper their further development or commercialization.
13.We may not be successful in developing a formulation of ACP with the sustained release delivery technology we in-licensed from DelSiTech or obtaining rights to and developing other sustained release delivery technologies for ACP.
14.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 and data integrity requirements. We may need to engage alternative manufacturers or suppliers sooner than we currently expect.
15.We plan to rely on third-party distribution and other commercial services vendors to assist us with the commercialization of ACP, if approved, and those third parties may not perform satisfactorily for any number of reasons.
16.We rely heavily on our third-party contract research organizations as well as our clinical trial sites. They may have different priorities than we do and may fail to follow regulatory requirements, including good laboratory practice, good clinical practice and other data integrity requirements.
17.We plan to explore collaboration opportunities for the further development and potential commercialization of ACP in one or more territories outside the United States. We may not be able to enter into a collaboration on favorable terms, or at all. Even if we are able to do so, the collaboration may not be successful.
18.We rely on patents to protect our proprietary position. We may not obtain the patent rights that we seek and/or we may not be able to exclude our competitors from relevant markets. We may be subject to litigation involving our patents or those of third parties.
19.We are highly dependent on our information security systems and those of third parties we work with. A cybersecurity incident may cause interruptions to the progress of our operations, financial or regulatory penalties and/or harm to our 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 avacincaptad pegol, which is also referred to as ACP or Zimura®, a complement C5 inhibitor. We are currently targeting the following diseases with 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; 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 October 2019, we announced positive 12-month data for GATHER1, our first Phase 3 clinical trial evaluating ACP 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 observed 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 35.4% (p-value = 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 FDA, in accordance with our Special Protocol Assessment, or the SPA, which we describe further below. We analyzed the endpoint by using the square root transformation of the GA area, which we refer to as the primary analysis, and we analyzed the endpoint by using the observed GA area (without square root transformation), which we refer to as the supportive analysis. In GATHER1, through month 12, we did not observe any events of endophthalmitis or ischemic optic neuropathy events, and only one case of intraocular inflammation, which was mild and transient and reported as related to the injection procedure. The incidence of choroidal neovascularization, or CNV, in the study eye through month 12 was 6 patients (9.0%) in the ACP 2 mg group and 3 patients (2.7%) in the corresponding sham control group.
In June 2020, we started enrolling patients in GATHER2, our second Phase 3 clinical trial evaluating ACP for the treatment of GA secondary to AMD. In July 2021, we received a written agreement from the FDA under the SPA for the overall design of GATHER2. The SPA is a procedure by which the FDA provides a clinical trial sponsor with an official evaluation and written guidance on the design of a proposed protocol intended to form the basis for a new drug application, or NDA. In connection with our SPA, the FDA recommended, and we accepted, modifying the primary efficacy endpoint for the GATHER2 trial from the mean rate of change in 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.
In September 2022, we announced positive 12-month top-line data for 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% (p-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 a 17.7% (p-value = 0.0039) reduction in the mean rate of growth (slope) in GA area between the two groups at 12 months with the supportive analysis. We did not observe any events of endophthalmitis, intraocular inflammation events, events of vasculitis or ischemic optic neuropathy events through month 12, and 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.
We believe that with the statistically significant results from our GATHER1 and GATHER2 trials and the safety profile of ACP to date, we have sufficient data from two independent, adequate and well-controlled pivotal clinical trials of ACP in GA secondary to AMD to support an application for marketing approval. In November 2022, the FDA granted breakthrough therapy designation to ACP for the treatment of GA secondary to 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.
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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.
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.
*We have an option to exclusively in-license intellectual property resulting from these programs.
2022 Highlights
•In 2022, we achieved a number of significant company milestones, including the following:
•In September 2022, we announced positive 12-month data from the GATHER2 trial. We achieved a 12-month injection fidelity rate of 92.5% for the GATHER2 trial.
•In November 2022, the FDA granted breakthrough therapy designation for ACP for the treatment of GA secondary to 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 June 2022, we entered into an exclusive license agreement with DelSiTech Ltd., or DelSiTech, for worldwide development and commercialization rights to its silica based sustained release delivery technology for use with ACP.
•In July 2022, we entered into a Loan and Security Agreement with Hercules Capital Inc. and Silicon Valley Bank, or the Loan Agreement, providing up to $250.0 million in term loans, or the 2022 Term 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
As we prepare for the potential marketing approval and potential commercial launch of ACP, progress our research and development programs and evaluate our overall strategic priorities, we 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 obtain rights to additional product candidates and technologies for retinal diseases, with a focus on additional sustained release delivery technologies for ACP. In addition, we plan to explore potential collaboration opportunities for the future development and potential commercialization of ACP in one or more territories outside the United States.
Please see later in this Business section for information about our exclusive license agreement with DelSiTech for its sustained release delivery technology for ACP and our asset purchase agreement with Opus Genetics Inc., or Opus, for our former preclinical stage gene therapy product candidates, 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 offering completed in December 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 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.
Eye Diseases
Eye diseases can be caused by many factors and can affect both the front and 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.
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. A 2022 review in the American Academy of Ophthalmology estimates that
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approximately 80% of AMD patients have the dry 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 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.
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 (between 63 µm and 125 µm in height) and/or one or more large drusen (larger than 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.
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.
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.
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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.
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 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, which begins in adolescence or adulthood. USH2A-associated 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 nonsyndromic autosomal recessive retinitis pigmentosa.
Avacincaptad pegol (ACP)
We are currently developing our product candidate ACP, a C5 complement inhibitor, for the treatment of GA and STGD1. 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. 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.
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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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.
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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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.
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, 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 ACP Clinical Programs
The following is a brief description of the completed GATHER1 trial and the ongoing GATHER2 and STAR trials and the open label extension 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 ACP for the treatment of GA secondary to AMD. We enrolled 286 patients in this trial across multiple treatment groups, including various 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.
•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 ACP for the treatment of GA secondary to AMD. We enrolled 448 patients in this trial, who were randomized on a 1:1 basis into either a treatment group with monthly intravitreal injections of ACP 2 mg or a sham control group. As agreed to with the FDA in connection with the SPA, the primary efficacy endpoint is 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. In September 2022, we announced positive 12-month data from this trial. We plan to treat and follow patients for 24 months in total.
•ISEE2009 (also known as the OLE study; open label extension study - ongoing): an international, open label, multicenter study evaluating the safety of ACP 2 mg for patients who completed their month 24 visits in the GATHER2 trial. We are continuing to enroll patients.
•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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•OPH2000: a Phase 1/2a clinical trial of various doses of ACP administered in combination with Lucentis® (ranibizumab), an anti-vascular endothelial growth factor, or anti-VEGF, agent, for the treatment of wet AMD, with a total of 60 patients enrolled;
•OPH2007, a Phase 2a clinical trial of various doses of ACP administered in combination with Lucentis for the treatment of wet AMD, with a total of 64 patients enrolled and treated; and
•OPH2002: a very small Phase 2a clinical trial of ACP in combination with anti-VEGF agents for the treatment of idiopathic polypoidal choroidal vasculopathy, or IPCV, in patients for whom anti-VEGF monotherapy had failed.
ACP is administered by intravitreal injection. Patients receiving intravitreal injections typically receive topical numbing drops or injection of a 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 exposure to non-ocular tissues.
An intravitreal injection results in elevation of intraocular pressure, or IOP, which is usually transient. In our clinical trials, the IOP is monitored before and after each intravitreal injection. Certain of the dosing regimens we are evaluating in STAR involve multiple intravitreal injections administered on the same day. Based on our clinical experience to date, we have not seen any meaningful or sustained 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.
Our ACP clinical experience to date is described in greater detail below.
ACP - GA Trials
GATHER1: Completed Clinical Trial Assessing the Safety and Efficacy of Various Doses of ACP 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.
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 | 26 | 25 | 26 | |||||||||||||||||
In Part 1 of 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.
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 | ACP 2 mg | ACP 4 mg | Sham | |||||||||||||||||
| Patients | 42 | 83 | 84 | |||||||||||||||||
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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 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.
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
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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 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 | 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) | ||||||||||||||||||||||||||||||||
| 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 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, 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 ACP-related adverse events, no cases of ACP-related intraocular inflammation, no cases of ACP-related increased intraocular pressure, no cases of endophthalmitis, and no discontinuations attributed by investigators to 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 | |||||||||||||||||||||||||||||||||||||
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 (ACP or sham) are set forth in the table below:
Reported Systemic TEAEs Related to ACP or Sham
| Part 1 | Part 2 | |||||||||||||||||||||||||||||||||||||
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 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||||||||||||||||||||||||||
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 | |||||||||||||||||||||||||||||||||||||
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 (ACP or sham) is set forth in the table below:
Reported Ocular TEAEs in the Study Eye Related to ACP or Sham
| Part 1 | Part 2 | |||||||||||||||||||||||||||||||||||||
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 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||||||||||||||||||||||||||
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 ACP 1 mg group, 6 patients (9.0%) in the ACP 2 mg group, and 8 patients (9.6%) in the 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 ACP 2 mg and 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 ACP 2 mg to sham control is provided by data from both Part 1, with a 1:1 randomization ratio of patients receiving 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 ACP 2 mg (42 patients) and sham (84 patients), for a total of 67 patients receiving 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 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 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 ACP 2 mg should be comparable to the 84 patients receiving sham. The efficacy of ACP 2 mg was therefore evaluated through an analysis which included a regression factor by trial part. The statistical analysis for the ACP 4 mg group as compared to sham compares data for patients from Part 2 of the trial only. Data from patients receiving 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 ACP 2 mg and 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 | ACP 2 mg (N = 67) | Sham 2 mg (N = 110) | 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 ACP 1 mg group (7.7% withdrawals), 12 patients were from the combined ACP 2 mg group (17.9% withdrawals), 25 patients were from the 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 ACP 2 mg and ACP 4 mg groups. The difference between the 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 ACP 2 mg group and 0.12 mm for the 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 ACP treatment group, while missing values in the 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.
Statistical significance for the reduction in mean rate of GA growth for the ACP 2 mg and ACP 4 mg groups as compared to the corresponding sham groups was retained for all arbitrary imputation approaches.
•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 ACP 2 mg and 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 | 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 | 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 ACP 2 mg as compared to Sham 2 mg was adjusted for the fact that this dose of 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 | 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 | 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 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 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 ACP 2 mg and 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 ACP 2 mg and 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 | 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 | 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.
(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.
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 ACP treatment groups was not different from
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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 | 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 | 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 | 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 | 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.
ACP 1 mg 12-Month Efficacy Data
Efficacy data from patients receiving ACP 1 mg was not part of the prespecified statistical analysis. The total number of patients randomized to the 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 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 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 | 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 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 ACP 1 mg group as compared to the sham control group in Part 1, when
21
combined with the statistically significant results observed for the primary efficacy endpoint for the ACP 2 mg and 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 ACP 2 mg group as compared to the corresponding sham control group and 29.97% for the 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 ACP 2 mg group and p=0.0021 for the 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 ACP 2 mg and 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 | 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 | 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 ACP 2 mg and 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 | ||||
| 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 | ||||
| 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 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 ACP 2 mg as compared to the corresponding sham control group over 18 months was adjusted for the fact that this dose of 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 | 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 | 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 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 ACP 2 mg and sham control groups is 0.168 mm, representing a 28.11% relative benefit in the 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
23
analysis was also part of the prespecified statistical analysis plan for this trial. The observed mean GA area data for the ACP 2 mg and 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 | 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 | 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.
(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.
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 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 | ACP 2 mg (N = 67) | Sham (N = 110) | Difference | |||||||||||||||||
Mean Change in BCVA(a) | -12.7(b) | -15.1(b) | 2.37 | |||||||||||||||||
| Cohort | 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 | ACP 2 mg (N = 67) | Sham (N = 110) | Difference | |||||||||||||||||
Mean Change in LL BCVA(a) | -2.72(b) | -3.10(b) | 0.37 | |||||||||||||||||
| Cohort | 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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ACP 1 mg 18-Month Efficacy Data
We performed descriptive analyses on the 18 month data for patients in the 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 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 | 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 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 ACP 1 mg group as compared to the sham control group, when compared with the results observed in the ACP 2 mg and 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, ACP was generally well tolerated after 18 months of administration. During the trial, there were no investigator-reported ACP-related adverse events, no ACP-related intraocular inflammation, no ACP-related increased intraocular pressure, no cases of endophthalmitis, and no discontinuations attributed by investigators to 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 ACP 1 mg group, 8 patients (11.9%) in the ACP 2 mg group, and 13 patients (15.7%) in the 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 | |||||||||||||||||||||||||||||||||||||
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 ischemic optic neuropathy (in the ACP 2 mg group) and one TEAE was a retinal detachment (in the ACP 4 mg group). Neither of these TEAEs were reported as related to ACP.
The number of patients with one or more TEAEs, including serious TEAEs, identified by the investigator as related to the study drug (ACP or sham) are set forth in the table below:
Reported TEAEs Related to ACP or Sham
| Part 1 | Part 2 | |||||||||||||||||||||||||||||||||||||
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 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||||||||||||||||||||||||||
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 | |||||||||||||||||||||||||||||||||||||
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 (ACP or sham) is set forth in the table below:
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Reported Ocular TEAEs in the Study Eye Related to ACP or Sham
| Part 1 | Part 2 | |||||||||||||||||||||||||||||||||||||
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 | 0 | 0 | 0 | 0 | 0 | 0 | ||||||||||||||||||||||||||||||||
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 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 using the FDA Required Analysis of Primary Efficacy Endpoint
In parallel discussions with those for the GATHER2 SPA, the FDA indicated that, as part of a future NDA for 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 ACP 2 mg and 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.
ACP 2 mg Data
| 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) | ||||||||||||
Explanatory notes:
•the estimates for the 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.
ACP 4 mg Data
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| MRM Analysis | 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.
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 ACP 2mg were enrolled in Part 1 of the trial and 42 patients receiving ACP 2mg were enrolled in Part 2 of the trial.
Below are the month 12 and month 18 results for the 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 is used for the GATHER2 trial:
Part 1 Only Data
| MRM Analysis | 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 | 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% | ||||||||||
GATHER2: Ongoing Phase 3 Clinical Trial Assessing Safety and Efficacy of ACP 2 mg for GA Secondary to AMD
In September 2022, we announced positive 12-month data from the GATHER2 trial.
Trial Design
In this trial, we enrolled 448 patients, who were randomized into two groups: a first group receiving monthly administrations of 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 re-randomized patients in the ACP 2 mg arm to receive either monthly or every other month administrations of ACP 2 mg, and patients receiving monthly administrations of sham 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 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
29
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.
30
•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%) | ||||||||||||
31
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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the same three time points (baseline, month 6, and month 12) as the slope analyses. The results for the 12-month point analysis were consistent with the slope analyses and are described below.
The 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.
| 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) | ||||||||||||
Explanatory notes - in the above presentation:
(a) Indicates pre-specified primary endpoint analysis; statistically significant;
(b) Indicates descriptive p-value.
As part of the pre-specified statistical analysis plan for GATHER2, we also analyzed the mean rate of growth (slope) in GA area for ACP 2 mg as compared to sham for pre-specified patient subgroups based on baseline lesion size, baseline visual acuity, baseline autofluorescence pattern, age, and gender. ACP 2 mg showed a reduction in the mean rate of growth (slope) in GA area for all analyzed subgroups.
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 ACP 2 mg was observed, which is consistent with GATHER1. For LL BCVA, a favorable trend was not observed.
Trial Conduct and Patient Retention
We achieved a 12-month injection fidelity rate for GATHER2 of 92.5%. The 12-month injection fidelity rate for GATHER1 was 87%. The injection fidelity rate 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. We believe injection fidelity to be the most important and stringent measure of patient retention because it reflects the timely administration of the study drug into the 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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ISEE2009: Open Label Extension Study for Patients Who Completed the GATHER2 Trial
In September 2022, we iniated an open-label extension study, or the OLE study, which is an international, multi-center clinical trial assessing the safety of intravitreal administration of ACP in patients who completed their month 24 visits in the GATHER2 trial. All patients participating in the OLE study will receive monthly doses of ACP 2 mg, regardless of the treatment arm (ACP or sham procedure) that they were randomized to in the GATHER2 trial. The trial will continue until each patient has completed their month 18 study visit or until ACP is commercially available in the relevant jurisdiction.
OPH2001: Completed Phase 1/2a Clinical Trial of ACP 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 ACP 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 ACP over a 36-week treatment period. Patients received an intravitreal injection of ACP at day 0, week 4, week 8, week 24 and week 36 of the trial, with a final follow-up visit at week 48.
ACP 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 ACP. 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 ACP dose groups, or the efficacy of ACP 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.
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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, 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 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.
Regulatory Pathway for Marketing Approval of ACP in GA secondary to AMD
To obtain marketing approval of ACP for the treatment of GA secondary to AMD, we expect that we will need favorable results from a total of two independent, adequate and well-controlled pivotal clinical trials, demonstrating the safety and efficacy of ACP in this indication. We believe the results we have obtained from our GATHER1 and GATHER2 trials satisfy this requirement and provide below further explanation for this belief.
FDA Requirements and Status
Based on our interactions with the FDA, we believe it would be sufficient to establish efficacy 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 (slope) estimated based 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.
Based on our interactions with the FDA, we believe it would be sufficient to establish safety by using 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 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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•Over 2021 and 2022, we had 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.
•In November 2022, the FDA granted breakthrough therapy designation for ACP for GA secondary to AMD based on the 12-month results from GATHER1 and GATHER2.
•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 portions of the NDA submitted in November 2022 and the chemistry, manufacturing and controls portion of the NDA submitted in December 2022.
In February 2023, the FDA accepted the NDA for filing and granted us priority review with a PDUFA target action date of 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 ACP.
EMA and The Medicines and Healthcare Products Regulatory Agency (MHRA) Requirements and 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:
•ACP 2 mg, followed by ACP 2mg 14 days later, monthly for three months during an induction phase; followed by ACP 4 mg, administered as two injections of 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 ACP in STGD1 patients and thus do not have any clinical data regarding the effect of 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
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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.
ACP - Wet AMD Trials
OPH2000: Completed Phase 1/2a Clinical Trial of 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 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 ACP dose levels: 0.03 mg, 0.3 mg, 1 mg, 2 mg and 3 mg. 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 ACP, mild subcapsular cataract in one patient in the group treated with 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 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 ACP dose groups or the efficacy of 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 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 ACP for Treatment-Experienced Wet AMD Patients
During the fourth quarter of 2015, we initiated an open-label Phase 2a clinical trial to evaluate 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 ACP development programs, we stopped enrolling patients in this trial as we determined that we would initiate a new 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.
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OPH2007: Completed Phase 2a Clinical Trial of ACP for Treatment-Naïve Wet AMD 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 ACP 2 mg on the same day, followed by 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 ACP 2 mg on the same day and in Group 4, ACP 2 mg followed two days later with Lucentis 0.5 mg and ACP 2 mg.
From a safety perspective, 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 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 ACP dose groups or to evaluate the efficacy of 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.
ACP - IPCV Trials
OPH2002: Completed Phase 2a Clinical Trial of ACP for IPCV
In late 2014, we initiated a very small, uncontrolled, open-label, Phase 2a clinical trial to evaluate 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 ACP for IPCV
In late 2017, we initiated a randomized, dose-ranging, open-label Phase 2a clinical trial of ACP in combination with Eylea in treatment-experienced patients with IPCV. We did not enroll any patients in this clinical trial and decided to
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discontinue this clinical 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. We have developed a formulation that we believe will be safe and effective for intravitreal administration into the eye, and are conducting cGMP manufacturing activities for IC-500. We are conducting additional preclinical studies to optimize the dosage, delivery and formulation of IC-500, and planning for IND-enabling toxicology studies to start later in 2023. 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 during the first half of 2024.
Gene Therapy Research and Development Programs
As we continue to assess our strategic priorities and the market for orphan and age-related retinal diseases and available technologies for addressing those unmet medical needs, 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 for LCA10, STGD1 and USH2A, respectively. We describe below the December 2022 transaction in which Opus acquired all of our rights, title and interests in and to our assets primarily related to our former gene therapy product candidates IC-100 and IC-200, which we previously developed for rhodopsin-mediated autosomal dominant retinitis pigmentosa and BEST1-related IRDs, respectively.
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. 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.
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
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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.
Minigene Programs
Starting in 2018, we funded several sponsored research programs at the University of Massachusetts Medical School, or 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 several employees 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 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
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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 conducted 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 were 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 ACP, IC-500 or any other product candidate we may develop. We have not yet conducted any process development or manufacturing for our minigene programs. Although we rely and intend to continue to rely upon third-party contract
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manufacturing organizations, or CMOs, to produce our products and product candidates, we have personnel with experience to manage the third-party CMOs 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.
ACP Manufacturing
The process for manufacturing ACP 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 ACP API is dissolved in a liquid solution that includes certain chemicals and then is aseptically filled into vials from which the intravitreal injection solution is drawn. This process of rendering the API into a liquid solution and placing it into vials is referred to as fill/finish.
We are working 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 working with our historical fill/finish manufacturer, Ajinomoto Bio-Pharma Services, or Ajinomoto, on fill/finish of ACP 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 ACP drug product using the new vial, which we are using for a portion of the second-year study visits for patients in the GATHER2 trial and for the OLE study. We believe Ajinomoto has the capacity to supply us with ACP drug product with the new vial for our expected commercial supply needs upon launch, if approved. We are continuing discussions with Ajinomoto for long-term supply of ACP drug product and are assessing additional suppliers 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
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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. We are continuing preclinical studies to optimize the dosage, delivery and formulation of IC-500.
Human Capital
Our Workforce
As of December 31, 2022, we had 163 full-time employees, compared to 89 full-time employees as of 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 continue to hire strategically to support key areas of our business, including the hiring of a commercial sales force. We expect to complete the hiring of our commercial team of approximately 120 individuals, including a field based sales force of between 50 and 70 representatives, by early April 2023. Diversity is a key factor that we are considering in our hiring of a sales force.
The following are additional data about our full-time employees, as of December 31, 2022:
•49% of our workforce are women;
•45% of our workforce are racially diverse (which we define as Asian, African American, Native American and Hispanic);
•44% of our leadership roles (which we define as Director level and above) are women and 44% of those in leadership roles are racially diverse;
•31% of our Executive Leadership Team are women; and
•38% of our Executive Leadership Team are racially diverse.
Throughout 2022, we promoted 12.7% of our workforce into leadership roles. Of these promotions, 47% are women and 43% are racially diverse.
Compensation and Benefits
We believe that our employees are vital to our company's success. To attract and retain talent, we provide competitive compensation and benefits to our workforce, including two medical plans to choose from along with generous Health Reimbursement Account and Health Savings Account offerings. We also offer generous vacation and parental leave. Starting in 2023, we increased the offering periods for our employees to join our Employee Stock Purchase Plan from two to four times per year.
Our turnover rate for 2022 was 6.2%, which is low compared to our peers in our 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 2022, we rolled out an employee volunteering and company match program. Based on available information, in 2022, over 25% of our workforce donated funds to or volunteered time for charitable organizations, including for Genspace NYC, a Brooklyn community lab that we sponsor. Our committee for diversity, equity and inclusion, which we established in 2020, continues to find ways to encourage employee volunteering and fundraising for charitable organizations, and bring in outside speakers on topics such as living with disabilities and overcoming unconscious bias.
Sales and Marketing
Our commercial strategy for ACP, as well as for any other product candidate that may be approved, 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. For 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 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), many of whom are 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 ACP for GA.
We are continuing to build our commercial capabilities and infrastructure, including our own sales and marketing organization, in anticipation of our potential launch of ACP in the United States for GA, if approved. We are actively hiring qualified personnel across core commercial functions including sales, marketing, patient access and reimbursement, analytics and operations, and product distribution. We expect to complete the hiring for our commercial team by early April 2023, with a total of approximately 120 individuals, including a field based sales force of between 50 and 70 representatives. We believe our field sales force will be 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.
Based on publicly available information, we are aware of the following competitive products and programs. Other competitive programs may exist of which we are not aware.
Competitive considerations for GA or dry AMD:
•In February 2023, the FDA approved Apellis Pharmaceuticals, Inc., or Apellis’s, pegylated, synthetic peptide targeting complement protein C3, pegcetacoplan, for the treatment of GA secondary to AMD. This product has a dosing regimen of once every 25 to 60 days. In December 2022, Apellis submitted an MAA to the EMA. Apellis announced that the EMA had validated their MAA and the application was under review, with a decision expected in early 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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Corporation, or AGTC, Biogen Inc., Gemini Therapeutics, Inc. (which merged with Disc Medicine, Inc.), Gyroscope Therapeutics (which was acquired by Novartis AG), IONIS Pharmaceuticals, Inc. (in collaboration with Roche AG), Janssen Pharmaceuticals Inc. (which acquired its program through the acquisition of Hemera Biosciences, LLC), Kanaph Therapeutics Inc, NGM Biopharmaceuticals Inc. and Novartis AG each have complement inhibitors in development for GA or dry AMD, including, in the cases of Gyroscope Therapeutics and Janssen Pharmaceuticals, complement inhibitor 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 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, 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 was Genentech's monoclonal antibody HtrA1 inhibitor, which was being studied in a Phase 2 clinical trial until it was discontinued in October 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 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 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. We also rely upon trade secrets, know-how, continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position.
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Our patent portfolio includes the following:
•patents and patent applications in-licensed from Archemix Corp., or Archemix:
•patents and patent applications covering 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 2025, subject to any patent term extensions; and
•patents and patent applications covering the treatment of certain complement mediated disorders with ACP, ACP for use in a method of treating certain complement mediated disorders or a composition comprising 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 2025, 2026 and 2027, subject to any patent term extensions; and
•patents and patent applications owned by IVERIC bio, Inc.:
•patents and patent applications covering methods of use for treating GA, Stargardt disease, IPCV and other conditions, and other proprietary technology relating to ACP, which include two issued United States patents with claims covering methods for treating GA with ACP that are expected to expire in 2034, subject to any patent term extensions, and 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 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 patents and patent applications covering compositions and methods of use of IC-500 and other HtrA1 inhibitors owned by Orion, some of which are 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
•patent applications in-licensed by Iveric Subsidiary from UMass:
•two families of 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, China and certain other jurisdictions, and which, if granted, are expected to expire in 2038 and 2040, respectively, subject to any patent term adjustments or extensions.
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
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the length of the clinical trials for each drug and other factors. If ACP is approved and we elect a composition of matter patent for patent term extension, we expect to be eligible for up to the full five years of patent term extension in 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 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 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 seek collaboration opportunities for 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.
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.
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 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