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

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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 in the "Risk Factors" section, 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.

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PART I

Item 1.    Business

        We are a biopharmaceutical company specializing in the development of novel therapeutics to treat diseases of the back of the eye, with a focus on developing therapeutics for age-related macular degeneration, or AMD. AMD is a disorder of the central portion of the retina, known as the macula, which is responsible for central vision and color perception. There are two forms of AMD, wet AMD and dry AMD. Our most advanced product candidate is Fovista, whichFovista® (pegpleranib), an anti-platelet derived growth factor, or PDGF, aptamer that is in Phase 3 clinical development for use in combination with anti-VEGFanti-vascular endothelial growth factor, or VEGF, drugs that represent the current standard of care for the treatment of wet AMD. We have completed one Phase 1 and one Phase 2b clinical trial of Fovista administered in combination with the anti-VEGF drug Lucentis® (ranibizumab), have completed patient enrollment for two Phase 3 clinical trials of Fovista administered in combination with Lucentis (ranibizumab).and expect to complete enrollment in a third Phase 3 clinical trial evaluating Fovista in combination with Eylea® (aflibercept) or Avastin® (bevacizumab) in 2016. We have either initiated or plan to initiatecompleted enrollment in two additional Phase 22a clinical trials of Fovista administered in combination with anti-VEGF drugs (Lucentis, Eylea or Avastin), one of which is studying the potential of Fovista to investigate whetherreduce subretinal fibrosis in wet AMD patients and the useother of which is investigating the optimized regimen of Fovista in combination with anti-VEGF drugs, can inhibitas well as the developmentpotential of subretinal fibrosis in wet AMD patients, canFovista to reduce the frequency of intravitreal injections required to effectively treat wet AMD, and can prove beneficialtreatment burden for wet AMD patients who are anti-VEGF resistant.patients. We are also developing our product candidate ZimuraZimura® (avacincaptad pegol) as a monotherapy for the treatment of patients with geographic atrophy, or GA, a form of dry AMD, as well as in combination with anti-VEGF therapydrugs for the treatment of wet AMD and for the treatment of polypoidal choroidal vasculopathy, a specific type of wet AMD;,AMD, in patients who do not respond adequately to treatment with anti-VEGF monotherapy or for whom anti-VEGF monotherapy fails; and, potentially, in combination with anti-VEGF therapy and Fovista forfails. We are also investigating the treatment of anti-VEGF resistant wet AMD patients who are believed to have complement mediated inflammation. We have recently begun work to investigate the possibilitypotential of an ophthalmic formulation for tivozanib, an anti-VEGF compounda small molecule VEGF tyrosine kinase inhibitor for which we have an option for a license.

Fovista

        We are developing our product candidate Fovista to be administered in combination with anti-VEGF drugs for the treatment of wet AMD. Wet AMD is characterized by abnormal new blood vessel formation, referred to as neovascularization, which results in blood vessel leakage and retinal distortion. If untreated, neovascularization in wet AMD patients typically results in formation of a scar,

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or fibrosis, under the macular region of the retina. The use of anti-VEGF drugs has significantly improved visual outcomes for wet AMD patients compared to untreated patients newly diagnosed with wet AMD. However, we believe that persistence or growth of neovascularization and the development of fibrosis under the retina are involved in limiting the visual benefit from anti-VEGF monotherapy, and, therefore, a significant unmet medical need remains.

        Wet AMD is the leading cause of blindness in people over the age of 55 in the United States and the European Union. The current standard of care for wet AMD is monotherapy administration of drugs that target vascular endothelial growth factor, or VEGF, one of several proteins involved in neovascularization. The anti-VEGF market for the treatment of wet AMD consists of two drugs that are approved for marketing and primarily prescribed for the treatment of wet AMD, Lucentis and Eylea, and a third drug, Avastin, a cancer drug used on an off-label basis. In 2015, annual worldwide sales of Lucentis and Eylea totaled approximately $7.7 billion for multiple retinal disease indications, including wet AMD, macular edema following retinal vein occlusion (also known as RVO), diabetic macular edema (also known as DME) and diabetic retinopathy in patients with DME. This sales number does not include sales of Avastin, which is used off-label to treat wet AMD in the United States and in the European Union. The anti-VEGF market for the treatment of wet AMD in China includes conbercept, sales of which are also not reflected in the sales number above.

        We believe that Fovista's mechanism of action, when administered in combination with an anti-VEGF drug, may result in two relevant biological responses: neovascular regression and inhibition of fibrosis under the retina, also known as subretinal fibrosis. Fovista binds to and inhibits a protein known as platelet derived growth factor, or PDGF, causing the stripping of pericytes, which are cells that cover the outside of newly formed blood vessels. After the pericytes are stripped from the new blood vessels, endothelial cells lining the inside of the newly formed blood vessels are left unprotected and are highly vulnerable to the effects of anti-VEGF drugs. Fovista also inhibits migration of other retinal cells attracted by PDGF, such as retinal pigment epithelium, or RPE, cells and glial cells, which play a role in the formation of subretinal fibrosis. We further believe that the administration of Fovista in combination with anti-VEGF drugs in patients with wet AMD may cause regression of neovascularization and may inhibit subretinal fibrosis more effectively than anti-VEGF monotherapy. We believe that Fovista may provide meaningful added benefit in the treatment of wet AMD regardless of which anti-VEGF drug is administered in combination with Fovista.

        In 2012, we completed a large Phase 2b clinical trial in newly diagnosed wet AMD patients in which 1.5 mg of Fovista administered in combination with one of the standard of care anti-VEGF drugs, Lucentis, demonstrated statistically significant superiority compared to Lucentis monotherapy based on the primary endpoint of mean change in visual acuity from baseline at 24 weeks. Patients receiving the combination of 1.5 mg of Fovista and Lucentis gained a mean of 10.6 letters from baseline on a standardized chart of vision testing compared to a mean gain of 6.5 letters from baseline for patients receiving Lucentis monotherapy, representing a 62% comparative benefit from baseline. Based on the pre-specified secondary endpoints in our Phase 2b study and on retrospective analyses of commonly evaluated parameters used in wet AMD trials, Fovista combination therapy resulted in improved visual outcome, with more patients experiencing vision gain and fewer patients experiencing vision loss, in a broad range of patient groups in this trial compared to Lucentis monotherapy. Fovista was generally well tolerated in this clinical trial.

        We have initiated aOur pivotal Phase 3 clinical program for Fovista that consists of three separate Phase 3 clinical trials to evaluate the safety and efficacy of 1.5 mg of Fovista administered in combination with anti-VEGF drugs for the treatment of wet AMD compared to anti-VEGF monotherapy, and are actively enrolling patients in these trials.monotherapy. Two of these trials, referred to as the Fovista Phase 3 Lucentis Trials, are evaluating Fovista in combination with Lucentis andcompared to Lucentis monotherapy. The third trial, referred to as the otherFovista Phase 3 Eylea/Avastin Trial, is evaluating Fovista in combination with Eylea (aflibercept) or Avastin (bevacizumab). We plancompared to enroll a total of 1,866 patients at more than 225 centers internationally across the three trials. Based on our estimates regarding patient enrollment, we expect to have initial, top-line data from our Phase 3 clinical program for Fovista available in 2016. If the results of this Phase 3 clinical program are favorable, we plan to submit applications for marketing approval for Fovista in the United States and, together with our ex-U.S. commercialization partner Novartis, in the European Union. We have also initiated a Phase 2a open-label clinical trial designed to investigate the potential effect of administration of Fovista in combination with anti-VEGF therapy in reducing theEylea or Avastin monotherapy.

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formationOur development strategy for Fovista is to be agnostic with respect to the choice of the anti-VEGF drug administered in combination with Fovista.

        We completed patient enrollment in one of the Fovista Phase 3 Lucentis Trials in May 2015 and in the other Fovista Phase 3 Lucentis Trial in November 2015. The Fovista Phase 3 Lucentis Trials are investigating Fovista in combination with Lucentis compared to Lucentis monotherapy and are identical with respect to the trial design in the first year. Therefore, the databases from both of the Fovista Phase 3 Lucentis Trials will be locked and analyzed together, which will allow for the pooled analysis of certain relevant endpoints in accordance with the statistical analysis plan. We expect initial, top-line data from both of the Fovista Phase 3 Lucentis Trials to be available during the fourth quarter of 2016.

        We are continuing to actively enroll patients in the Fovista Phase 3 Eylea/Avastin Trial and expect to complete enrollment in 2016, with initial, top-line data from this trial to be available in 2017 based on current enrollment estimates. This trial is investigating Fovista in combination with either Eylea or Avastin compared to Eylea or Avastin monotherapy. Our Phase 2b trial utilized Lucentis as the only anti-VEGF drug because Eylea was not yet approved and Avastin's non-inferiority status compared to Lucentis was not yet established at the time the Phase 2b clinical trial commenced. Therefore, in order to gain more experience with Fovista when administered in combination with Eylea or Avastin prior to starting a pivotal Phase 3 clinical trial, the Fovista Phase 3 Eylea/Avastin Trial started later (May 2014) than the Fovista Phase 3 Lucentis Trials (August 2013). This time period of approximately nine months allowed us to perform initial preclinical and clinical assessments and ensure compatibility of Eylea or Avastin when administered in combination with Fovista.

        Our key objective and plan is to make Fovista commercially available to physicians to treat their patients with wet AMD as quickly as possible, subject to obtaining favorable data from the Phase 3 clinical program. We are continuing to explore various regulatory filing options. We plan to initially submit a New Drug Application, or NDA, to the U.S. Food and Drug Administration, or FDA, for Fovista in combination with Lucentis based upon data from the two Fovista Phase 3 Lucentis Trials and subsequently submit an amendment to the NDA with data from the Fovista Phase 3 Eylea/Avastin Trial, subject to a favorable data outcome from these trials. Alternatively, we may choose to file a supplemental NDA for Fovista in combination with Eylea or Avastin following FDA review of the NDA for Fovista in combination with Lucentis. In addition, we continue to evaluate various filing strategies for marketing authorizations in Europe and other ex-U.S. territories with Novartis AG, or Novartis, our ex-U.S. commercialization partner for Fovista.

        In addition to our ongoing Phase 3 clinical program for Fovista, we have initiated additional clinical trials to evaluate the potential additional benefits of Fovista administered in combination with anti-VEGF drugs in wet AMD patients. We refer to these trials collectively as the Fovista Expansion Studies. They include:

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OPH1005 Fovista Anti-Fibrosis Study.  During the third quarter of 2014, we initiated an open-label Phase 2a clinical trial of 1.5 mg of Fovista administered in combination with anti-VEGF drugs (Lucentis, Eylea or Avastin), to study subretinal fibrosis in wet AMD patients. We completed enrollment in this trial in May 2015 with a total of 101 patients enrolled. Patients in this trial are followed over a 24-month period. In late 2015, we presented interim data for two subgroups of patients in this trial. See "—Potentially Expanding the Use of Fovista—Fovista Expansion Studies in Wet AMD" below for a description of the interim data we have also recentlypresented to date.



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OPH1006 Fovista Treatment Burden Reduction Study.  During the fourth quarter of 2014, we initiated aan open-label Phase 2a clinical trial to assess whether the useof 1.5 mg of Fovista when administered in combination with anti-VEGF drugs can(Lucentis, Eylea or Avastin) to investigate the optimized regimen of Fovista administration in combination with anti-VEGF drugs. In addition, this trial may allow us to evaluate the potential of Fovista to reduce the frequency of intravitreal injections required to effectively treattreatment burden for wet AMD patients. We plan to initiate

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completed enrollment in this trial in October 2015 with a total of 64 patients enrolled. Patients in this trial are followed over an initial18-month period.

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OPH1007 Fovista in Combination with Avastin Discontinuous Regimen Study.  During the fourth quarter of 2015, we initiated a randomized, double-masked, controlled Phase 22b clinical trial to investigate whetherevaluate the safety and efficacy of a discontinuous, bi-monthly regimen of 1.5 mg of Fovista administered in combination with an anti-VEGF drug may prove beneficialAvastin during the maintenance phase of wet AMD treatment compared to a discontinuous, bi-monthly regimen of Avastin monotherapy. The maintenance phase for wet AMD patients who aretreatment generally follows an induction phase, when treatment is administered more frequently over a shorter period of time. We believe that off-label use of Avastin for the treatment of wet AMD has not been extensively studied in randomized, controlled clinical trials, similar to those that have been conducted for approved anti-VEGF resistant. drugs.



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OPH1008 Fovista Imaging Study.  During the fourth quarter of 2015, we initiated an open-label Phase 2a clinical trial to investigate the role of multi-modal imaging in assessing anatomic responses to various wet AMD treatment regimens of Fovista administered in combination with anti-VEGF drugs (Lucentis, Eylea or Avastin).

We are also planningmay in the future seek to pursue additional clinical trials to assess the potential therapeutic benefit of Fovista in other groups of wet AMD patients andas well as other ophthalmic conditions.

        Wet AMD is characterized by abnormal new blood vessel formation, referred to as neovascularization, which results in blood vessel leakage and retinal distortion. If untreated, neovascularization in wet AMD patients typically results in formation of a scar, or fibrosis, under the macular region of the retina. The use of anti-VEGF therapy has significantly improved visual outcomes for wet AMD patients compared to untreated patients newly diagnosed with wet AMD. However, we believe that persistence or growth of neovascularization and the development of fibrosis under the retina are involved in limiting the visual benefit from anti-VEGF monotherapy, and, therefore, a significant unmet medical need remains.

        Wet AMD is the leading cause of blindness in people over the age of 55 in the United States and the European Union. The current standard of care for wet AMD is monotherapy administration of drugs that target vascular endothelial growth factor, or VEGF, one of several proteins involved in neovascularization. The anti-VEGF market for the treatment of wet AMD consists predominantly of two drugs that are approved for marketing and primarily prescribed for the treatment of wet AMD, Lucentis and Eylea, and off-label use of the cancer therapy Avastin. In 2014, annual worldwide sales of Lucentis and Eylea for all indications totaled approximately $7.1 billion. This sales number does not include Avastin, which is commonly used off-label to treat wet AMD in the United States and in the European Union.

        We believe that Fovista's mechanism of action, when administered in combination with an anti-VEGF drug, may result in two relevant biological responses: neovascular regression and inhibition of fibrosis under the retina, also known as subretinal fibrosis. Fovista binds to and inhibits a protein known as platelet derived growth factor, or PDGF, causing the stripping of pericytes, which are cells that cover the outside of newly formed blood vessels. After the pericytes are stripped from the new blood vessels, endothelial cells lining the inside of the newly formed blood vessels are left unprotected and are highly vulnerable to the effects of anti-VEGF therapy. Fovista also inhibits migration of other retinal cells attracted by PDGF, such as retinal pigment epithelium, or RPE, cells and glial cells, which play a role in the formation of subretinal fibrosis. We further believe that the administration of Fovista in combination with anti-VEGF drugs in patients with wet AMD may cause regression of neovascularization and may inhibit subretinal fibrosis more effectively than anti-VEGF monotherapy. We believe that Fovista may provide meaningful added benefit in the treatment of wet AMD regardless of which anti-VEGF drug is administered in combination with Fovista.

Zimura

        We are developing our product candidate Zimura with an initial focus onfor the treatment of patients with geographic atrophy,GA, a form of dry AMD, and in combination with anti-VEGF drugs for the treatment of wet AMD. Zimura is an inhibitor of complement factor C5, which we refer to as C5, a protein that is associated with complement mediated inflammation and cell damage, which we believe may be involved in the development and/or progression of dry and wet AMD.

        Dry AMD is typically associated with yellow-white dots or deposits under the retina, known as drusen. Unlike in wet AMD, there is an absence of pathological neovascularization in dry AMD. Significant vision loss results if dry AMD evolves into geographic atrophy. Geographic atrophyGA affecting the macula. GA appears as abrupt and deep levels of macular tissue loss and can be a significant cause of loss of central vision,

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affecting vision in both eyes in most patients. Geographic atrophyGA results in progressive and chronic degeneration of the macularetina characterized by variable thinning and dysfunction of retinal tissue.

        In addition, dry AMD can also progress to wet AMD. Although dry AMD is the most common form of AMD, there are no therapies approved by the U.S. Food and Drug Administration, or FDA or European Medicines Agency, or EMA, to treat this condition. According to a 2011 publication from AMD Alliance International, approximately 30 million people worldwide have some form of AMD, with dry AMD accounting for 85% to 90% of these cases. A study published inOphthalmology in 2012 analyzing age and gender variations in AMD prevalence estimates that approximately 8 million people worldwide are affected by geographic atrophy.GA.

        Multiple published studies have implicated local inflammation in the pathogenesis of dry AMD. Specifically, these studies suggest that the complement pathway, which consists of a series of proteins involved in the defense against infection and modulates a variety of immune and inflammatory responses, has a central role in dry AMD. The complement system is generally tightly regulated and requires the proper balance of activation and inhibition of proteins to function properly. Poorly regulated or aberrant activation of proteins in the complement pathway without a balanced or proportional inhibition of other proteins may result in the stimulation of inflammation and production of immune mediated inflammation, or inflammation that is triggered by activation of the immune response, andproteins, which eventually lead to damage to normal tissue. We believe that excessive activation of C5, which is one of the complement proteins, and the resulting formation of downstream complement molecules,

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protein complexes, results in tissue damage that plays an important role in the development of both dry AMD and certain forms of wet AMD. Our product candidate Zimura is designed to inhibit C5 activation.

        We have completed a small, multicenter, uncontrolled, open label Phase 1/2a clinical trial evaluating the safety and tolerability of Zimura administered as a monotherapy to patients with geographic atrophy, a form of dry AMD.GA. We did not observe any evidence of drug related adverse events in this clinical trial. We observed a relative trend in this clinical trial, in favor offavoring the higher of the two dose groups, of a relativewith respect to the reduction in the mean growth of the geographic atrophyGA lesion area, as measured by an independent reading center, at 24 weeks. When the injections were administered in a reduced dosing schedule was implemented during the subsequent 24 weeks, weeks 24 through 48, this relative trend in reduced growth in geographic atrophyGA lesion area was no longer present.evident. We believe this apparent trend in reduction of growth in geographic atrophyGA lesion area size when Zimura was dosed more frequently, together with greater frequency compared to less frequent dosing in the relative losssame group of the benefit when Zimura was dosed less frequently,patients, may suggest a possible drug effect. In addition, recently released dataData from a third party clinical trials of drug candidates targeting the complement pathway also exhibitedpathways have been conflicting. However, there was a trendsuggestion in reductionone trial of the potential to reduce growth of geographic atrophy withGA lesions in a pronounced effect in patients withfashion where specific biomarkers.biomarkers were present.

        Based on the results of ourWe have also completed a multicenter, ascending dose and parallel group open label Phase 1/2a clinical trial evaluating the safety and tolerability of Zimura administered in combination with Lucentis for the recent resultstreatment of wet AMD. None of the patients in this trial experienced any dose limiting toxicities at any of the dose levels tested and adverse events were primarily ocular adverse events in the study eye which were related to the injection procedure. We performed assessments of visual acuity primarily as safety assessments to detect any decrease in vision associated with the intravitreal drug combination or the injection procedure. In a subgroup of 43 patients who had not previously been treated with anti-VEGF drugs and who received six injections at doses of 0.3 mg, 1.0 mg or 2.0 mg of Zimura administered in combination with Lucentis, we observed a mean increase in visual acuity from baseline at all time points based on the third-partynumber of letters the patient can read on a standardized chart of vision testing. In this subgroup, 22 patients (51%) gained at least 15 letters, consisting of six patients (46%) in the 0.3 mg dose group, seven patients (47%) in the 1.0 mg dose group and nine patients (60%) in the 2.0 mg dose group.

        Currently, we have the following ongoing clinical trial,trials for Zimura:

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Zimura Phase 2/3 GA Study.  During the fourth quarter of 2015, we plan to initiateinitiated a randomized, double-masked, controlled Phase 2/3 clinical trial to evaluate the safety and efficacy of Zimura monotherapy in patients with geographic atrophyGA. We plan to enroll approximately 300 patients in the second halfinitial stage of 2015. We recentlythe trial. During this stage, patients will be randomized into three groups, and will receive monthly injections of 1.0 mg of Zimura per eye, monthly injections of 2.0 mg of Zimura per eye or monthly sham injections as the control arm. At month 18, we plan to conduct an interim analysis to assess the safety and efficacy of Zimura compared to sham. Upon review of this interim analysis, a determination will be made whether to continue the trial and whether to expand the trial by enrolling additional patients. Patients in the trial will receive monthly injections for 24 months.



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Zimura Phase 2a Wet AMD Study.  During the fourth quarter of 2015, we initiated an open-label Phase 2a clinical trial to evaluate Zimura's potential role when administered in combination with anti-VEGF drugs (Lucentis, Eylea or Avastin) for the treatment of wet AMD.



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Zimura PCV Study.  In late 2014, we commenced a very small, open-label Phase 2 clinical trial to evaluate Zimurainvestigating Zimura's potential role when administered in combination with anti-VEGF drugs for the treatment of polypoidal choroidal vasculopathy, or PCV, a specific type of wet AMD, in patients who do not respond adequately to treatment with anti-VEGF monotherapy or for whom anti-VEGF monotherapy fails, who we referfails. Our initial, preliminary analysis of the data from this trial has not revealed any safety concerns related to as anti-VEGF resistant. Additionally, we plan to initiate in 2015 or early 2016 a Phase 2 clinical trialZimura.

Table of Zimura and Fovista administered in combination with an anti-VEGF drug in a subpopulation of wet AMD patients who are anti-VEGF resistant and who are believed to have complement mediated inflammation.Contents

Our Management Team

        We are led by a team of experienced pharmaceutical industry executives and recognized experts in retinal disease. Our management team includes our co-founder and Chief Executive Officer, David

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R. Guyer, M.D., and our co-founder and President, Samir C. Patel, M.D. Dr. Guyer and Dr. Patel were co-founders and senior executives of Eyetech Pharmaceuticals, Inc., which was acquired by OSI Pharmaceuticals, Inc. in 2005. While at Eyetech Pharmaceuticals, Dr. Guyer and Dr. Patel were responsible for the clinical development and commercialization of Macugen (pegaptanib sodium), the first anti-VEGF drug approved for the treatment of wet AMD. While at Eyetech Pharmaceuticals, they also were responsible for the preclinical development of Fovista, the rights to which we subsequently acquired from OSI (Eyetech), Inc. pursuant to a divestiture agreement prior to initiation of any clinical development. We believe that our senior management provides us with significant capabilities in the development and commercialization of novel therapies to treat diseases of the back of the eye.

Our Strategy

        Our goal is to become a leading biopharmaceutical company focused on developing and commercializing novel therapeutics to treat diseases of the back of the eye, with a particular focus on developing novel therapeutics for the treatment of AMD. The key elements of our strategy to achieve this goal are:

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Complete the Phase 3 clinical program evaluating Fovista administered in combination with anti-VEGF drugs for the treatment of wet AMD and, if successful, seek marketing approval for Fovista in this indication.  We are devoting a significant portion of our resources and business efforts to the clinical development and manufacture of Fovista, which we are developing to be used in combination with anti-VEGF drugs for wet AMD. We have initiated a pivotal Phase 3 clinical program comprised of three separate Phase 3 clinical trials evaluating Fovista administered in combination with anti-VEGF drugs for the treatment of newly diagnosed wet AMD patients. Based on our estimates regarding patient enrollment, we expect to have initial, top-line data from thisboth of the Fovista Phase 3 clinical programLucentis Trials to be available during the fourth quarter of 2016, with initial, top-line data from the Fovista Phase 3 Eylea/Avastin Trial to be available in 2016. If the results of this Phase 3 clinical program are favorable, we2017 based on current enrollment estimates. We plan to initially submit applications for marketing approvalan NDA to the FDA for Fovista in combination with Lucentis based upon data from the United Statestwo Fovista Phase 3 Lucentis Trials and togethersubsequently submit an amendment to the NDA with data from the Fovista Phase 3 Eylea/Avastin Trial, subject to a favorable data outcome from these trials. Alternatively, we may choose to file a supplemental NDA for Fovista in combination with Eylea or Avastin following FDA review of the NDA for Fovista in combination with Lucentis. In addition, we continue to evaluate various filing strategies for marketing authorizations in Europe and other ex-U.S. territories with Novartis, our ex-U.S. commercialization partner Novartis, in the European Union. Ourfor Fovista. In accordance with their protocols, our Phase 3 clinical trials will continue after such submissions in accordance with the protocols for these trials.submissions.



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Further evaluate the potential benefit of Fovista in wet AMD, when administered in combination with anti-VEGF drugs, and in other ophthalmic diseases and conditions with unmet need.drugs.  In the third quarter of 2014, weWe have completed patient enrollment in our OPH1005 Fovista Anti-Fibrosis Study and OPH1006 Fovista Treatment Burden Reduction Study, and have initiated a Phase 2a open-label clinical trial designed to investigate the potential effect of the administration ofour OPH1007 Fovista in combinationCombination with anti-VEGF therapy in reducing the formationAvastin Discontinuous Regimen Study and OPH1008 Fovista Imaging Study, all as part of subretinal fibrosis in wet AMD patients.our Fovista Expansion Studies. We may also recently initiated a Phase 2a clinical trial to assess whether the use of Fovista in combination with anti-VEGF drugs can reduce the frequency of intravitreal injections required to effectively treat wet AMD. We plan to initiate in 2015 an initial Phase 2 clinical trial to investigate whether Fovista administered in combination with an anti-VEGF drug may prove beneficial for wet AMD patients who are anti-VEGF resistant. We are also evaluatingevaluate other ophthalmic conditions for which we believe Fovista treatment may be beneficial. We are planning to supply Fovista for a clinical trial to be conducted by the National Eye Institute, part of the U.S. National Institutes of Health, to evaluate Fovista's potential to inhibit the visual loss resulting from retinal complications associated with von Hippel-Lindau disease, an inherited disease characterized by multiple benign and malignant tumors and cysts in the eye and other organs. We expect this clinical trial will commence in 2015 or 2016. We are also planning to initiate, potentially in 2015 or 2016, a clinical trial to assess the potential therapeutic benefit of Fovista, and in particular its potential to inhibit the development of retinal scarring, in proliferative vitreoretinopathy, a complication associated with retinal detachment.



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Advance the development of Zimura for the treatment of AMD.  We are developing our product candidate Zimura for the treatment of geographic atrophy,GA, a form of dry AMD, and, in combination with anti-VEGF drugs for the treatment of wet AMD. Zimura is an inhibitor of complement factor C5, a protein that is associated with complement mediated

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subfoveal scar or subfoveal atrophy; or



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diabetes mellitus.

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        Fovista administered in combination with Lucentis was generally well tolerated in our Phase 1 clinical trial. None of the patients experienced any dose limiting toxicities at any of the dose levels tested. We did not observe any evidence of drug related adverse events. Adverse events were primarily ocular adverse events in the study eye which were related to the injection procedure. There were no adverse events related to Fovista or Lucentis, and no patients discontinued from the trial due to an adverse event. We did not observe any meaningful clinical immunologic reactions to Fovista.

        Our Phase 1 clinical trial had a small sample size and a short follow up period. It was not designed to compare Fovista combination therapy to another therapy. However, we noted improvements in visual acuity and anatomical changes in the newly formed blood vessels of the eye that suggested the Fovista combination therapy was enhancing the visual outcome compared to results previously seen with anti-VEGF monotherapy.

Completed Phase 2b Clinical Trial of Fovista Combination Therapy for Wet AMD

        In 2012, we completed a multicenter, randomized, double-masked, controlled Phase 2b clinical trial evaluating the safety and efficacy of Fovista administered in combination with Lucentis for the treatment of patients newly diagnosed with subfoveal wet AMD. We conducted this trial in 449 patients at approximately 69 centers in North America, South America, Europe and Israel.

        The primary objective of this trial was to evaluate the effect of two different doses of Fovista administered in combination with Lucentis compared to Lucentis monotherapy. The primary efficacy endpoint of this trial was mean change in visual acuity from baseline at 24 weeks for Fovista and Lucentis combination therapy compared to Lucentis monotherapy. Prior to enrollment in the trial, we measured each patient's visual acuity to establish a baseline. Following assessment at baseline, visual acuity was measured at each subsequent four-week timepoint.time point. We had diagnostic imaging techniques of fluorescein angiography and SD-OCT performed and assessed by an independent reading center at baseline and at week 24.

        Secondary efficacy endpoints for this trial included the following:

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mean change in visual acuity in ETDRS letters from baseline at 12 weeks;



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proportion of patients in each treatment group gaining 15 or more ETDRS letters from baseline at 12 weeks;



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proportion of patients in each treatment group gaining 15 or more ETDRS letters from baseline at 24 weeks; and



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mean change in area of choroidal neovascularization from baseline at 24 weeks.

        We randomly assigned patients in this trial to one of three treatment groups. Patients were treated and assessed once every four weeks for 24 weeks. Treatment for the three groups in the trial was as follows:

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In the first group, 149 patients received intravitreal injections of 0.3 mg of Fovista following intravitreal injections of 0.5 mg of Lucentis.



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In the second group, 152 patients received intravitreal injections of 1.5 mg of Fovista following intravitreal injections of 0.5 mg of Lucentis.



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In the third group, which served as the control arm of the trial, 148 patients received sham injections following intravitreal injections of 0.5 mg of Lucentis.

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        To reduce potential bias, the protocol for our Phase 2b clinical trial provided for a double-masked design so that neither the patient nor the investigational staff involved with assessing the vision of the patient knew to which group each patient belonged. The sham injection included all steps involved in

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the intravitreal treatment injections with the exception that patients in the control group had an empty syringe pressed against their eye walls without a needle. This procedure mimicked an intravitreal injection and helped to maintain proper masking.

        We made no meaningful changes to the inclusion and exclusion criteria in our Phase 2b clinical trial from those we used in our Phase 1 clinical trial. As in our Phase 1 clinical trial, we did not enroll patients with pure occult choroidal neovascularization because it would be difficult to adequately observe and measure the changes in the choroidal neovascular morphology using the imaging techniques that were generally available at most enrolling sites at the time we initiated our Phase 2b clinical trial. We believed that data regarding neovascular regression would be useful in assessing the effects of Fovista administered in combination with Lucentis and in supporting the anti-neovascularization element of our proposed mechanism of action for Fovista.

Measures of Mean Visual Acuity—Primary Efficacy Endpoint

        Mean Change in Visual Acuity from Baseline at 24 Weeks.    In this trial, the combination of 1.5 mg of Fovista and Lucentis demonstrated statistically significant superiority compared to Lucentis monotherapy based on the pre-specified primary endpoint of mean change in visual acuity from baseline at the 24 week timepoint.time point. We determined statistical significance based on a widely used, conventional statistical method that establishes the p-value of clinical results. Typically, a p-value of 0.05 or less represents statistical significance. However, when multiple doses of a drug are tested against a single control group, a more stringent statistical method that accounts for multiple comparisons must be applied. For this purpose, we used the Hochberg multiple comparison procedure. Under the Hochberg procedure, in order to demonstrate statistical significance for any particular dose, it is necessary to establish a p-value that meets a stricter standard than the conventional standard of 0.05 or less unless each dose is statistically significant with a p-value of 0.05 or less. In the case of our Phase 2b clinical trial, in which we evaluated two doses of Fovista administered in combination with Lucentis, the Hochberg procedure required a more stringent p-value of 0.025 or less to establish statistical significance for the comparison of the combination of 1.5 mg of Fovista and Lucentis to Lucentis monotherapy.

        At 24 weeks, patients receiving the combination of 1.5 mg of Fovista and Lucentis gained a mean of 10.6 ETDRS letters compared to a mean of 6.5 ETDRS letters for patients receiving Lucentis monotherapy, representing a 62% comparative benefit from baseline, with a p-value of 0.019. This result was statistically significant. At 24 weeks, patients receiving the combination of 0.3 mg of Fovista and Lucentis gained a mean of 8.8 ETDRS letters. This result was not statistically significant, having a p-value greater than 0.05, compared to Lucentis monotherapy. However, as discussed in more detail below, we believe that the relative visual benefit of the combination of 1.5 mg of Fovista and Lucentis compared to the relative visual benefit of the combination of 0.3 mg of Fovista and Lucentis at all timepointstime points exhibits a dose-response curve in which the response to treatment increases with higher drug concentrations of Fovista. We are not testing the combination of 0.3 mg of Fovista and Lucentis compared to Lucentis monotherapy in our Phase 3 clinical program.

        The graph below sets forth the results of the pre-specified primary endpoint in this Phase 2b clinical trial.

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Mean Change in Visual Acuity (VA) from Baseline at 24 Weeks

Measures of Mean Visual Acuity—Mean Change in Visual Acuity From Baseline Over Time

        Patients treated with the combination of 1.5 mg of Fovista and Lucentis showed greater improvement in visual acuity from baseline compared to patients treated with Lucentis monotherapy at week four and at each subsequent four-week assessment. In addition, the relative magnitude of visual benefit favoring the combination of 1.5 mg of Fovista and Lucentis increased over the study period. The graph below sets forth the mean change in visual acuity from baseline for each treatment group over the course of the trial.

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Mean Change in Visual Acuity (VA) from Baseline Over Time

        We believe that the divergence of the efficacy curves suggests an increasing relative benefit in visual outcome for the combination of 1.5 mg of Fovista and Lucentis over time compared to Lucentis monotherapy. If we observe a similar pattern of visual benefit in our Phase 3 clinical program, we believe that chronic administration of 1.5 mg of Fovista with Lucentis may be indicated. In addition, we believe that the relative visual benefit of the combination of 1.5 mg of Fovista and Lucentis compared to the relative visual benefit of the combination of 0.3 mg of Fovista and Lucentis at all timepointstime points exhibits a dose-response curve in which the response to treatment increases with higher drug concentrations of Fovista.

Measures of Mean Visual Acuity—Secondary Endpoints

        We evaluated measures of visual outcomes as secondary endpoints. Results from secondary endpoints are used to help interpret the primary result of the trial and to provide information for future research and clinical development. However, the statistical analysis plan for our Phase 2b clinical trial was not designed to establish and, as a result, we could not and did not demonstrate, statistical significance with respect to these secondary endpoints. Accordingly, only descriptive analyses and trends for secondary endpoints are presented below.

        Mean Change in Visual Acuity from Baseline at 12 Weeks.    We observed differences on the secondary endpoint of mean change in visual acuity from baseline at the 12 week timepointtime point favoring the combination of 1.5 mg of Fovista and Lucentis compared to Lucentis monotherapy. At 12 weeks, patients receiving the combination of 1.5 mg of Fovista and Lucentis gained a mean of 8.7 ETDRS letters compared to patients receiving Lucentis monotherapy who gained a mean of 5.1 ETDRS letters. The graph below sets forth the results of this secondary endpoint of visual acuity at 12 weeks.

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Mean Change in Visual Acuity (VA) from Baseline at 12 Weeks

        Proportion of Patients Gaining 15 or More Letters from Baseline at 12 Weeks and at 24 Weeks.    We observed differences in the proportion of patients that showed improvement of 15 ETDRS letters, or three lines, or better in visual acuity favoring the combination of 1.5 mg of Fovista and Lucentis compared to Lucentis monotherapy both at 12 weeks and at 24 weeks of treatment.

        The table below sets forth at 12 weeks and 24 weeks the number of patients in the treatment group and the percentage of patients in such treatment group who gained the specified number of lines in visual acuity and the percentage of patients whose final visual acuity improved to the specified level.

Proportion of Patients Gaining 15 or More ETDRS Letters

Measures of Mean Visual Acuity—Clinically Relevant Retrospective Analyses

        We performed additional retrospective analyses of visual acuity measures that were not pre-specified primary or secondary endpoints in our Phase 2b clinical trial design. Although a retrospective analysis performed after unblinding trial results can result in the introduction of bias, we believe that these retrospective analyses may further support the results from our primary endpoint and the anti-neovascularization element of our proposed mechanism of action for Fovista.

        Retrospective Analysis of Visual Gain.    We observed differences in the proportion of patients that showed improvement when measured by the number of lines of improvement in visual acuity from baseline, referred to as final visual acuity, favoring the combination of 1.5 mg of Fovista and Lucentis compared to Lucentis monotherapy. The graphs below set forth for each of these two treatment groups

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at 24 weeks the percentage of patients in such treatment group who gained the specified number of lines in visual acuity and the percentage of patients whose final visual acuity improved to the specified level.

Visual Gain at 24 Weeks

        Retrospective Analysis of Visual Loss.    We observed differences in loss of visual acuity from baseline favoring the combination of 1.5 mg of Fovista and Lucentis compared to Lucentis monotherapy. The graphs below set forth for each of these two treatment groups the percentage of patients in such treatment group who lost the specified number of lines in visual acuity and the percentage of patients whose final visual acuity declined to the specified level.

Visual Loss at 24 Weeks

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Measures of Anatomical Changes—Secondary Endpoint

        We evaluated one measure of anatomical change as a secondary endpoint. Results from secondary endpoints are used to help interpret the primary result of the trial and to provide information for future research and clinical development. However, the statistical analysis plan for our Phase 2b clinical trial was not designed to establish and, as a result, we could not and did not demonstrate, statistical significance with respect to this secondary endpoint. Accordingly, only descriptive analyses and trends for this secondary endpoint are presented below.

        Mean Change in Area of Choroidal Neovascularization from Baseline at 24 Weeks.    In our Phase 2b clinical trial, the mean change in area of choroidal neovascularization, or CNV, from baseline at 24 weeks as determined by review of fluorescein angiograms was greater in patients treated with Lucentis monotherapy than in patients treated with the combination of 1.5 mg of Fovista and Lucentis. We believe that the inclusion of both larger and smaller CNV sizes in the single analysis of this secondary endpoint had the potential to create a distortion in the analysis of the mean change in area of CNV. This is because the average level of regression, as numerically measured, was approximately tenfold greater in the large CNV size patient group compared to the small CNV size patient group. The treatment group with the greater number of patients with larger CNV sizes will show a markedly larger amount of regression on average. That was the case in our Phase 2b trial in which the Lucentis monotherapy group had a greater proportion of patients with large CNV sizes compared to the group treated with a combination of 1.5 mg of Fovista and Lucentis. Therefore, as discussed in more detail below, we performed retrospective analyses by creating subgroups based on the size of CNV at baseline.

Measures of Anatomical Changes—Retrospective Analyses

        We performed retrospective analyses of anatomical changes, based on choroidal neovascularization and subretinal hyper-reflective material, or SHRM, that were not pre-specified primary or secondary endpoints in the trial design. Although a retrospective analysis performed after unblinding trial results can result in the introduction of bias, we believe that these retrospective analyses may further support the results from our primary endpoint and the anti-neovascularization element of our proposed mechanism of action for Fovista.

        Retrospective Analysis of Choroidal Neovascularization.    We performed several retrospective analyses of neovascular regression by creating subgroups based on CNV sizes. Size of CNV is measured in units called disc area. A disc area is the size of the area of the retina where a standard sized optic nerve emerges. We determined that the mean CNV size for all patients in the Phase 2b clinical trial at baseline was 1.62 disc areas. We created two subgroups of patients based on mean CNV size at baseline. One subgroup of patients, referred to as the large CNV size patients, had initial CNV size greater than 1.62 disc areas. The other subgroup of patients, referred to as the small CNV size patients, had initial CNV size of less than or equal to 1.62 disc areas.

        We believe the results described below of our retrospective analyses of mean change in area of choroidal neovascularization from baseline at 24 weeks determined by review of fluorescein angiograms in patients treated with the combination of 1.5 mg of Fovista and Lucentis compared to patients receiving Lucentis monotherapy may support the anti-neovascularization element of our proposed mechanism of action for Fovista. We included in these retrospective analyses only those patients whose CNV size we were able to assess both at baseline and at 24 weeks.

        Patients in both the large CNV size patient subgroup and small CNV size patient subgroup showed greater reductions in the size of choroidal neovascularization from baseline when treated with the combination of 1.5 mg of Fovista and Lucentis as compared to patients in the applicable subgroup receiving Lucentis monotherapy. The graphs below set forth the results of this subgroup analysis.

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Mean Change in Area of CNV at 24 Weeks

        In addition, we performed a further retrospective subgroup analysis of patients who experienced a visual gain of more than three lines from baseline after 24 weeks of treatment. Both large CNV size patients and small CNV size patients treated with the combination of 1.5 mg of Fovista and Lucentis showed a marked reduction in the average size of choroidal neovascularization from baseline when compared to large CNV size patients and small CNV size patients treated with Lucentis monotherapy. The graphs below set forth the results of this subgroup analysis.

Mean Change in Area of CNV at 24 Weeks
in Patients with Visual Gain of More Than 3-Lines

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        Retrospective Analysis of Subretinal Hyper-Reflective Material.    We performed a retrospective review of SD-OCT images of patients who participated in the trial without regard to baseline size of choroidal neovascularization. SD-OCT is the imaging technique most widely used today in clinical practice for the evaluation of wet AMD. Unlike fluorescein angiograms, SD-OCT images show a cross-sectional view of the retina that permits excellent resolution of the space under the retina and at the RPE-choroid interface where the neovascularization of wet AMD is present. The presence of subretinal hyper-reflective material is thought by many experts to indicate the presence of the CNV lesion. The subsequent resolution of subretinal hyper-reflective material is thought to correlate with regression of the CNV lesion.

        In our retrospective analysis, masked readers trained in the reading of the SD-OCT retinal images assessed the retinal images of patients who participated in the trial for the presence of subretinal hyper-reflective material at baseline and at 24 weeks. We conducted this retrospective analysis based on the SD-OCT retinal images which were read for each patient group at baseline and at week 24. The analysis at week 24 included only patients who completed the study and had SD-OCT retinal images acceptable for analysis.

        Patients treated with the combination of 1.5 mg of Fovista and Lucentis exhibited greater resolution of subretinal hyper-reflective material from baseline compared to patients treated with Lucentis monotherapy. In addition, based on our review of SD-OCT images, patients who experienced a visual gain of more than three lines from baseline at 24 weeks and were treated with the combination of 1.5 mg of Fovista and Lucentis exhibited greater resolution of subretinal hyper-reflective material from baseline than patients who experienced a similar visual gain and were treated with Lucentis monotherapy. The graphs below set forth for each of these two treatment groups the percentage of patients in such treatment group who had subretinal hyper-reflective material at baseline and the percentage of those patients who exhibited an absence of such subretinal hyper-reflective material at 24 weeks.

Subretinal Hyper-Reflective Material

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        We believe the results of our retrospective analysis of SD-OCT retinal images at baseline and at 24 weeks in patients treated with the combination of 1.5 mg of Fovista and Lucentis compared to patients receiving Lucentis monotherapy supports the anti-neovascularization element of our proposed mechanism of action for Fovista.

Retrospective Analysis of Subretinal Fibrosis

    Development of subretinal fibrosis is typically associated with poor visual outcomes in wet AMD patients. We have undertaken a retrospective analysis of retinal images from patients who experiencedhad vision loss or lack of visual gain at 24 weeks following treatment with either 1.5 mg of Fovista in combination with 0.5 mg of Lucentis or Lucentis monotherapy in our Phase 2b clinical trial to investigate the development of subretinal fibrosis in these patients. Our initial retrospective assessment of retinal images of these patients indicates a reduction, on average, in the development and severity of subretinal fibrosis at the 24 week timepointtime point in patients treated with the combination of 1.5 mg of Fovista and Lucentis compared to patients receiving Lucentis monotherapy. We have engaged independent third-party retinal experts to review these images to assess the development of subretinal fibrosis in this group of patients. In October 2014, findings from an independent subgroup analysis assessing the development and progression of subretinal fibrosis in our Phase 2b clinical trial waswere presented at the American Academy of Ophthalmology annual meeting. This retrospective analysis showed that the mean change in severity of subretinal fibrosis from baseline to conclusion of the study at 24 weeks was 0.97 vs.for the Fovista (1.5 mg) combination therapy group as compared to 2.0 for the Lucentis monotherapy group (P = 0.003), favoring the Fovista (1.5mg) combination therapy group.based on a five-step grading scale developed by Dr. Usha Chakravarthy, an internationally recognized key opinion leader. At 24 weeks, approximately twice the number of patients on standard of care anti-VEGF monotherapy (54%) were noted to have progression of subretinal fibrosis compared to the Fovista (1.5mg)(1.5 mg) combination therapy group (27%). In eyes without any subretinal fibrosis at baseline, subretinal fibrosis developed in 10% of patients who received Fovista (1.5mg)(1.5 mg) combination therapy, compared to 51% of the patients who received monotherapy Lucentis. We believe such findings may provide support for the anti-fibrotic element of our proposed mechanism of action for Fovista.

        In August 2014,May 2015, we commencedcompleted enrollment in our OPH1005 Fovista Anti-Fibrosis Study. See "—Potentially Expanding the Use of Fovista—Fovista Expansion Studies in Wet AMD" below for a Phase 2a open-label clinical trial designed to further investigatedescription of Dr. Chakravarthy's fibrosis grading scale, the potential effectOPH1005 Fovista Anti-Fibrosis Study and the interim data for two subgroups of the administration of Fovistapatients in combination with anti-VEGF therapy in reducing the formation of subretinal fibrosis in wet AMD patients.this trial.

Safety

        Fovista was generally well tolerated in the Phase 2b trial at both doses tested in combination with Lucentis. We did not observe any cases of infection inside the eye, or endophthalmitis. We observed one case of severe intraocular inflammation among the patients treated with 0.3 mg of Fovista in combination with Lucentis and no such cases among the patients treated with 1.5 mg of Fovista in combination with Lucentis. We did not observe any significant imbalances among treatment groups in the incidence of ocular adverse events or systemic adverse events, including cardiovascular events or stroke. The number of patients in our Phase 2b clinical trial with one or more serious systemic adverse events, the most common systemic serious adverse events in this trial organized by MedDRA system

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organ class, a standard method of reporting adverse events, and by antiplatelet trialists' collaboration events, a standard method of reporting cardiovascular adverse events, are set forth in the table below.

        There was one serious adverse event in the study eye in each of the treatment groups. The serious adverse event was different among each of the treatment groups as shown in the table below.

        The most common adverse events in the study eye are set forth in the table below.

Ocular Adverse Events Reported in Study Eye in 5% or More of Patients in Any Arm

        Most of the common ocular adverse events in this trial were related to the intravitreal preparation and injection procedure and were not drug related. These intravitreal adverse events, as reflected in the table above, included conjunctival hemorrhage, punctate keratitis, eye pain and conjunctival hyperemia. Most adverse events of increased intraocular pressure occurred after injection, were transient, were

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related to the injection and were treated and resolved the same day. Mean intraocular pressure in each treatment group returned to pre-injection level at the next assessment, including at the end of the trial.

Ongoing Phase 3 Clinical Program for Fovista Combination Therapy for Wet AMD

        We have initiated aOur pivotal Phase 3 clinical program consistingconsists of three separate Phase 3 clinical trials, to evaluate the safety and efficacytwo of which are evaluating Fovista administered in combination with anti-VEGF drugs forLucentis and the treatmentother of newly diagnosed wet AMD patients compared to anti-VEGF monotherapy.which is evaluating Fovista in combination with Avastin or Eylea. We plan to enroll a total of approximately 1,866 patients atin more than 225250 centers internationally.internationally across the three trials. We completed patient enrollment in one of the Fovista Phase 3 Lucentis Trials in May 2015 and in the other Fovista Phase 3 Lucentis Trial in November 2015. We are continuing to actively enroll patients in the Fovista Phase 3 Eylea/Avastin Trial and expect to complete enrollment in 2016 based on current enrollment estimates. We expect initial, top-line data from both of the Fovista Phase 3 Lucentis Trials to be available during the fourth quarter of 2016, with initial, top-line data from the Fovista Phase 3 Eylea/Avastin Trial to be available in 2017 based on current enrollment estimates.

        The primary efficacy endpoint of our Phase 3 clinical trials is mean change in visual acuity from baseline for Fovista and anti-VEGF combination therapy compared to anti-VEGF monotherapy at 12 months. Secondary efficacy endpoints for our Phase 3 clinical trials will include the following:

•

proportion of patients in each treatment group gaining 20 or more ETDRS letters from baseline at month 12;



•

proportion of patients in each treatment group gaining 25 or more ETDRS letters from baseline at month 12; and



•

proportion of patients in each treatment group losing 5 or more ETDRS letters from baseline at month 12; and



•

mean change inother visual acuity in ETDRS letters from baseline at month six.and anatomical measures.

        Two of our threeThe two Fovista Phase 3 clinical trialsLucentis Trials are evaluating the safety and efficacy of 1.5 mg of Fovista administered in combination with Lucentis compared to Lucentis monotherapy. The thirdFovista Phase 3 clinicalEylea/Avastin trial is evaluating the safety and efficacy of 1.5 mg of Fovista administered in combination with each of AvastinEylea or EyleaAvastin compared to AvastinEylea or EyleaAvastin monotherapy. All of these Phase 3 clinical trials incorporate significant aspects from the design of our completed Phase 2b clinical trial.

        The protocols for our Phase 3 clinical trials and other supporting information are subject to review by the FDA and regulatory authorities outside the United States. The FDA is not obligated to comment on our protocols within any specified time period or at all or to affirmatively clear or approve our Phase 3 clinical program. We submitted the protocols for our Phase 3 clinical trials to the FDA in July 2013 and initiated the three trials in our Phase 3 clinical program in the United States without waiting for any such comments.2013. To date, we have not received any such comments on the design of our Phase 3 clinical program from the FDA. The FDA or other regulatory authorities may request additional information, require us to conduct additional non-clinical trials or require us to modify our proposed Phase 3 clinical program, including its endpoints, patient enrollment criteria or selection of anti-VEGF drugs, to receive clearance to initiate such program or to continue such program once initiated. In September 2013, the FDA notified us that we have obtained fast track designation for Fovista for the treatment of wet AMD.

        Outside the United States, we have made regulatory submissions in selected countries to initiate the three Phase 3 clinical trials. We have obtained all but one of the necessary country approvals to proceed with the twoour Phase 3 trials of Fovista administered in combination with Lucentis in those countries and have received substantially all of the necessary country approvalsexcept for the trial ofBrazilian approval required to proceed with our Fovista administered in combination with Eylea or Avastin.Phase 3 Eylea/Avastin Trial, which we are pursuing. In the European Union, as further described below, in addition to filing in selected countries with national competent authorities responsible for approving clinical trial applications, we have had interactions regarding our planned application for marketing approval with the EMA's CHMP, which is the committee responsible for preparing opinions on questions concerning medicines for human use. The national competent authorities in those countries from which we have not yet received approval may follow the advice described below of the CHMP that we consider toxicity studies with Fovista administered in combination with Avastin or Eylea prior to initiating our corresponding Phase 3 clinical trial in those countries.

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        In the fourth quarter of 2013, the CHMP provided scientific advice on our proposed Phase 3 clinical program for Fovista and our plan to seek regulatory approval for Fovista. As part of that scientific advice, the CHMP advised us that the planned primary endpoint for each of the Phase 3 clinical trials for Fovista, mean change from baseline in best corrected visual acuity, was acceptable. In addition, the CHMP confirmed that carcinogenicity studies are not needed for our Phase 3 clinical program. The CHMP also advised us that we should justify our proposal to initiate, at the Phase 3 clinical trial stage, certain previously untested combinations of Fovista with Avastin or Eylea, and, as described above, that we should consider conducting toxicity studies with Fovista administered in combination with Avastin or Eylea prior to initiating our corresponding Phase 3 clinical trial. In addition, the CHMP informed us that given that Avastin is not approved for intravitreal use in the European Union, the final label for Fovista, if it receives marketing approval, may be required to specify only the licensed anti-VEGF drugs approved for intravitreal use that were studied in combination with Fovista, given

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that Avastin is not approved for intravitreal use, rather than a label specifying Fovista for use in combination with any anti-VEGF drug.

        In the first quarter of 2014, we received a written response from the CHMP on these issues. The CHMP is in agreement with our plan to use the less frequent dosing schedule approved for Eylea in the European Union as the dosing schedule in our Phase 3 clinical trial evaluating Fovista administered in combination with Eylea. The CHMP has also agreed with our plan for monthly dosing for the first 12 months of each of our Phase 3 clinical trials evaluating Fovista administered in combination with Lucentis and, to slightly modify the dosing regimen in the second 12 months for one of these two trials so that it is consistent with the less frequent dosing schedule approved for Lucentis in the European Union. The dosing schedule for the second 12 months in the other study evaluating Fovista administered with Lucentis remains unchanged.

        Based on our estimates regarding patient enrollment, weWe expect to have initial, top-line data from thisboth of the Fovista Phase 3 clinical programLucentis Trials to be available during the fourth quarter of 2016, with initial, top-line data from the Fovista Phase 3 Eylea/Avastin Trial to be available in 2016. If the results of this Phase 3 clinical program evaluating Fovista are favorable, we2017 based on current enrollment estimates. We plan to initially submit applications for marketing approval seeking a broad label with regardsan NDA to patient and/or lesion characteristicsthe FDA, for Fovista in combination with anti-VEGF drugsLucentis based upon data from the two Fovista Phase 3 Lucentis Trials and subsequently submit an amendment to the NDA with data from the Fovista Phase 3 Eylea/Avastin Trial, subject to a favorable data outcome from these trials. Alternatively, we may choose to file a supplemental NDA for Fovista in combination with Eylea or Avastin following FDA review of the United StatesNDA for Fovista in combination with Lucentis. In addition, we continue to evaluate various filing strategies for marketing authorizations in Europe and togetherother ex-U.S. territories with Novartis, our ex-U.S. commercialization partner Novartis, in the European Union. In September 2013, the FDA notified us that we have obtained fast track designation for Fovista for the treatment of wet AMD.Fovista.

        We expect to submit applications for marketing approval of Fovista administered in combination with anti-VEGF drugs for the treatment of wet AMD in the United States and, together with our commercialization partner, Novartis, in the European Union if we obtain positive outcomes in at least two of our three Phase 3 clinical trials.        We believe that clinically meaningful favorable results from two of our Phase 3 clinical trials in which a combination of 1.5 mg of Fovista with an anti-VEGF drug achieves superiority over anti-VEGF drug monotherapy with statistical significance on the primary endpoint of mean change in visual acuity from baseline at 12 months, together with the results of our Phase 1 and Phase 2b clinical trials, will be sufficient to support applications for marketing approval of Fovista for the treatment of wet AMD in the United States and the European Union. However, if favorable results from two of our three Phase 3 clinical trials include results from only one of our Phase 3 clinical trials evaluating the safety and efficacy of a combination of 1.5 mg of Fovista and Lucentis, the FDA, the EMA or other regulatory authorities may not grant, or may request additional information, including the results of additional clinical trials, prior to granting, marketing approval for Fovista.

        We expect to submit our applications for marketing approval based on data regarding the primary efficacy endpoint from our Phase 3 clinical trials after 12 months of treatment. We also expect that 12-month safety data will satisfy the safety database requirements for submission of our applications. OurIn accordance with their protocols, our Phase 3 clinical trials will continue after such submissions in accordance with the protocols for these trials.submissions. We expect that each of the FDA and the EMA will review any additional safety and efficacy data that is available from the ongoing Phase 3 clinical trials, or any other clinical trials involving Fovista, at the time of the FDA's or EMA's review of our applications for marketing approval.

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        For each patient enrolled in the Phase 3 clinical trials, we are measuring the patient's best-corrected visual acuity prior to treatment to establish a baseline against which subsequent visual acuity changes after treatment can be compared. The protocols for each of these trials provide that patients be assessed monthly. The administration of treatment varies among the three trials. In the two trials investigating the administration of Fovista in combination withPhase 3 Lucentis Trials, patients are treated monthly for the first 12 months. In one of the two Fovista Phase 3 Lucentis trials,Trials, during the second 12 months, patients will be treated every other month and can be retreated during the intervening months in accordance with specific retreatment criteria set forth in the protocol for the trial based on visual acuity and imaging. In the second Fovista Phase 3 Lucentis trial,Trial, during the second 12 months treatment will be administered based upon the stability of the patient's visual acuity, ophthalmic examination and imaging consistent with EU labeling of Lucentis. These two Fovista Phase 3 Lucentis trialsTrials build upon and incorporate significant aspects from the design of our Phase 2b clinical trial of Fovista administered in combination with Lucentis while evaluating the administration of Fovista combination therapy over a longer overall treatment period in a greater number of patients.

        In these first two trials,each of the Fovista Phase 3 Lucentis Trials, we are randomly assigningassigned patients to one of two treatment groups with approximately 311 patients in each group. Treatment for the two groups in each of these two trials is as follows:

•

Patients in the first group receive intravitreal injections of 1.5 mg of Fovista following intravitreal injections of 0.5 mg of Lucentis.

drug without an unacceptable increase in IOP. However, if we apply for marketing approval for Fovista, the FDA, the EMA or other regulatory authorities will determine, based on the data we present and the regulatory authority's assessment of risk to patients, whether the label for Fovista will provide for the administration of Fovista immediately after the anti-VEGF drug, 30 minutes after the anti-VEGF drug or after some other waiting period. If we determine that the potential Fovista label may provide for a waiting period between the administration of the anti-VEGF drug and Fovista, we likely would conduct an appropriate clinical trial to evaluate the safety of administration of Fovista immediately after the administration of the anti-VEGF. Additionally, our preclinical research shows that Fovista could be co-formulated with an anti-VEGF drug, and we may conduct a clinical trial to evaluate the safety of such a co-formulation.

Potentially Expanding the Use of Fovista

Additional Planned Phase 2 Clinical Trials Further Evaluating Potential to Provide BenefitFovista Expansion Studies in Wet AMD

        In addition to conducting our ongoing Phase 3 clinical program for Fovista, we have initiated multiple additional clinical trials to evaluate the potential additional benefits of Fovista administered in combination with anti-VEGF drugs for the treatment ofin wet AMD we are currently conducting, and planpatients. We refer to further conduct, additionalthese trials to evaluate Fovista's potential to provide benefitas the Fovista Expansion Studies. They include:

OPH1005 Fovista Anti-Fibrosis Study

        Wet AMD patients who develop subretinal fibrosis affecting the central macula, on average, have worse visual outcomes compared to patients who do not develop subretinal fibrosis. Moreover, during the maintenance phase of anti-VEGF treatment, data from multiple third-party clinical trials suggest that patients who receive discontinuous anti-VEGF monotherapy during the maintenance phase of anti-VEGF treatment have suboptimal visual outcomes compared to patients who receive continuous anti-VEGF monotherapy. Discontinuous anti-VEGF monotherapy consists of eitherpro re nata, or PRN, meaning "as needed" based on the physician's assessment, or regular bi-monthly or quarterly dosing regimens. Continuous anti-VEGF monotherapy for Lucentis or Avastin consists of monthly administration or, in the case of Eylea, bi-monthly administration. Moreover, data from these third-party clinical trials also suggest that on average, once patients lose vision following the switch from a continuous regimen to a discontinuous regimen, a subsequent increase in the frequency of anti-VEGF dosing does not appear to improve patient vision to the level achieved prior to switching the regimen.

        In preclinical animal models of subretinal fibrosis, inhibition of PDGF has been shown to reduce the amount of scar tissue formation. We believe that the retrospective analysis conducted by independent readers of retinal images of patients in our completed Phase 2b trial with visual loss or lack of visual gain at 24 weeks following treatment with either 1.5 mg of Fovista administered in combination with Lucentis or Lucentis monotherapy is consistent with our hypothesis that Fovista mediated PDGF inhibition may result in inhibition of subretinal fibrosis. See "Completed Phase 2b Clinical Trial of Fovista Combination Therapy for Wet AMD—Retrospective Analysis of Subretinal Fibrosis" above for a discussion of the results of this analysis.

        During the third quarter of 2014, we initiated an open-label Phase 2a clinical trial of 1.5 mg of Fovista administered in combination with either Lucentis, Eylea or Avastin, to study subretinal fibrosis in wet AMD:AMD patients. Because the objective of the trial was to investigate Fovista combination therapy and subretinal fibrosis, the trial protocol permitted enrollment of a broader range of patients as compared to standard anti-VEGF treatment naïve protocols used in large registration trials. For example, patients with the following characteristics could be enrolled in the trial:

•

patients with scarring or fibrosis affecting 50% or more of their total CNV lesion area (so long as scarring or fibrosis was not sub-foveal);



•

patients with atrophy affecting 50% or more of their total CNV lesion area (so long as the atrophy was not sub-foveal);

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•

patients with sub-retinal hemorrhage covering greater than 50% of their total CNV lesion area; and



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patients with baseline visual acuity of up to 20/400.

The enrollment of patients in the trial was based upon investigator discretion and interpretation of the eligibility criteria contained in the protocol. This trial does not have any pre-specified efficacy endpoints as it is an uncontrolled, open-label Phase 2a study with broad patient eligibility criteria, which typically would not permit an adequate efficacy assessment.

        The protocol for this trial requires an initial induction phase of six monthly injections of Fovista administered in combination with Lucentis, Eylea or Avastin, followed by a discontinuous regimen of quarterly administrations of Fovista combination therapy. The protocol permits retreatment with Fovista combination therapy during the intervening monthly visits between quarterly administrations if the patient incurs vision loss of at least five ETDRS letters, regardless of any other objective findings. In addition, absent a loss in vision, investigators may decide to retreat at monthly visits in between quarterly administrations based upon increases in hemorrhage and/or intraretinal fluid. We completed enrollment in this trial in May 2015 with a total of 101 patients enrolled. Patients are followed for a 24-month period.

        In December 2015 at our R&D Investor Day, we presented initial interim data for a subgroup of patients that had reached the month 14 time point (n=6) and month 13 time point (n=16, inclusive of the six patients reaching month 14) as of a predetermined data collection date approximately six weeks prior to data presentation. The analysis for these 16 patients consisted of visual acuity data, as well as data regarding subretinal fibrosis obtained from fundus images taken at the month 12 time point. To illustrate the broad eligibility criteria for the trial, we presented selected images, including SD-OCT, fundus images and fluorescein angiograms, for ten of the 16 patients.

ReductionFibrosis Data at Month 12 Time Point

        Subretinal fibrosis was evaluated based on the assessment of fundus images using a continuous five-step grading system. This grading system was developed by an internationally recognized key opinion leader, Dr. Usha Chakravarthy, Professor, Ophthalmology and Vision Sciences, at the Royal Victoria Hospital (The Belfast Trust) and Queens University of Belfast, Northern Ireland. Dr. Chakravarthy graded the fundus images at baseline and the month 12 time point in a masked fashion. The grading system assigns a numerical score for each fundus image from "0 to 4" as follows:

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"0"—Fibrosis is absent



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"1"—Fibrosis is barely visible



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"2"—Fibrosis is mild



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"3"—Fibrosis is moderate



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"4"—Fibrosis is severe.

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        That data revealed that none of the 16 patients who had reached the month 13 time point exhibited development or progression of fibrosis at the month 12 time point. Development or progression of fibrosis is defined as a two-step progression in grading.

Visual Acuity Data for Month 13 and 14 Time Points

        Visual acuity was evaluated as the mean and median change in ETDRS letters from baseline. On average, we observed a trend of increasing visual acuity during the induction phase of six continuous monthly administrations, followed by a relative drop in visual acuity in between quarterly administrations during the maintenance phase. In addition, on average, relative improvements in visual acuity were noted at the next monthly visit following retreatment at the protocol-mandated quarterly time points. At the latest evaluated time point in this subgroup of patients, visual acuity had, on average, returned to the approximate level of visual acuity observed at month 6 following the induction phase.

        The graph below sets forth the mean and median gain in ETDRS letters from baseline at each month of the study through month 13 for these 16 patients. Both the mean and the median are presented as one patient in this subgroup of 16 patients experienced a significant amount of relative visual loss.

Mean and Median Change in Visual Acuity (VA) from Baseline through Month 13

        We also presented visual acuity data for the six patients that reached the month 14 time point as of the pre-specified data collection date. The graph below sets forth for these six patients the change in visual acuity, measured in ETDRS letters, from month 13 to month 14.

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Change in Visual Acuity (VA) from Month 13 at Month 14

        In addition, we also presented a similar visual acuity graph, displaying both mean and median change in visual acuity from baseline, for this subgroup of 16 patients at the 14 month time point based on the last observation carried forward, or LOCF, method to impute missing values. The LOCF method is a method to account for missing values at specific time points for a specific patient by carrying forward the value observed at the last time point for which data is available for that specific patient. In the case of this trial, data were missing for the month 14 time point for the ten patients who had not yet reached that time point. The graph below sets forth for these 16 patients both the mean and median gain in ETDRS letters from baseline at each month of the study through month 14 using the LOCF method.

Mean and Median Change in Visual Acuity (VA) from Baseline through Month 14
LOCF Method

        The analysis of the interim data presented from this open-label trial was not pre-specified in the trial protocol. The foregoing data consisted of data for only 16 of 101 patients enrolled, was preliminary in nature and, as with any interim data collected from a clinical trial, may be inconsistent with, or not representative of the final data outcome from the trial. Given the small sample size and

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lack of control group, we believe inferences with respect to efficacy or safety findings at the time points for which data were presented are challenging to assess and may not be reliable. However, relative to published data from other clinical trials regarding visual outcomes for wet AMD patients receiving discontinuous administration of anti-VEGF monotherapy during the maintenance phase, we believe the data from this trial suggests a potential role for Fovista combination therapy to reduce the treatment burden for wet AMD patients.

Visual Acuity Data for Patients with Baseline 20/40 Vision or Better

        As part of the R&D Investor Day, a key opinion leader also presented real world data outcomes collected from U.S. electronic medical records showing that wet AMD patients who typically receive discontinuous anti-VEGF monotherapy, on average, lose vision at the one year time point. These data are consistent with published data from European studies. In addition to the data for the 16-patient subgroup described above, at R&D Investor Day, we presented additional data from our OPH1005 Anti-Fibrosis Study for a subgroup of 20 patients with baseline vision of 20/40 or better. These patients were followed prospectively based on visual acuity criteria. Seventeen of these patients reached the month 6 time point at the time of data collection. These patients experienced a mean improvement in visual acuity of 4.5 ETDRS letters, equivalent to 20/32 vision, at the month 6 time point. In addition, seven of these patients reached the month 11 time point and experienced an average additional gain of 0.43 ETDRS letters as compared to the month 6 time point. This data is summarized in the following graph.

Mean Change in Visual Acuity (VA) from Baseline
for Patients with Baseline 20/40 Vision or Better

        We believe Fovista combination therapy may result in better outcomes in this subgroup of patients with 20/40 or better vision compared to what the real world outcome studies suggest. However, given the small sample size and lack of control group, we believe inferences with respect to efficacy or safety findings at the time points for which data were presented are challenging to assess and may not be reliable. Therefore, a confirmatory, well-controlled clinical trial with a larger sample size may be warranted before drawing any conclusions regarding the role of Fovista combination therapy for these patients.

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OPH1006 Fovista Treatment Burden Trial in Wet AMD.Reduction Study.

        We believe that Fovista combination therapy may allow for less frequent dosing and patient visits compared to anti-VEGF monotherapy, thus potentially reducing patient treatment burden. In retrospective analyses of our completed Phase 2b clinical trial of Fovista, we observed that treatment with Fovista combination therapy, on average, results in a larger reduction in the sizegreater degree of resolution of the choroidal neovascular complex or decreased size of the neovascular tissue in patients with both small and large lesions in wet AMD patients, compared to treatment with anti-VEGF monotherapy. OCT and fluorescein angiography imaging modalities were used to assess these anatomic measures. We believe that the reduction in the size of the choroidal neovascular complex impliescould lead to a reduction in the number of cellular elements releasing angiogenic mediators, including VEGF andand/or PDGF, which may translate into a reduced need for intravitreal injections to achieve similar levels of inhibition of these mediators. During the fourth quarter of 2014, we initiated an open-label Phase 2a clinical trial of 1.5 mg of Fovista administered in combination with anti-VEGF drugs (Lucentis, Eylea or Avastin), to investigate the optimized regimen of Fovista administration in anti-VEGF drugs. In addition, this trial may also allow us to evaluate the potential of Fovista to reduce the treatment burden for wet AMD patients. We have recentlycompleted enrollment in this trial in October 2015 with a total of 64 patients enrolled. Patients are followed over an 18-month period.

OPH1007 Fovista in Combination with Avastin Discontinuous Regimen Study

        During the fourth quarter of 2015, we initiated a randomized, double-masked, controlled Phase 2b clinical trial to evaluate the safety and efficacy of a discontinuous, bimonthly regimen of 1.5 mg of Fovista administered in combination with Avastin during the maintenance phase of wet AMD treatment, compared to a discontinuous, bimonthly regimen of Avastin monotherapy. We believe that off-label use of Avastin for the treatment of wet AMD has not been extensively studied in randomized, controlled clinical trials, similar to those that have been conducted for approved anti-VEGF drugs. Our initial sites for this study are in the Netherlands, where we believe Avastin administered through a discontinuous, bimonthly regimen is the current standard of care for the treatment of wet AMD. We expect to expand the trial to include additional sites and/or countries.

OPH1008 Fovista Imaging Study

        During the fourth quarter of 2015, we initiated an open-label Phase 2a clinical trial to assess whetherinvestigate the userole of multi-modal imaging in assessing anatomic responses to various wet AMD treatment regimens of Fovista (1.5 mg) administered in combination with anti-VEGF drugs can reduce the frequency of intravitreal injections required to effectively treat wet AMD. We expect to receive initial results from this Phase 2 clinical(Lucentis, Eylea or Avastin). This trial in late 2015 or early 2016

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ability to read one or more letters on a standardized chart of vision testing. Third-party preclinical studies suggest that pericyte coverage of abnormally proliferating new blood vessels may be a potential cause of anti-VEGF resistance. We therefore believe that Fovista administered in combination with an anti-VEGF drug may result in improved visual outcomes in these anti-VEGF resistant patients. We plan to initiate in 2015 an initial Phase 2 clinical trial withwill include both wet AMD patients who arehave previously received anti-VEGF resistanttreatment, whom we refer to investigate whether Fovista administered in combination with an anti-VEGF drug may prove beneficial.

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Anti-Fibrosis Trial in Wet AMD.  Data from two large, recently published third-party clinical studies show that 40% to 45% ofas treatment experienced, as well as wet AMD patients develop subretinal fibrosis after two years ofwho have not previously received anti-VEGF treatment, with an anti-VEGF drug. Wet AMD patients who develop subretinal fibrosis have worse visual outcomes, on average, comparedwhom we refer to patients who do not develop subretinal fibrosis. In preclinical animal models of subretinal fibrosis, Fovista mediated inhibition of PDGF reduced the amount of scar tissue formation. We believe that our initial retrospective assessment of retinal images of patients who experienced vision loss followingas treatment with either 1.5 mg of Fovista in combination with Lucentis or Lucentis monotherapy in our completed Phase 2b Fovista trial is consistent with our hypothesis that Fovista mediated PDGF inhibition may be associated with inhibition of retinal scar formation. This belief is further supported by a retrospective analysis of the images conducted by an independent reading center. In August 2014, we initiated a Phase 2a open label clinical trial in which we plan to enroll approximately 100 patients with wet AMD patients to investigate the effect of the administration of Fovista in potentially reducing the formation of subretinal fibrosis, independent of the specific anti-VEGF regimen administered to patients. We expect to receive initial data from this Phase 2 clinical trial in late 2015.naïve.

Investigator Sponsored Trials

        In addition, we have supplied Fovista for use in small, investigator sponsored, pilot clinical trials designed to assess the safety and efficacy of differing treatment regimens of Fovista administered in combination with each anti-VEGF drug.drugs. The trials seek to evaluate differing treatment regimens, including variations to the order in which Fovista and the anti-VEGF drug are administered and to the time between intravitreal injections.administered.

        Initial data from one of these investigator sponsored trials, an ongoing anti-fibrosis trial concerning a patient subgroupbeing conducted at the Retinal Consultants of Arizona, has been presented at various medical meetings beginning in February 2015. In this 24-month study of 30 patients, 27 of whom are considered to be monotherapy anti-VEGF treatment resistant, was recently presented. This investigator sponsored trial is being conducted by Dr. Pravin Dugel and Retinal Consultants of Arizona. It is an uncontrolled study with a small sample size. Initial findings from this study were presented at the Bascom-Palmer Eye Institute Angiogenesis, Exudation, and Degeneration Meeting on February 7, 2015 by Dr. Dugel. Dr. Dugel reported that 30 patients are enrolled in an ongoing open label 24 month anti-fibrosis study. Twenty-seven of these 30 patients were considered to be monotherapy anti-VEGF treatment resistant, patients and were treated for three months withreceive administration of 1.5 mg of Fovista (1.5mg) administered in combination with either Avastin or Eylea, or Avastin. Anti-VEGF treatment resistant was defined in this study in the same manner as in most previously conducted switch studies as having persistent and/or recurrent exudation, or leakage,either with similar demographics. Switch studies are clinical studies in which patients treatedpre-treatment with one or more anti-VEGF agents are switched to another previously unused anti-VEGF agent if they were deemed non-responsive. In this study, patients had received an average of 25 anti-VEGF injections prior to receiving Fovista (1.5mg) combination therapy. Dr. Dugel reported that after three doses1.5 mg of Fovista (1.5mg)two days in advance of combination therapy patients gained, on average, 7.07 letters (n=27) based on10) or combination therapy without pretreatment (n=17). In February 2015 data were