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+Commercial Code.
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+Our website address is www.gensight-biologics.com
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+The information on the website does not form part of this Universal Registration Document unless that information is incorporated by reference into it.
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+44 – GENSIGHT BIOLOGICS – 2023 Universal Registration Document
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+BUSINESS OVERVIEW
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+5
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+5
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+BUSINESS OVERVIEW
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+5.1 OVERVIEW
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+lead product candidate, LUMEVOQ®,
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+We are an innovative clinical-stage gene therapy company with a focus on discovering, developing and commercializing novel therapies for severe retinal neurodegenerative diseases. We are developing a pipeline of proprietary product candidates to provide patients with long-lasting potential cures for severe inherited retinal diseases with high unmet medical need. Our current product candidates are designed to be administered in a single treatment to each eye by intravitreal, or IVT, injection. We are leveraging our expertise in ophthalmology, gene therapy, drug and medical device development to restore vision by combining a gene therapy-based approach with our proprietary technology platforms of mitochondrial targeting sequence, or MTS, and optogenetics. We believe our technology platforms have broad applicability both within and outside of ophthalmology as well as central nervous system, or CNS, disorders. Our is a recombinant AAV2-based gene therapy for the treatment of Leber Hereditary Optic Neuropathy, or LHON. We have recently withdrawn our application for LUMEVOQ® in Europe and intend to discuss the best possible path forward with the EMA, aiming at submitting a new application addressing remaining objections as soon as possible, in Europe and other countries. It is currently in Phase III clinical trials in the United States and has not been registered in any country at this stage. We reported 48-week top- line data from our Phase III clinical trials REVERSE (37 patients) in April 2018 and RESCUE (39 patients) in February 2019. Further follow-up demonstrated sustained efficacy and safety 96 weeks after a single injection in one eye, and clear superiority to published natural history data. Longer term follow-up for both trials, conducted in the trial RESTORE, has confirmed efficacy and safety up to 5 years post-injection. A third Phase III trial with LUMEVOQ®, REFLECT (98 patients), which was designed under a Special Protocol Assessment with the FDA, reported 78-week top-line data in the June 2021 demonstrating the safety of bilateral injections of LUMEVOQ® and a trend towards greater efficacy for bilateral versus unilateral injections. The follow-up at Year 2 of REFLECT, issued in December 2021, showed that the vision improvement was maintained. The indirect comparison of treated eyes in all the Phase III trials against a sample of untreated eyes (natural history), which was published in the December 2022 issue of Ophthalmology Therapy, demonstrated that the visual improvement following treatment is significantly superior to the trend expected without treatment. In March 2023, GenSight reported topline efficacy and safety results at 3 years post-treatment administration in the REFLECT Phase III clinical trial and announced that LUMEVOQ® efficacy and safety data from early access programs for ND4-LHON patients confirmed the efficacy and safety profile of LUMEVOQ® in a real-world setting. Our second most advanced product candidate, GS030, for the treatment of Retinitis Pigmentosa, or RP, is currently in an open-label, dose escalation
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+46 – GENSIGHT BIOLOGICS – 2023 Universal Registration Document
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+Phase I/II trial. The first subject was treated in October 2018, and after three cohorts treated with different doses, the Data Safety Monitoring Board (DSMB) recommended the use of the highest dose in the extension cohort. Two patient case studies have shown that patients who had long been blinded by RP recovered the ability to detect, locate and count objects in high-contrast settings. In February 2023, we announced favorable safety data and encouraging efficacy signals at 1 year post-gene therapy administration for the PIONEER Phase I/II clinical trial evaluating GS030 for the treatment of retinitis pigmentosa (RP) in 9 patients, with a follow-up up to 4 years (n = 1).
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+In April 2023, based on interactions with the EMA’s CAT indicating that the data provided thus far would not be sufficient to support a positive opinion of the marketing authorization of LUMEVOQ® by EMA, we decided to withdraw our application before the CAT issued a final opinion. This decision enabled us to discuss the best possible path forward for LUMEVOQ® with the EMA, aiming at submitting a new application addressing remaining objections as soon as possible, in Europe and other countries.
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+Given our decision to withdraw the EMA application, there was no immediate need for a PPQ campaign until a new MAA is submitted. Consequently, we decided to manufacture 3 Good Manufacturing Practice (“GMP”) batches as planned, using the commercial process but outside the context of a validation campaign, to generate more batch data for a future MAA filing and provide more experience with the manufacturing process to operating teams, while fulfilling the immediate requirement of supplying product for a possible new clinical trial and for the resumption of an early access program for patients in Q3 2024. On September 18, 2023, we announced the successful manufacture of the drug substance (DS) in the first LUMEVOQ® GMP batch. In September 2023, a minor delay in the production of the second GMP batch led to a postponement of the date on which results from this batch were expected. In November 2023, we announced the successful manufacture of the second LUMEVOQ® GMP drug substance batch.
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+On September 27, 2023, we received from the EMA the results of a scientific advice meeting regarding the design of a new Phase III trial for LUMEVOQ® named RECOVER. RECOVER is planned to be a randomized controlled trial with a two-arm design (i) an untreated control arm and (ii) a treatment arm, in which subjects will be given bilateral intravitreal injections of LUMEVOQ® (also known as GS010). The proposed study design also contains an open-label extension in which subjects in the untreated arm will be eligible to receive LUMEVOQ® bilateral injection if the primary endpoint is met. The RECOVER study is designed to address the questions raised by the EMA’s CAT when it reviewed the MAA filed in 2020.
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+5
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+BUSINESS OVERVIEW
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+The proposed design for the Phase III trial RECOVER has also been shared with the EMA, the MHRA and the FDA. We are currently refining the RECOVER study design to incorporate feedback from the regulatory agencies prior to the launch of the study, in order to both fulfil regulatory requirements and then support both US and EU regulatory submissions for registration. Additional consultations with the regulatory agencies may be necessary to finalize the study design. RECOVER will be able to begin recruiting once the design is finalized, the product is released for human use and approval is obtained from local competent authorities and ethics committees. We are prioritizing the allocation of the next available LUMEVOQ® vials to supply of the AAP/AAC program and considering the need of refining the RECOVER study design, the inclusion of the first patient in the trial is expected in H2 2025. The duration of the trial will depend on its final design currently being determined.
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+LUMEVOQ® for the Treatment of LHON
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+LHON is an orphan mitochondrial disease that causes the sudden and dramatic loss of vision, leading to bilateral blindness in less than a year, most frequently in teens and young adults and for which we believe there is currently no effective treatment option. LHON is estimated to have a prevalence of between one in 31,000 and one in 40,000 in the United States and the European Union, respectively. LHON originates mainly from mutations in three NADH dehydrogenase mitochondrial genes: ND1, ND4 and ND6. NADH dehydrogenase is an enzyme that acts on NADH and is the key enzyme in cellular and mitochondrial metabolism, the complex that supplies energy to cells that promote vision. ND4 and ND1 mutations account for approximately 70% and 15% of the LHON populations, respectively.
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+Our lead product candidate, LUMEVOQ®, was developed to leverage our MTS technology platform and is designed to treat LHON by restoring the function of NADH dehydrogenase that had been impaired by a mutation in the ND4 gene. Our MTS technology platform facilitates efficient expression of a mitochondrial gene by active delivery of messenger ribonucleic acid, or mRNA, to polysomes located at the mitochondrial surface. This enables the synthesis, translocation, and internalization of the missing mitochondrial protein into the matrix of the mitochondrion. We believe that our MTS technology is the only existing technology that permits missing mitochondrial proteins to be actively shuttled into the mitochondrion, enabling the restoration of mitochondrial function necessary to effectively treat LHON.
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+LUMEVOQ® received orphan drug designation for the treatment of LHON in the United States and the European Union. We conducted a Phase I/II trial for LUMEVOQ® in France in 15 subjects with long-standing vision loss from LHON with the ND4 gene mutation. This trial established the safety of the gene therapy and selected the therapeutic dose used in the three
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+As the MHRA informed us that the existing clinical data for LUMEVOQ® are sufficient and acceptable and therefore do not require an additional trial to submit a MAA in the UK, we plan to further discuss with the MHRA to clarify the quickest path towards a regulatory submission. If our clinical trials or applications are successful and we obtain regulatory approval for drug candidates that we develop, we will incur commercialization expenses before these drug candidates are marketed and sold.
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+In addition, we met the MHRA in November 2023 to discuss a possible regulatory pathway for LUMEVOQ® in the United Kingdom; the agency issued the minutes in December 2023 and indicated that the clinical evidence from the three Phase III trials REVERSE, RESCUE and REFLECT could be the basis for a marketing authorization application.
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+Phase III clinical trials that evaluated the efficacy and safety of the gene therapy in a larger sample of subjects. RESCUE enrolled LHON patients with an onset of vision loss of less than six months in duration, while REVERSE enrolled patients with an onset of vision loss between 6 and 12 months. REFLECT enrolled patients with an onset of vision loss of up to 12 months.
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+We reported top-line data from our first Phase III clinical trial REVERSE in April 2018, highlighting the favorable safety and tolerability profile of LUMEVOQ®, and showing a clinically meaningful improvement of visual acuity of +11 ETDRS letters in treated eyes at 48 weeks as compared to baseline in all 37 patients. A similar improvement was reported in untreated eyes and caused the trial not to meet its primary endpoint, defined as a difference of improvement in visual acuity in LUMEVOQ®-treated eyes compared to sham-treated eyes at 48 weeks. We reported additional results at 72 and 96 weeks in October 2018 and May 2019, showing a clinically meaningful improvement of visual acuity from baseline of +15 ETDRS letters in treated eyes, and of +13 ETDRS letters in untreated eyes at Week 96, sustained from Week 72. The trial also demonstrated a statistically significant relative preservation of the structure of the retina in treated eyes, specifically the volume of the retinal ganglion cells and the thickness of the nerve layers, while untreated eyes continued to deteriorate. We also reported increasing improvements in quality of life at both 48, 72 and 96 weeks. In addition, we also observed that 68% of REVERSE subjects achieved a Clinically Relevant Recovery (CRR) from baseline compared to 15% in a natural history study conducted by Santhera(1). We reported similar top-line results from our second Phase III trial RESCUE in February 2019, showing visual acuity in LUMEVOQ® - treated eyes and sham-treated eyes evolving with similar trajectories, worsening to a low point, or nadir, before beginning to improve by Week 48. We reported additional results at 72
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+fiber
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+GENSIGHT BIOLOGICS – 2023 Universal Registration Document – 47
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+5
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+BUSINESS OVERVIEW
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+and 96 weeks in April and September 2019, showing sustained recovery from nadir. By Week 96, LUMEVOQ®-treated eyes improved by +26 ETDRS letters from nadir, sustained from improvement of Week 72, compared to the Week 48 +13 ETDRS letters. This recovery at Week 96 could not yet completely offset deterioration from baseline through the acute phase: LUMEVOQ® -treated eyes were still below baseline by 9 ETDRS letters, compared to ‑19 ETDRS letters ‑at Week 48. The strength of the bilateral recovery shifted the mean BCVA in both sets of eyes from being off-chart at Week 48 to on-chart at Weeks 72 and 96. In addition, 63% of LUMEVOQ®-treated eyes improved by a clinically meaningful difference of +15 ETDRS letters from nadir. Similarly, 71% of subjects treated with LUMEVOQ® improved by a clinically meaningful difference of +10 ETDRS letters from nadir. We also reported that 63% of REVERSE subjects achieved a CRR from nadir compared to 28% in a natural history study conducted by Santhera(1).
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+The RESCUE and REVERSE trials demonstrated that LUMEVOQ® was well-tolerated, with no unexpected treatment- emergent adverse events, no serious adverse events related to the treatment or procedure, and no suspected unexpected serious adverse reactions. Results of REVERSE and RESCUE trials were published in Science Translational Medicine (December 2020) and in Ophthalmology (January 2021), respectively.
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+To further investigate the bilateral effect observed in both REVERSE and RESCUE trials, we conducted a non-clinical study with non-human primates. In this study, we reported evidence that LUMEVOQ® vector DNA reached the

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+the (BLA); and
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+• FDA review and approval, or licensure, of the BLA.
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+Where a gene therapy study is conducted at, or sponsored by, institutions receiving NIH funding for recombinant DNA research, prior to the submission of an IND application to the FDA, a protocol and related documentation is submitted to and the study is registered with the NIH Office of Biotechnology Activities, or OBA, pursuant to the NIH Guidelines for Research Involving Recombinant DNA Molecules, or NIH Guidelines. Compliance with the NIH Guidelines is mandatory for investigators at institutions receiving NIH funds for research involving recombinant DNA; however, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them. Institutions that receive NIH funding also are potentially subject to review by the NIH Office of Biotechnology Activities’ RAC; the RAC will only publicly review clinical trials if the trials cannot be evaluated by standard oversight bodies and pose unusual risks.
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+The clinical trial sponsor must submit the results of the information, preclinical tests, together with manufacturing analytical data, any available clinical data or literature and a
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+proposed clinical protocol, to the FDA as part of the IND. Some is preclinical testing may continue even after the IND submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA places the clinical trial on a clinical hold within that 30-day time period. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. The FDA may impose clinical holds on a biological product candidate at any time before or during clinical trials due to safety concerns or non-compliance. If the FDA imposes a clinical hold, studies may not recommence without FDA authorization and then only under terms authorized by the FDA.
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+Clinical trials involve the administration of the biological product candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the study sponsor’s control. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety, including stopping rules that assure a clinical trial will be stopped if certain adverse events should occur. Each protocol and amendments to the protocol must be submitted to the FDA as part of the IND. Clinical trials must be conducted and monitored in accordance with the FDA’s regulations comprising the GCP requirements, including the requirement that all research subjects provide informed consent. Further, each clinical trial must be reviewed and approved by an Institutional Review Board (IRB) at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with protecting the welfare and rights of study participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. Clinical trials also must be reviewed by an institutional biosafety committee, or IBC, a local institutional committee that reviews and oversees basic and clinical research conducted at that institution. The IBC assesses the safety of the research and identifies any potential risk to public health or the environment.
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+In some cases, the FDA may condition approval of a BLA for a product candidate on the sponsor’s agreement to conduct additional clinical trials after the product’s approval. In other cases, a sponsor may voluntarily conduct additional clinical trials post-approval to gain more information about the product. Post-approval clinical trials, sometimes referred to as Phase IV clinical trials, may be conducted after initial marketing approval. These clinical trials are used to gain additional information from
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+GENSIGHT BIOLOGICS – 2023 Universal Registration Document – 145
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+9
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+REGULATORY ENVIRONMENT
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+the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up. The FDA recommends that sponsors observe subjects for potential gene therapy-related delayed adverse events for a 15-year period, including a minimum of five years of annual examinations followed by ten years of annual queries, either in person or by questionnaire, of study subjects.
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+listed
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+in the protocol or
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+During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA. Written IND safety reports must be promptly submitted to the FDA, the NIH and the investigators for serious and unexpected adverse events, any findings from other studies, tests in laboratory animals or in vitro testing that suggest a significant risk for human subjects, or any clinically important increase in the rate of a serious suspected adverse reaction over that investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting. The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information. Phase I, Phase II and Phase III clinical trials may not be completed successfully within any specified period, if at all. The FDA or the sponsor or its data safety monitoring board may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the biological product has been associated with unexpected serious harm to patients.
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+U.S. Biological Product Review and Approval Processes
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+After the completion of clinical trials of a biological product, FDA approval of a BLA must be obtained before commercial marketing of the biological product. The BLA must include results of product development, laboratory and animal studies, human studies, information on the manufacture and composition of the product, proposed labeling and other relevant information. In addition, under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA must contain data to assess the safety and effectiveness of the biological product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may grant deferrals for submission of data or full or partial waivers. Unless otherwise required by regulation, PREA does not apply to any biological product for an
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+146 – GENSIGHT BIOLOGICS – 2023 Universal Registration Document
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+Sponsors of clinical trials of investigational products are required to register on clinicaltrials.gov, a National Institute of Health website registry database, and disclose certain clinical trial information. Information related to the product, patient population, phase of investigation, study sites and investigators, and other aspects of the clinical trial is then made public as part of the registration. Sponsors are also obligated to discuss the results of their clinical trials after completion. Disclosure of the results of these trials can be delayed until the new product or new indication being studied has been approved. Competitors may use this publicly-available information to gain knowledge regarding the progress of development programs.
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+The NIH and the FDA have a publicly accessible database, the Genetic Modification Clinical Research Information System which includes information on gene transfer studies and serves as an electronic tool to facilitate the reporting and analysis of adverse events on these studies.
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+Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the physical characteristics of the biological product as well as finalize a process for manufacturing the product in commercial quantities in accordance with GMP requirements. To help reduce the risk of the introduction of adventitious agents (unwanted viruses or bacteria), with use of biological products, the PHS Act emphasizes the importance of manufacturing control for products whose attributes cannot be precisely defined. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the sponsor must develop methods for testing the identity, strength, quality, potency and purity of the final biological product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the biological product candidate does not undergo unacceptable deterioration over its shelf life.
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+indication for which orphan designation has been granted. The testing and approval processes require substantial time and effort and there can be no assurance that the FDA will accept the BLA for filing and, even if filed, that any approval will be granted on a timely basis, if at all.
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+Under the Prescription Drug User Fee Act, or PDUFA, as amended, each BLA must be accompanied by a user fee. The FDA adjusts the PDUFA user fees on an annual basis. PDUFA also imposes an annual program fee on prescription biologics. in certain Fee waivers or reductions are available circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on BLAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.
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+9
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+REGULATORY ENVIRONMENT
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+Within 60 days following submission of the application, the FDA reviews a BLA submitted to determine if it is substantially complete before the agency accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA must be resubmitted with the additional information. The resubmitted application also is subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the BLA. The FDA reviews the BLA to determine, among other things, whether the proposed product is safe and potent, or effective, for its intended use, and has an acceptable purity profile, and whether the product is being manufactured in accordance with GMP to assure and preserve the product’s identity, safety, strength, quality, potency and purity. The FDA may refer applications for novel biological products or biological products that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an Advisory Committee, but it considers such recommendations carefully when making decisions. During the biological product approval process, the FDA also will determine whether a Risk Evaluation and Mitigation Strategies (REMS) is necessary to assure the safe use of the biological product. If the FDA concludes REMS is needed, the sponsor of the BLA must submit proposed REMS; the FDA will not approve the BLA without REMS, if required.
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+facilities are
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+Before approving a BLA, the FDA will inspect the facilities at which the product is manufactured. The FDA will not approve it determines that the manufacturing the product unless processes and in compliance with GMP requirements and adequate to assure consistent production of the product within required specifications. For a gene therapy product, the FDA also will not approve the product if the manufacturer is not in compliance with the Good Tissue Practices (GTPs). The GTPs are FDA regulations that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissues, and cellular and tissue based products, or HCT/Ps, which are human cells or tissue intended for implantation, transplant, infusion, or transfer into a human recipient. The primary intent of the GTP requirements is to ensure that cell and tissue based products are manufactured in a manner designed to prevent the introduction, transmission and spread of communicable disease. FDA regulations also require tissue establishments to register and list their HCT/Ps with the FDA and, when applicable, to evaluate donors through screening and testing. Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure that the clinical trials were conducted in compliance with IND study requirements and GCP requirements. To assure cGMP,
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+GTP and GCP compliance, an applicant must incur significant expenditure of time, money and effort in the areas of training, record keeping, production and quality control.
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+the submission of relevant data and Notwithstanding information, the FDA may ultimately decide that the BLA does its regulatory criteria for approval and deny not satisfy approval. Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data. If the agency decides not to approve the BLA in its present form, the FDA will issue a complete response letter that usually describes all of the specific deficiencies in the BLA identified by the FDA. The deficiencies identified may be minor, for example, requiring labeling changes, or major, for example, requiring additional clinical trials.