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1
1. PERSON RESPONSIBLE, THIRD PARTY INFORMATION, EXPERTS’ REPORTS AND COMPETENT AUTHORITY APPROVAL
1.1 Identity of the person responsible
1.2 Declaration of the person responsible
1.3 Experts’ reports
1.4 Third party information
1.5 Competent authority approval
2
2. STATUTORY AUDITORS
2.1 Statutory auditors
2.2 Change in Statutory auditors
3
3. RISK FACTORS
3.1 Financial risks
3.2 Risks related to the discovery and development of and obtaining regulatory approval for our product candidates
3.3 Risks related to manufacturing and commercialization of our product candidates
3.4 Risks related to our business operations
3.5 Legal risks and risks related to our intellectual property
3.6 Insurance and risk management
3.7 Internal control and risk management procedures
4
4. INFORMATION ABOUT THE ISSUER
4.1 Legal and commercial name
4.2 Place of registration, registration number and legal entity identifier (“LEI”)
4.3 Date of incorporation, length of life of the issuer
4.4 Domicile, legal form, legislation, country of incorporation, address, telephone number and website
5
5. BUSINESS OVERVIEW
5.1 Overview
5.2 Our Product Development Pipeline
5.3 Important events in the development of the Company
5.4 Strategy and objectives
5.5 Research and development, patents and licenses
5.6 Competition
5.7 Investments
5.8 Manufacturing
5.9 Sales and marketing
6
6. ORGANIZATIONAL STRUCTURE
7
7. OPERATING AND FINANCIAL REVIEW
7.1 Overview
7.2 Financial Operations Overview
7.3 Results of operations
8
8. CAPITAL RESOURCES
8.1 Overview
8.2 Analysis of Cash Flow
8.3 Funding sources
8.4 Principal uses of cash
8.5 Information regarding the anticipated sources of funds needed
9
9. REGULATORY ENVIRONMENT
10
10. TREND INFORMATION
10.1 Most significant recent trends since the end of the last financial year
10.2 Information on any known trends, uncertainties, demands, commitments or events that are reasonably likely to have a material effect on the company’s prospects
11
11. PROFIT FORECAST OR ESTIMATES
12
12. ADMINISTRATIVE, MANAGEMENT AND SUPERVISORY BODIES AND SENIOR MANAGEMENT
12.1 Composition of management and supervisory bodies
12.2 Conflicts of interest
13
13. COMPENSATION AND BENEFITS
13.1 Compensation and benefits of Senior Executives and Directors
13.2 Directors’ Compensation
13.3 Share Warrants, Share Warrants for founders, stock options and free Shares Granted to Senior Executives and Directors
13.4 History of Allocation of Share Warrants, Share Warrants for Founders and Stock Options
13.5 Share Warrants, Share Warrants for Founders or Stock Options of the Company granted to the Company’s top ten employees
13.6 History of Allocation of Free Shares
13.7 Benefits of Senior Executives
13.8 Equity ratio between the level of compensation of the Chairman and Chief Executive Officer and the compensation average and median of the Company’s employees
13.9 Compliance of Total Executive Director Compensation with the Recommendations of Middlenext Code
13.10 Amount of Provisions Made or Recorded by the Company for the Payment of Pensions, Retirement Plans or Other Benefits
14
14. BOARD PRACTICES
14.1 Terms of Office of Members of the Corporate Bodies and Management Bodies
14.2 Information on Service Contracts between Members of the Administrative and Management Bodies and the Company
14.3 Committees of the Board of Directors
14.4 Statement Relating to Corporate Governance
14.5 Operating Principals of the Board of Directors
15
15. EMPLOYEES
15.1 Human Resources Management
15.2 Shareholdings and stock options
15.3 Employee arrangements
16
16. MAJOR SHAREHOLDERS
16.1 Allocation of share capital
16.2 Shareholders’ Voting Rights
16.3 Control structure
16.4 Agreement likely to a change of control
17
17. RELATED PARTY TRANSACTIONS
17.1 Agreements with the Company’s Major Shareholders
17.2 Transactions with Key Management Persons
17.3 Regulated Agreements
17.4 Statutory Auditors’ Special Report on regulated agreements
18
18. FINANCIAL INFORMATION CONCERNING THE GROUP’S ASSETS AND LIABILITIES, FINANCIAL POSITION AND PROFITS AND LOSSES
18.1 Historical Financial Information
18.2 Interim and Other Financial Information
18.3 Auditing of Historical Annual Financial Information
18.4 Proforma Financial Information
18.5 Dividend Policy
18.6 Legal and Arbitration Proceedings
18.7 Significant Change In Financial Position
19
19. ADDITIONAL INFORMATION
19.1 Share Capital
19.2 Constitutive Documents and Bylaws
20
20. MATERIAL CONTRACTS
20.1 Collaboration, Partnership and Related Agreements
20.2 In-License Agreements
20.3 Manufacturing Agreement
20.4 Customer Agreement
21
21. DOCUMENTS AVAILABLE
22
22. GLOSSARY
23
23. ANNEXES

2021

UNIVERSAL REGISTRATION DOCUMENT

GenSight Biologics S.A.
Corporation (société anonyme) with a share capital of €1,158,389.78

Registered Office:
74, rue du Faubourg Saint-Antoine
75012 Paris, France
751 164 757 Paris Trade and Companies Register

2021

UNIVERSAL REGISTRATION DOCUMENT

This Universal Registration Document (URD) was filed on April 29, 2022 with the AMF (the French Financial Markets Regulator), as the competent authority under Regulation (EU) 2017/1129, without prior approval in accordance with Article 9 of the said Regulation. This Universal Registration Document may be used for the purpose of a public offer of securities or the admission of securities to trading on a regulated market if it supplemented by a securities note and, as the case may be, by a summary and all the amendments to the Universal Registration Document. These documents are together approved by the AMF in accordance with Regulation (EU) 2017/1129.

A concordance table is provided in this Universal Registration Document in order to facilitate the retrieval of the information
incorporated by reference and that which are updated or amended.

Copies of this Universal Registration Document are available free of charge from GenSight (74, rue du Faubourg Saint-Antoine 75012 Paris, France) and on its website (https://www.gensight-biologics.com).

CONCORDANCE TABLE

The concordance table below makes it possible to identify in this Universal Registration Document:

•the information which forms the annual financial report (article L.451-1-2 of the French Monetary and Financial Code and article 222-3 of the General Regulation of the AMF); and

•the information which forms the Annual Management report (article L.225-100 et seq. of the French Commercial Code);

•the information which forms the Corporate Governance report.

| Section(s) of the Document
1. CERTIFICATION OF THE PERSON ASSUMING RESPONSIBILITY FOR THE ANNUAL FINANCIAL REPORT | Section 1.2
2. COMPANY’S ANNUAL FINANCIAL STATEMENTS – FRENCH STANDARDS (FRENCH-GAAP) | Section 18.1.3
3. COMPANY’S ANNUAL CONSOLIDATED FINANCIAL STATEMENTS – INTERNATIONAL FINANCIAL REPORTING STANDARDS (IFRS) | Section 18.1.1
4. MANAGEMENT REPORT |
4.1. Information on the Company’s business |
•Presentation of the business (in particular progress achieved and difficulties encountered) and results of the Company | Sections 5, 7, 8 and 18
•Analysis of business development, results and financial position and in particular debt of the Company and the Group | Sections 18.1, 7 and 8
•Outlook of the Company and the Group | Section 10
•Key financial and non-financial indicators of the Company and the Group | Sections 18.1, 7 and 8
•Post-closing events of the Company and the Group | Section 18.1
•Internal control and risk management procedures relating to the preparation and processing of the accounting and financial information of the Company and the Group | Section 3.7
•Information on the use of financial instruments including financial risks and exposure to price, credit, liquidity and cash flow risks of the Company and the Group | Section 3.4
•Principal risks and uncertainties incurred by the Company and the Group | Section 3
•Financial risks linked to the effects of climate change and presentation of the measures taken to reduce them (low carbon strategy) by the Company and the Group | Section 5.7.4
•Information on R&D of the Company and the Group | Sections 5.5 and 18.1
•Subsidiaries | Section 6
4.2. Legal, financial and tax information on the Company |
•Shareholder structure and changes thereto | Section 16
•Names of company controlled participating in indirect control in the Company and the share of the capital they hold | N/A
•Material holdings in companies having their registered office in France | N/A
•Notice of holding more than 10% in the capital of other joint stock companies; transfer of cross-holdings | N/A
•Purchase and disposal by the Company of own shares (share buybacks) | Section 19.1.3
•Employee stock ownership plans | Sections 13.3, 13.4, 18.1, 19.1.4 and 19.1.5.2
•Summary of powers in progress granted by the General Meeting for capital increases | Section 19.1.6
•Reference to possible adjustments: |
—for securities giving access to the capital and stock options in the case of share buybacks; | Section 19.1.3
—for securities giving access to the share capital in the case of corporate actions. | N/A
•Disclosure of dividends distributed for the past three financial periods | Section 18.5
•Amount of expenses and charges not deductible from taxable income | N/A
•Aged trial balance information for trade payables and receivables by maturity date | Section 18.1 and Annex I
•Injunctions or fines for anticompetitive practices | N/A
•Agreements entered into between a director and/or officer or a shareholder holding more than 10% of the voting rights and a subsidiary of the Company (excluding ordinary agreements) | N/A
•Amount of inter-company loans | N/A
•Information on the operation of a SEVESO installation | N/A
4.3. Information concerning officers |
•Summary of dealings in own shares of the Company by executives and related parties | Section 12.1.5
4.4. CSR information of the Company | N/A
5. STATUTORY AUDITORS’ REPORT ON THE COMPANY’S ANNUAL FINANCIAL STATEMENTS – FRENCH STANDARDS (FRENCH-GAAP) | Section 18.1.4
6. STATUTORY AUDITORS’ REPORT ON THE COMPANY’S ANNUAL CONSOLIDATED FINANCIAL STATEMENTS – INTERNATIONAL FINANCIAL REPORTING STANDARDS (IFRS) | Section 18.1.2
•Results of the last five financial years | Annex I
•Aged Trade Payables | Annex I
7. BOARD’S REPORT ON CORPORATE GOVERNANCE |
7.1. Information relating to remuneration |
•Principles and criteria for determining, distributing and allocating fixed, variable and exceptional items making up the total remuneration and benefits of any kind attributable to corporate officers as a result of the mandate | Section 13.1.1
•Compensation and benefits of any kind paid during the period to each executive officer by the Company, companies that it controls and the company controlling it | Section 13.1.2
•Undertakings linked to assuming, terminating or changing functions | N/A
•In the case of stock option grants, reference to information according to which the Board of Directors took the decision to: |
—either prohibit executive managers from exercising their options prior to ceasing to exercise their functions; | N/A
—or to impose lockout obligations to registered holders until they cease to occupy their functions on all or part of the shares resulting from options already exercised (by specifying accordingly the portion that was set). | N/A
7.2. Information concerning the composition, operation and powers of the Board |
•List of offices and responsibilities exercised in any company by each executive officer during the year | Sections 12.1.1 and 12.1.2
•Agreements concluded between a corporate officer or a shareholder holding more than 10% of the voting rights and a subsidiary (excluding current agreements) | Section 17.3
•Summary of powers in progress granted by the General Meeting for capital increases | Section 19.1.6
•Choice made on one of the two methods for exercising executive management in the event of a modification | N/A
•Composition, conditions of preparation and organization of the Board’s work | Section 14
•Diversity Policy | Section 15.1.2
•Limitations of the powers of the general management | Section 12.1.4
•Reference to a corporate governance code or, failing this, justification and indication of the rules adopted in addition to the legal requirements | Section 14.4.1
•Specific terms and conditions of shareholder participation in the general meeting or provisions of the statutes providing for such terms and conditions | Section 19.2.5
•Procedure implemented to review the ordinary agreements with related parties | Section 14.5.5
7.3. Information related to the items having a potential impact in the event of public offerings: |
(i)Capital structure of the Company; | Section 19.1
(ii)Restrictions under the Articles of association on the exercise of voting rights or the transfer of shares disclosed in accordance with Article L.223-11 of the French Commercial Code; | N/A
(iii)Direct or indirect holdings in the share capital of the Company of which it is informed under Articles L.233-7 and L.233-12 of the French Commercial Code; | Section 16.1.2
(iv)Holders of any securities conferring special rights of control and descriptions thereof; | Sections 16.2 – 16.3
(v)Control mechanisms provided for in a potential employee stock ownership system where control rights are not exercised by the latter; | N/A
(vi)Shareholders’ agreements known to the Company and which may result in share transfer and voting rights restrictions; | Section 16.2
(vii)Rules and regulations pertaining to the appointment and replacement of members of the Board of Directors and modifications to the bylaws of the Company; | Section 19.2.2
(viii)Powers of the Board of Directors for the issuance and buybacks of shares; | Sections 19.1.3 and 19.1.6
(ix)Agreements concluded by the Company that may be modified or terminated in the event of a change in control of the Company, except if such disclosure, excluding the case where legally required, materially adversely affect its interest; | N/A
(x)Agreements providing for severance payments for members of the Board of Directors or employees in the event of resignation, dismissal without just and sufficient cause or termination of employment resulting from a public offering. | Section 17.2.3

The report on Corporate Governance and the information required under this report were prepared and elaborated by the Board of Directors pursuant to Article L.225-37 of the French Commercial Code, with the involvement of the Executive and Management Committees.

The report was adopted by the Board of Directors held on April 7, 2022, upon recommendation of the Audit Committee, which met on April 6, 2022 and was sent to the statutory auditors.

NOTE

In this Universal Registration Document, the terms “Company,” “GenSight Biologics,” “we,” “us” and “our” mean GenSight Biologics S.A. All references herein to “$” are to United States dollars, the currency of the United States of America.

This Universal Registration Document describes the Company as of the date hereof.

This Universal Registration Document includes our annual financial statements prepared in accordance with French accounting standards for the fiscal year ended December 31, 2021.

This Universal Registration Document also includes our consolidated financial statements prepared in accordance with International Financial Reporting Standards, or IFRS, as adopted by the European Union for the fiscal year ended December 31, 2021.

The Document may be consulted on the Company’s website (www.gensight-biologics.com).

Unless otherwise indicated the selected financial information and comments on the consolidated financial statements presented in this Universal Registration Document have been prepared on the basis of the consolidated financial statements prepared in accordance with IFRS as adopted by the European Union.

A glossary defining some of the terms used herein is appended to this Universal Registration Document.

Forward-looking Statements

This Universal Registration Document contains statements regarding our prospects and growth strategies. These statements are sometimes identified by the use of the future or conditional tense, or by the use of forward-looking terms such as “considers”, “envisages”, “believes”, “aims”, “expects”, “intends,” “should”, “anticipates”, “estimates”, “thinks”, “wishes” and “might”, or, if applicable, the negative form of such terms and similar expressions or similar terminology. Such information is not historical in nature and should not be interpreted as a guarantee of future performance. Such information is based on data, assumptions, and estimates that we consider reasonable. Such information is subject to change or modification based on uncertainties in the economic, financial, competitive or regulatory environments. This information is contained in several sections of this Universal Registration Document and includes statements relating to our intentions, estimates and targets with respect to our markets, strategies, growth, results of operations, financial situation and liquidity. Our forward-looking statements speak only as of the date of this Universal Registration Document. Absent any applicable legal or regulatory requirements, we expressly disclaim any obligation to release any updates to any forward-looking statements contained in this Universal Registration Document to reflect any change in our expectations or any change in events, conditions or circumstances, on which any forward-looking statement contained in this Universal Registration Document is based. We operate in a competitive and rapidly evolving environment; it is therefore unable to anticipate all risks, uncertainties or other factors that may affect our business, their potential impact on our business or the extent to which the occurrence of a risk or combination of risks could have significantly different results from those set out in any forward-looking statements, it being noted that such forward-looking statements do not constitute a guarantee of actual results.

Information on the Market and Competitive Environment

This Universal Registration Document contains, in particular in Section 5, “Business Overview”, information relating to our markets and to our competitive position. Unless otherwise indicated, the information contained in this Universal Registration Document related to market shares and the size of relevant markets are our estimates and are provided for illustrative purposes only. We believe that the information contained herein in relation to our markets and competitive position is reliable, but the information has not been verified by an independent expert, and we cannot guarantee that a third-party using different methods to collect, analyze or compute market data would arrive at the same results.

Risk Factors

Investors should carefully consider the risk factors in Section 3, “Risk Factors”. The occurrence of all or any of these risks could have an adverse effect on our business, reputation, results of operation, financial condition or prospects.

TABLE OF CONTENT

1

PERSON RESPONSIBLE, THIRD PARTY INFORMATION, EXPERTS’ REPORTS AND COMPETENT AUTHORITY APPROVAL

1.1Identity of the person responsible

Bernard Gilly, Chief Executive Officer of GenSight Biologics S.A. is responsible for the information contained in this Universal Registration Document.

1.2Declaration of the person responsible

I hereby declare that, after having taken all reasonable care to that purpose, to the best of my knowledge, the information contained in this Universal Registration Document is in accordance with the facts and contains no omission likely to affect its import.

I hereby declare that, to the best of my knowledge, the financial statements have been prepared in accordance with the applicable accounting standards and present a fair view of the assets, liabilities, financial position and results of the Company and all the other companies included in the scope of consolidation, and that the Annual Management Report for which a table of cross-references is presented in this Universal Registration Document, provides a fair presentation of the business developments, results and financial position of the Company and all the other companies included in the scope of consolidation, as well as a description of the main risks and contingencies to which they might be exposed.

April 29, 2022

Bernard Gilly, Chief Executive Officer of GenSight Biologics S.A.

1.3 Experts’ reports

N/A

1.4 Third party information

N/A

1.5 Competent authority approval

N/A

2

STATUTORY AUDITORS

2.1 Statutory auditors

Deloitte & Associés

Represented by Stéphane Lemanissier

Tour Majunga, 6 place de la Pyramide, 92908 Paris-La Défense Cedex

Deloitte & Associés is a member of the Compagnie Régionale des Commissaires aux Comptes de Versailles (the Regional Association of Auditors of Versailles).

Becouze

Represented by Fabien Brovedani

34, rue de Liège – 75008 Paris, France

Becouze is a member of the Compagnie Régionale des Commissaires aux Comptes d’Angers (the Regional Association of Auditors of Angers).

Deloitte & Associés’s initial appointment as statutory auditor has been expressed in the bylaws of April 17, 2012, for a six-year term, which has been renewed at the general shareholder’s meeting of the Company on June 11, 2019 for a six-year term and Becouze’s appointment as statutory auditor was approved by the general shareholders’ meeting of the Company on May 19, 2016 for a six-year term, which will end at the close of the Shareholders’ Meeting called to approve the financial statements for the fiscal year ending on December 31, 2021.

Guillaume Saby (substitute to Becouze)

1, rue Buffon – 49100 Angers, France

Guillaume Saby is a member of the Compagnie Régionale des Commissaires aux Comptes d’Angers (the Regional Association of Auditors of Angers).

Guillaume Saby was appointed substitute statutory auditor by our general shareholders’ meeting on May 19, 2016 for a six-year term, which will end at the close of the shareholders’ meeting called to approve the financial statements for the fiscal year ending on December 31, 2021.

2.2 Change in Statutory auditors

As of the date of this Universal Registration Document, none of the statutory auditors or substitute statutory auditors have resigned or been revoked.

3

RISK FACTORS

The Company has opted for a presentation of its risk factors by category of risk, with a hierarchization of these risks within each category from riskier to less risky.

Investors should carefully consider all of the information set forth in this Universal Registration Document before making an investment decision, including the risk factors set forth in this Section. Such risks are, as of the date of this Universal Registration Document, the risks that the Company believes, were they to occur, could have a material adverse effect on our business, results of operations, financial condition and prospects.

In order to identify and assess the risks likely to have an adverse impact on its business, prospects, financial position, results (or ability to achieve its objectives) and development, the Company has mapped the risks associated with its business since 2012. This enabled the Company first to identify potential risks and assess their probability of impact and, where possible, to assess their potential impact from a financial, legal and reputation point of view, as well as on the achievement of the Company’s objectives. This then made it possible to identify and evaluate ways to control these risks. Risk mapping is a management tool. It is reviewed twice a year by the Management Committee and the Audit Committee. At the time of the periodic risk review, all risks and mitigation measures are reviewed and reassessed. This tool is also supplemented by a detailed analysis of the causes and impacts in the event of the occurrence of any significant risk and takes into account the actions and control measures implemented by the Company. This methodology should provide an overview of the risk environment affecting the Company and should enable the Company to define, if necessary, the action plan for risk management and the areas of internal control and audit for the coming year.

The risk mapping exercise enabled the Company to summarize the main risks and group them into the categories indicated below. The Company has grouped these risks into five categories, with no hierarchy between them.

The table below summarizes the main risk factors identified by the Company and indicates, for each of them, the criticality level (combination of the probability of their occurrence and their negative impact on the Company) as at the filing date of this Universal Registration Document, taking into account the actions and control measures implemented by the Company as at the filing date of this Universal Registration Document. The probability of occurrence is assessed on three levels (“low”, “moderate” and “high”) and the magnitude of their negative impact is assessed on four levels (“low”, “moderate”, “high” and “critical”). In each of the five categories above, risks have been classified according to this classification, with risks with the highest probability of occurrence and the highest negative impact being placed first.

Ref. | Risk Factors | Criticality level
Probability of Occurrence | Magnitude of Negative Impact
1. | FINANCIAL RISKS |  |
1.1 | Liquidity Risk | High | Critical
1.2 | We have never generated revenue from product sales and have incurred significant operating losses since our inception. We expect to continue to incur significant losses for the foreseeable future and may never achieve profitability. | Moderate | Critical
1.3 | We will need to raise additional capital in the future, which may not be available on acceptable terms, or at all, and failure to obtain this necessary capital when needed may force us to delay, limit or terminate our product development efforts or other operations. | Moderate | Critical
1.4 | We may lose access to research tax credits in the event of regulatory or legislative changes or challenges by tax authorities. | Low | Moderate
1.5 | Our current and future shareholders may experience dilution. | High | Low
1.6 | The realization of the security interests attached to our bond financing could have an adverse impact on our capacity to operate our business. | Low | Moderate
1.7 | Risk related to the foreign investment screening procedure. | Low | Low
2. | RISKS RELATED TO THE DISCOVERY AND DEVELOPMENT OF AND OBTAINING REGULATORY APPROVAL FOR OUR PRODUCT CANDIDATES |  |
2.1 | The regulatory approval process of the FDA, the EMA and other regulatory authorities and the clinical trials that our product candidates will need to undergo, are time-consuming and expensive, the outcomes of which are unpredictable, and for which there is a high risk of failure. | High | Critical
2.2 | Our product candidates are based on novel technologies, including gene therapy, which may implicate ethical, social and legal concerns about genetic testing and genetic research in general, and such novel technologies make it difficult to predict the timing and costs of development of new and unforeseen regulatory requirements and of subsequently obtaining regulatory approval. | Low | High
2.3 | We may encounter substantial delays in our clinical trials, and we cannot guarantee that any clinical trials will be conducted as planned or completed on schedule, if at all. | Moderate | Moderate
2.4 | Our product candidates and the process for administering our product candidates using AAV vectors may cause undesirable side effects or have other properties that could delay or prevent their regulatory approval, limit the commercial potential or result in significant negative consequences following any potential marketing approval. | Moderate | Moderate
2.5 | Even if we complete the necessary clinical trials, we cannot predict when, or if, we will obtain regulatory approval to commercialize a product candidate and the approval may be for a narrower indication than we seek. | Moderate | Moderate
3. | RISKS RELATED TO MANUFACTURING AND COMMERCIALIZATION OF OUR PRODUCT CANDIDATES |  |
3.1 | Gene therapies are novel, complex and difficult to manufacture. We have limited manufacturing experience and could experience production problems that result in delays in our development or commercialization programs. | High | Critical
3.2 | We rely, and expect to continue to rely, on Brammer Bio, Catalent and other third parties to conduct, supervise and monitor manufacturing for our preclinical studies and clinical trials. If these third parties do not meet our deadlines, successfully carry out their contractual duties or otherwise conduct the manufacturing for these studies and trials as required, we may not be able to obtain regulatory approval for or commercialize our product candidates when expected or at all. | High | Critical
3.3 | We rely on third parties to conduct, supervise and monitor our preclinical studies and clinical trials. If these third parties do not meet our deadlines or otherwise conduct the studies and trials as required, our clinical development programs could be delayed or unsuccessful and we may not be able to obtain regulatory approval for or commercialize our product candidates when expected or at all. | Moderate | High
3.4 | Future insurance coverage and reimbursement status of our product candidates is uncertain. | Moderate | High
3.5 | If we are unable to establish sales, marketing and distribution capabilities for our product candidates, whether it be an internal infrastructure or an arrangement with a commercial partner, we may not be successful in commercializing those product candidates if and when they are approved. | Low | Moderate
3.6 | The commercial success of any of our product candidates will depend upon their degree of market acceptance by physicians, patients, third-party payors and others in the medical community. | Low | Moderate
4. | RISKS RELATED TO OUR BUSINESS OPERATIONS |  |
4.1 | Risks related to the impacts of the Covid-19 | High | Moderate
4.2 | Our future success depends on our ability to retain key employees, consultants and advisors and to attract, retain and motivate qualified personnel, and members of our management team may be affected by conflicts of interest to the extent that they serve in management or directorship capacities at our competitors. | Moderate | Moderate
4.3 | We may not be successful in our efforts to identify or discover additional product candidates and may fail to capitalize on programs or product candidates that may be a greater commercial opportunity or for which there is a greater likelihood of success. | Moderate | Moderate
4.4 | We may be subject to product liability lawsuits. | Low | Moderate
5. | LEGAL RISKS AND RISKS RELATED TO OUR INTELLECTUAL PROPERTY |  |
5.1 | We do not own any issued patents and our rights to develop and commercialize our product candidates are subject to the terms and conditions of intellectual property licenses granted to us by others. | Low | Critical
5.2 | We or our licensors may be unable to obtain and maintain adequate patent protection for our product candidates and technology. | Low | Critical
5.3 | We may fail to comply with our obligations under the agreements under which we in-license intellectual property and could thereby lose license rights that are important to our business. | Low | Critical
5.4 | We may not be able to protect our intellectual property rights throughout the world. | Moderate | Moderate
5.5 | Third parties may initiate legal proceedings alleging that we are infringing their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business. | Low | Moderate

3.1Financial risks

3.1.1 LIQUIDITY RISK.

As of the date of the filing of this Universal Registration Document, the Company does not have sufficient working capital to meet its obligations fort at least the next 12 months. Since its incorporation, the Company has funded its activities through several equity financings, grants, conditional advances and Research Tax Credit. Since the end of 2019, the Company started to generate revenue from the sale of LUMEVOQ® in France, since the French National Drug Safety Agency (ANSM) granted a named patient Temporary Authorization for Use (ATU nominative) for LUMEVOQ®.

As mentioned in note 27 Subsequent events of the Consolidated Financial Statements, following a delay in manufacturing validation batches of LUMEVOQ®, GenSight plan to restart the manufacturing of the validation batches at its Cambridge, US, manufacturing facility during Q3 2022. The Company therefore expects a delay in the commercialization of LUMEVOQ®. Considering the cash position as of December 31, 2021 (amounting to €44.3 million), the reimbursement of the 2021 Research Tax Credit contemplated in 2022 for a consideration of €2.4 million and additional cash related to the ATU sales in France granted during Q1 2022, the Company believes it will be able to fund its operations until early first quarter 2023.

In order to meet its obligations beyond this date, the Company will have to find additional funding. Various financing sources are considered among which, the issuance of new debt or equity instruments, in order to complete its working capital needs and to finance its operating expenses. The Company believes it will have the ability to raise additional funds during 2022.

However, no assurance can be given at this time as to whether the Company will be able to achieve these financing objectives, therefore there would be substantial doubt regarding its ability to continue as a going concern. However, beyond 2022, if the Company was not able to raise additional funds, the Company would modify its operating plans, in particular by delaying or limiting the scope of its research and development programs and would drastically reduce its sales and marketing expenses.

3.1.2 WE HAVE NEVER GENERATED REVENUE FROM PRODUCT SALES AND HAVE INCURRED SIGNIFICANT OPERATING LOSSES SINCE OUR INCEPTION. WE EXPECT TO CONTINUE TO INCUR SIGNIFICANT LOSSES FOR THE FORESEEABLE FUTURE AND MAY NEVER ACHIEVE PROFITABILITY.

Since inception, we have devoted substantially all of our efforts to research and development, including preclinical and clinical development of our product candidates, as well as to building our team. We have never generated revenue from product sales, and we have incurred operating losses since inception. We incurred net losses of €34.0 million and €28.6 million for the fiscal years ended December 31, 2020 and 2021, respectively, and these losses have adversely impacted, and will continue to adversely impact, our equity attributable to shareholders and net assets. We anticipate that our operating losses will continue for at least the coming years as we continue with our research and development activities and until we generate substantial revenues from approved product candidates. As of December 31, 2021, we had an accumulated fiscal deficit of approximately €199 million.

Our capacity to generate revenues from product sales and to achieve profitability will depend on our ability, alone or with collaborative partners, to successfully complete the development of and to obtain the regulatory approvals necessary to commercialize our product candidates with significant market potential. We do not currently have the required approvals to market our lead product candidate, LUMEVOQ®, and our second most advanced product candidate, GS030 or any other product candidates and we may never obtain such approvals or be able to commercialize any of our current or future product candidates. Our ability to generate future revenues from product sales will depend heavily mainly on our and any of our collaborators’ success in:

•continuing our research and development of our second lead product candidate, Phase I/II clinical trial for GS030;

•preparing our biologic license application, or BLA, and European Union centralized marketing authorization application, or MAA, for LUMEVOQ® and GS030, and seeking marketing approvals for any of our other product candidates that successfully complete clinical trials;

•establishing and maintaining supply and manufacturing relationships with third parties that can provide adequate, in both amount and quality, products and services to support clinical supply and the market demand for our product candidates, if approved;

•obtaining market acceptance of our product candidates, if approved, as a viable treatment option and satisfying any post-marketing requirements;

•avoiding and defending against third-party interference or infringement claims; and

•attracting, hiring and retaining qualified personnel.

We may never succeed in any or all of these activities and, even if we do, we may never generate revenues that are significant or large enough to achieve profitability. Even if we do achieve profitability, we may not be able to sustain or increase profitability on an annual basis and may need to obtain additional funding to continue operations. Our failure to become and remain profitable would decrease the value of our Company and could impair our ability to raise capital, maintain our research and development efforts, expand our business, diversify our product pipeline or continue our operations. A decline in the value of our Company could also cause investors to lose all or part of their investment.

3.1.3 WE WILL NEED TO RAISE ADDITIONAL CAPITAL IN THE FUTURE, WHICH MAY NOT BE AVAILABLE ON ACCEPTABLE TERMS, OR AT ALL, AND FAILURE TO OBTAIN THIS NECESSARY CAPITAL WHEN NEEDED MAY FORCE US TO DELAY, LIMIT OR TERMINATE OUR PRODUCT DEVELOPMENT EFFORTS OR OTHER OPERATIONS.

Our operations have consumed significant cash since inception. To date, we have financed our activities primarily through private placements of our ordinary shares and preferred shares, funding received from Bpifrance Financement, research tax credits (crédit d’impôt recherche), or CIR, and a sale of our ordinary shares in connection with our July 2016 initial public offering on the regulated market of Euronext Paris, or Euronext Paris.

We are currently advancing our product candidates through clinical development and towards potential commercialization. Developing product candidates is expensive, lengthy and risky, and we expect our expenses to increase in connection with our ongoing activities, particularly as we continue the research and development of, initiate further clinical trials of and seek marketing approval for, our product candidates. Our expenses could increase beyond our current expectations, mainly depending on:

•the scope, progress, results and costs of drug discovery, laboratory testing, preclinical development and clinical trials for our product candidates;

•the costs, timing and outcome of regulatory review of our product candidates, including, in particular, if we are required by the U.S. Food and Drug Administration, or FDA, the European Medicines Agency, or EMA, or other regulatory agencies to perform clinical trials and other studies in addition to those that we currently anticipate;

•the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims.

Until such time that we can generate substantial and recurring revenue from product sales, we expect to finance our operating activities through a combination of our existing liquidity sources and the proceeds of any future financings. If we are unable to generate revenue from product sales, in particular from LUMEVOQ® within our expected timeframes, or if our expenses increase to a level or at a rate beyond our expectations, we will need to raise additional capital. However, we may be unable to raise additional funds or enter into other funding arrangements when needed on favorable terms, or at all. If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate certain of our research and development programs. Any additional fundraising efforts may divert our management from their day-to-day activities, which may adversely affect our ability to develop and commercialize our product candidates.

To the extent that additional capital is raised through the sale of equity or equity-linked securities, the issuance of those securities could result in substantial dilution for our current shareholders and the terms may include liquidation or other preferences that adversely affect the holdings or the rights of our current shareholders. To the extent that additional capital is raised through a debt offering, the incurrence of indebtedness would result in increased fixed payment obligations, and we may be required to agree to certain restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business. We could also be required to seek funds through arrangements with collaborative partners or otherwise at an earlier stage than otherwise would be desirable, and we may be required to relinquish rights to some of our technologies or product candidates or otherwise agree to terms unfavorable to us.

3.1.4 WE MAY LOSE ACCESS TO RESEARCH TAX CREDITS IN THE EVENT OF REGULATORY OR LEGISLATIVE CHANGES OR CHALLENGES BY TAX AUTHORITIES.

Since incorporation, we have received the CIR, which is granted to companies by the French tax authorities in order to encourage them to conduct technical and scientific research. For the year ended December 31, 2020, we recorded CIR in the amount of approximately €2.8 million which was reimbursed in November 2021 For the year ended December 31, 2021, we recorded CIR in the amount of approximately €2.4 million, we expect will be reimbursed before the end of the fiscal year 2022.

Companies demonstrating that they have expenditures that meet the required criteria, including research expenditures located in France or, since January 1, 2005, within the European Community or in another State that is a party to the Agreement on the European Economic Area, or the EEA, that has concluded a tax treaty with France that contains an administrative assistance clause, receive a tax credit which can be used against the payment of the corporate tax due the fiscal year in which the expenditures were made and during the next three fiscal years, or, as applicable, can be reimbursed for the excess portion. The expenditures taken into account for the calculation of the CIR only involve research expenses.

Legislative or regulatory changes relating to CIR or challenges by the French tax authorities with respect to our research expenditures or our eligibility to receive CIR could have a material adverse effect on our ability to operate our business and our financial condition, results of operations and prospects.

3.1.5 OUR CURRENT AND FUTURE SHAREHOLDERS MAY EXPERIENCE DILUTION.

Since incorporation, we have issued or allotted share warrants for founders (Bons de souscription de parts de créateur d’entreprise, or BCE), share warrants (Bons de souscription d’actions, or BSA) and free shares (Attributions gratuites d’actions, or AGA). As of December 31, 2021, 502,182 BCE, 735,333 BSA, 1,535,000 AGA and 129,792 SO have been allotted (giving the right to subscribe for or acquire, respectively, 502,182, 735,333, 1,535,000 and 129,792 new shares). See Section 19.1.5.1, “Warrants” of this Universal Registration Document.

In the context of the “Kreos Transaction” completed in December 2019 and August 2020, part of the bond issuances was in the form of convertible bonds (Obligations Convertibles en Actions or OCA) (giving the right to subscribe to 1,452,852 new shares) and we had also issued 668,151 share warrants (BSA) subscribed by Kreos, giving the right to subscribe to 668,151 new shares. As of the date of this Universal Registration Document, Kreos Capital has exercised 50% of all the issued convertible bonds and converted the totality of its share warrants.

As of December 31, 2021, the exercise of all BCE, all BSA, all SO, all OCA and the definitive acquisition of all AGA allotted and outstanding will thus allow for a subscription or acquisition of 3,628,733 new ordinary shares, generating a dilution of 7.27% based on fully diluted capital.

Moreover, the exercise of delegations of authority granted to the Board of Directors by the combined general meeting of April 29, 2021 and by the combined general meeting to be held on May 25, 2022 to carry out one or more capital increases could lead to additional dilution. See Section 19.1.5, “Other Securities Giving Access to Share Capital” of this Universal Registration Document.

As part of our policy to provide incentives for our executive officers and employees, and in order to attract additional expertise, we may in the future issue or allot shares or new financial instruments giving access to our share capital, which could result in additional, potentially significant, dilution for our current and future shareholders.

3.1.6 THE REALIZATION OF THE SECURITY INTERESTS ATTACHED TO OUR BOND FINANCING COULD HAVE AN ADVERSE IMPACT ON OUR CAPACITY TO OPERATE OUR BUSINESS.

The bonds and convertible bonds issued in relation to the Kreos Transaction occurred in December 2019 and August 2020 benefit from pledge agreements on our bank accounts, on our business assets, on the intellectual property rights owned by us (trademarks, patents, software, and domain names) and on our receivables. In the event of default by us in our obligations, including our repayment obligations under the Kreos Transaction, Kreos may be granted ownership of the pledged rights and may proceed against the collateral granted to it to secure repayment of these amounts. In such event, our ability to develop its products could be affected or delayed, which would consequently have a material adverse effect on us, our business, prospects, ability to achieve our objectives, our financial position or operating result.

3.1.7 RISK RELATED TO THE FOREIGN INVESTMENT SCREENING PROCEDURE.

Any investment (i) by (a) a non-French citizen, (b) a French citizen not residing in France within the meaning of Article 4B of the General Tax Code, (c) a non-French entity or (d) a French entity controlled by one of the aforementioned individuals or entities; (ii) which would have the consequence to (a) acquire the control, within the meaning of Article L.233-3 of the French Commercial Code, of an entity governed by French law (a “French Entity”), (b) acquire all or part of a business line of a French Entity or, (c) for non EU or non-EEA investors, to cross directly or indirectly, alone or in concert, a 25% threshold of voting rights in a French Entity and (iii) such French Entity develops its activities in certain strategic sectors essential to the protection of public health, including research and development in critical technologies including biotechnology, is subject to prior authorization by the Minister of Economy, which authorization may be conditioned on certain undertakings.

In the context of the ongoing Covid-19 pandemic, the Decree (décret) n° 2020-892 dated July 22, 2020, as amended on December 22, 2021 by the Decree n° 2021-1758, has supplemented the 25% threshold with an additional temporary 10% threshold of the voting rights for the non-European investments in (i) in an entity with its registered office in France and (ii) whose shares are admitted to trading on a regulated market, applicable, at the date of this Universal Registration Document, until December 31, 2021. A fast-track procedure shall apply for any non-European investor exceeding this 10% threshold who will have to notify the Minister of Economy who will then have 10 days to decide whether or not the transaction should be subject to further examination.

If an investment requiring the prior authorization of the Minister of Economy is completed without such authorization having been granted, the Minister of Economy might direct the relevant investor to nonetheless (i) submit a request for authorization, (ii) have the previous situation restored at its own expense or (iii) amend the investment. The relevant investor might also be found criminally liable and might be sanctioned with a fine which cannot exceed the greater of: (i) twice the amount of the relevant investment, (ii) 10% of the annual turnover before tax of the target company and (iii) €5 million (for an entity) or €1 million (for an individual).

Failure to comply with such measures could result in significant consequences on the applicable investor. Such measures could also delay or discourage a takeover attempt, and we cannot predict whether these measures will result in a lower or more volatile market price of our ordinary shares.

3.2Risks related to the discovery and development of and obtaining regulatory approval for our product candidates

3.2.1 THE REGULATORY APPROVAL PROCESS OF THE FDA, THE EMA AND OTHER REGULATORY AUTHORITIES AND THE CLINICAL TRIALS THAT OUR PRODUCT CANDIDATES WILL NEED TO UNDERGO, ARE TIME-CONSUMING AND EXPENSIVE, THE OUTCOMES OF WHICH ARE UNPREDICTABLE, AND FOR WHICH THERE IS A HIGH RISK OF FAILURE.

The regulatory approval process for novel product candidates such as ours can be more expensive and take longer than for other, better known or more extensively studied product candidates. The limited number of gene therapy products approved by regulatory authorities as of the date of the Universal Registration Document makes it difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for our product candidates in either the United States or the European Union or how long it will take to commercialize our product candidates.

Since the EMA and the FDA have different procedures and evaluation criteria, approvals by the EMA may not be indicative of what the FDA may require for approval, and vice versa. The Company has submitted the Marketing Authorization Application (MAA) for its lead product LUMEVOQ® to the EMA in September 2020. Even if the EMA grants such marketing authorization, it does not mean there will be a similar outcome with the FDA in the United States.

In addition, we believe that certain of our product candidates, such as LUMEVOQ® and GS030, and certain of our underlying technology platforms, such as Mitochondrial Targeting Sequence and Optogenetics, may be immediately transferable to the treatment of other diseases, including dry age-related macular degeneration, or dry AMD, and geographic atrophy, or GA, as well as diseases outside of ophthalmology, including central nervous system, or CNS, disorders. These other indications, as well as additional potential product candidates, will require additional, time-consuming and costly development efforts prior to commercial sale, which may be unpredictable and may differ significantly from those of our initial product candidates.

3.2.2 OUR PRODUCT CANDIDATES ARE BASED ON NOVEL TECHNOLOGIES, INCLUDING GENE THERAPY, WHICH MAY IMPLICATE ETHICAL, SOCIAL AND LEGAL CONCERNS ABOUT GENETIC TESTING AND GENETIC RESEARCH IN GENERAL, AND SUCH NOVEL TECHNOLOGIES MAKE IT DIFFICULT TO PREDICT THE TIMING AND COSTS OF DEVELOPMENT OF NEW AND UNFORESEEN REGULATORY REQUIREMENTS AND OF SUBSEQUENTLY OBTAINING REGULATORY APPROVAL.

We have concentrated our research and development efforts on gene therapy approaches using our core platform technologies, mitochondrial targeting sequence, or MTS, and optogenetics, and our future success depends on our successful development of viable product candidates. We may experience problems or delays in developing LUMEVOQ®, GS030, or any other new product candidates, and such problems or delays may result in unanticipated costs, and there can be no assurance that any such development problems can be solved. We also may experience unanticipated problems or delays in developing a sustainable, reproducible and scalable manufacturing process or transferring that process to commercial partners, which may prevent us from completing our clinical trials, meeting the obligations of our collaborations or commercializing our products on a timely or profitable basis, if at all. For example, we, a collaborator or another group may uncover a previously unknown risk associated with the adeno-associated virus, or AAV, which is the vector currently used in our gene therapy approaches, and this may prolong the period of observation required for obtaining regulatory approval or may necessitate additional clinical testing.

Because human gene therapy is a relatively new and expanding area of novel therapeutic interventions, and because we are developing product candidates for the treatment of mitochondrial and neurodegenerative diseases of the eye and central nervous system for which there are no or limited therapies and/or treatments, and for which there is little clinical trial experience, there is an increased risk that the FDA, EMA or other regulatory authorities may not consider the endpoints of our clinical trials to be sufficient for marketing approval. In addition, ethical, social and legal concerns about gene therapy, genetic testing and genetic research could result in additional regulations restricting or prohibiting the processes we may use. The product specifications and the clinical trial requirements of the FDA, EMA and other regulatory authorities and the criteria these regulators use to determine the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and intended use and market of such product candidate. The regulatory approval process for novel product candidates such as ours is unclear and may be lengthier and more expensive than the process for other, better-known or more extensively studied product candidates. For example, clinical trial protocols for some gene therapies are potentially subject to review by the Recombinant DNA Advisory Committee, or RAC, a committee of the U.S. National Institutes of Health, or NIH, and the RAC review process can delay the initiation of a clinical trial, even if the FDA has approved the initiation of the trial. In addition, the FDA generally requires multiple well-controlled clinical trials to provide the evidence of effectiveness necessary to support a BLA, although FDA guidance provides that reliance on a single pivotal trial may be appropriate if the trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with a potential serious outcome, and where confirmation of the result in a second trial would be practically or ethically impossible.

Regulatory requirements governing gene and cell therapy products have changed frequently and may continue to change in the future. The FDA has established the Office of Tissues and Advanced Therapies within its Center for Biologics Evaluation and Research, or CBER, to consolidate the review of gene therapy and related products, and has established the Cellular, Tissue and Gene Therapies Advisory Committee to advise CBER in its review.

CBER and its Advisory Committee, and any new guidelines they promulgate, may lengthen the regulatory review process, require us to perform additional preclinical studies or clinical trials, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our current or future product candidates or lead to significant post-approval limitations or restrictions. As we advance our product candidates, we will be required to consult with these regulatory and advisory groups and comply with applicable guidelines. If we fail to do so, we may be required to delay or discontinue development of our product candidates. These additional processes may result in a review and approval process that is longer than we otherwise would have expected. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product to market could decrease our ability to generate sufficient product revenue, and our business, financial condition, results of operations and prospects would be harmed. Even if our product candidates are approved, we expect that the FDA will require us to submit follow-up data regarding our clinical trial subjects for a number of years after approval. If these follow-up data show negative long-term safety or efficacy outcomes for these patients, the FDA may revoke its approval or change the label of our products in a manner that could have an adverse impact on our business.

In addition, adverse developments in clinical trials of gene therapy products conducted by others may cause the FDA or other oversight bodies to change the requirements for approval of our product candidates. Similarly, the EMA may issue new guidelines concerning the development and marketing authorization for gene therapy products and require that we comply with these new guidelines.

As a result, it is difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for LUMEVOQ®, GS030, or any other new product candidates in either the United States or the European Union or how long it will take to commercialize our other product candidates. Approvals by the EMA may not be indicative of what the FDA may require for approval and vice versa.

3.2.3 WE MAY ENCOUNTER SUBSTANTIAL DELAYS IN OUR CLINICAL TRIALS, AND WE CANNOT GUARANTEE THAT ANY CLINICAL TRIALS WILL BE CONDUCTED AS PLANNED OR COMPLETED ON SCHEDULE, IF AT ALL.

Before obtaining marketing approval from regulatory authorities for the sale of our product candidates, we must conduct extensive clinical trials to demonstrate the safety and efficacy of the product candidates. Clinical testing is expensive and time-consuming and the results are uncertain. We cannot guarantee that any clinical trial will be conducted as planned or completed on schedule, if at all. Failure of a clinical trial can occur at any stage of testing. Events that may prevent successful or timely completion of clinical development include:

•delays in raising, or inability to raise, sufficient capital to fund the planned or ongoing clinical trials;

•delays in reaching a consensus with the FDA, EMA or regulatory authorities on trial design;

•delays in reaching agreement on acceptable terms with prospective CROs and clinical trial sites;

•delays in opening clinical trial sites or obtaining required independent IRB approval in the United States or approval by an independent ethics committee in the European Union at each clinical trial site;

•delays in recruiting suitable patients to participate in our clinical trials;

•imposition of a clinical hold by regulatory authorities, including as a result of a serious adverse event or after a negative finding following an inspection of our clinical trial operations or clinical trial sites;

•delays in the testing, validation, manufacturing and delivery of our product candidates to the clinical trial sites, including delays by any third parties with whom we have contracted to perform certain of those functions;

•selection of clinical endpoints that require prolonged periods of clinical observation or analysis of the resulting data.

We do not know whether any of our preclinical studies or clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all. Any inability to successfully complete preclinical and clinical development could result in additional costs or impair our ability to generate revenues from product sales, regulatory and commercialization milestones and royalties. In addition, if we make manufacturing or formulation changes to our product candidates, we may need to conduct additional studies to bridge our modified product candidates to earlier versions. Clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our competitors to bring products to market before we do, which could impair our ability to successfully commercialize our product candidates and may harm our business, financial conditions, results of operations and prospects.

3.2.4 OUR PRODUCT CANDIDATES AND THE PROCESS FOR ADMINISTERING OUR PRODUCT CANDIDATES USING AAV VECTORS MAY CAUSE UNDESIRABLE SIDE EFFECTS OR HAVE OTHER PROPERTIES THAT COULD DELAY OR PREVENT THEIR REGULATORY APPROVAL, LIMIT THEIR COMMERCIAL POTENTIAL OR RESULT IN SIGNIFICANT NEGATIVE CONSEQUENCES FOLLOWING ANY POTENTIAL MARKETING APPROVAL.

During the conduct of clinical trials, patients report changes in their health, including illnesses, injuries and discomforts, to their study doctor. Often, it is not possible to determine whether the product candidate being studied caused these conditions. Various illnesses, injuries and discomforts have been reported from time to time during clinical trials of our product candidates. Regulatory authorities may draw different conclusions or require additional testing to confirm these determinations.

In addition, it is possible that as we test our product candidates in larger, longer and more extensive clinical programs, or as use of these product candidates becomes more widespread if they receive regulatory approval, illnesses, injuries, discomforts and other adverse events that were observed in earlier trials, as well as conditions that did not occur or went undetected in previous trials, will be reported by patients. Many times, side effects are only detectable after investigational products are tested in large-scale, Phase III clinical trials or, in some cases, after they are made available to patients on a commercial scale after approval. If additional clinical experience indicates that our product candidates cause serious or life-threatening side effects, the development of our product candidates may fail or be delayed, or, if the product candidate has received regulatory approval, such approval may be revoked, which would harm our business, prospects, operating results and financial condition.

Our product candidates may lead to undesirable side effects or adverse reactions. In previous studies involving gene therapy treatments, some subjects experienced significant adverse side effects, including reported cases of leukemia and death seen in other clinical trials using other vectors. While new recombinant vectors have been developed to reduce these side effects, gene therapy is still a relatively new approach to disease treatment and additional adverse side effects could develop. Insertional oncogenesis, where the vector is inserted near a cancer causing gene, or an oncogene, may cause adverse immunologic reactions and we cannot assure that such reactions will not occur in any of our planned or future studies. There also is the potential risk of delayed adverse events following exposure to gene therapy products due to persistent biologic activity of the genetic material or other components of products used to carry the genetic material.

Possible adverse side effects that could occur with treatment with gene therapy products include an immunologic reaction shortly after administration which, while not necessarily adverse to the patient’s health, could substantially limit the effectiveness of the treatment. In previous clinical trials involving AAV vectors for gene therapy, some patients experienced the development of a T-cell response, whereby after the vector is within the target cell, the cellular immune response system triggers the removal of transduced cells by activated T-cells. If our products demonstrate a similar effect, we may decide or be required to halt or delay further clinical development of our product candidates. There are also risks inherent in intravitreal injections, including those used to administer LUMEVOQ® and GS030, such as intraocular inflammation, cataract, sterile and culture-positive endophthalmitis, retinal detachment and retinal tear.

In addition to any potential side effects caused by our product candidates, the administration process or related procedures also can cause adverse side effects. If any such adverse events occur, our clinical trials could be suspended or terminated.

If in the future we are unable to demonstrate that such adverse events were not caused by the product candidate, the FDA, the EMA or other regulatory authorities could deny approval or order us to cease further development of our product candidates for any or all targeted indications. Even if we are able to demonstrate that all future serious adverse events are not product-related, such occurrences could affect patient recruitment or the ability of enrolled patients to complete the clinical trial. Moreover, if we elect or are required to delay, suspend or terminate any clinical trial of any of our product candidates, the commercial prospects of such product candidates may be harmed and our ability to generate product revenues from any of these product candidates may be delayed or eliminated. Any of these occurrences may harm our ability to develop other product candidates and may harm our business, financial condition and prospects significantly.

Additionally, if any of our product candidates receives marketing approval, the FDA and the EMA could require us to adopt a Risk Evaluation and Mitigation Strategy, or REMS, or a Risk Management Plan, or RMP, to ensure that its benefits outweigh its risks, which may include, among other things, a medication guide outlining the risks of the product for distribution to patients and a communication plan to healthcare practitioners.

Furthermore, if we or others later identify undesirable side effects caused by any of our product candidates, several potentially significant negative consequences could result, including:

•regulatory authorities may suspend or withdraw approvals of such product candidate;

•regulatory authorities may require additional warnings on the label;

•we may be required to change the way a product candidate is administered or conduct additional clinical trials;

•we could be sued and held liable for harm caused to patients; and

•our reputation may suffer.

Any of these events could prevent us from achieving or maintaining market acceptance of our product candidates and could significantly harm our business, prospects, financial condition and results of operations.

3.2.5 EVEN IF WE COMPLETE THE NECESSARY CLINICAL TRIALS, WE CANNOT PREDICT WHEN, OR IF, WE WILL OBTAIN REGULATORY APPROVAL TO COMMERCIALIZE A PRODUCT CANDIDATE AND THE APPROVAL MAY BE FOR A NARROWER INDICATION THAN WE SEEK.

We cannot commercialize a product candidate until the appropriate regulatory authorities have reviewed and approved the product candidate. Even if our product candidates meet their safety and efficacy endpoints in clinical trials, regulatory authorities may not complete their review processes in a timely manner and may recommend non-approval or may place restrictions on approval. In addition, we may experience delays or rejections as a result of future legislation or administrative action, or changes in regulatory authority policy during the period of product development, clinical trials and the review process.

Regulatory authorities also may approve a product candidate for more limited indications than requested, may require precautions or contraindications or they may grant approval subject to the performance of costly post-marketing clinical trials or implementation of REMS. In addition, regulatory authorities may not approve the labeling claims that are necessary or desirable for the successful commercialization of our product candidates. Any of the foregoing events could materially harm the commercial prospects for our product candidates.

3.3Risks related to manufacturing and commercialization of our product candidates

3.3.1 GENE THERAPIES ARE NOVEL, COMPLEX AND DIFFICULT TO MANUFACTURE. WE HAVE LIMITED MANUFACTURING EXPERIENCE AND COULD EXPERIENCE PRODUCTION PROBLEMS THAT RESULT IN DELAYS IN OUR DEVELOPMENT OR COMMERCIALIZATION PROGRAMS.

We have limited experience manufacturing our product candidates. We may be unable to produce commercial materials or meet demand to support a commercial launch for our product candidates. Any such failure could delay or prevent the development of our product candidates and would have a negative impact on our business, financial condition and results of operations.

As of the date of this Universal Registration Document, we have contracts with Brammer Bio and Catalent to manufacture clinical and commercial supplies of our product candidates, and we expect to continue to rely on third parties for our manufacturing needs. This is and will continue to be especially challenging as the manufacturing process to produce our product candidates is complex, novel and has not been validated for commercial use. Several factors could cause production interruptions, including equipment malfunctions, facility contamination, raw material shortages or contamination, natural disasters, disruption in utility services, human error or disruptions in the operations of our current and future suppliers.

Our product candidates require processing steps that are more complex than those required for most chemical pharmaceuticals because the physical and chemical properties of a biologic such as ours generally cannot be fully characterized. As a result, assays of the finished product may not be sufficient to ensure that the product will perform in the intended manner. Accordingly, we employ multiple steps to control the manufacturing process to assure that the product candidate is made in strict and consistent compliance with our requirements. Problems with the manufacturing process, including even minor deviations from our requirements, could result in product defects or manufacturing failures that result in lot failures, product recalls, product liability claims or insufficient inventory. In addition, we may encounter problems achieving adequate quantities and quality of clinical-grade materials that meet FDA, EMA or other applicable standards or specifications with consistent and acceptable production yields and costs.

The FDA, the EMA and other regulatory authorities may also require submission of samples of any lot of an approved product together with the protocols showing the results of applicable tests. Under some circumstances, the FDA, the EMA or other regulatory authorities may require that a lot not be distributed until the agency authorizes its release. Slight deviations in the manufacturing requirements, including those affecting quality attributes and stability, may result in unacceptable changes in the product that could result in lot failures or product recalls. Lot failures or product recalls could cause us to delay product launches or clinical trials, which could be costly to us and otherwise harm our business, financial condition, results of operations and prospects.

We may also encounter problems hiring and retaining the experienced specialist scientific, quality control and manufacturing personnel needed to supervise manufacturing processes carried out by third parties, which could result in delays in our production or difficulties in complying with applicable regulatory requirements.

Any problems in the manufacturing process or facilities for our product candidates could make us a less attractive collaborator for potential partners, including larger pharmaceutical companies and academic research institutions, which could limit our access to additional attractive development programs. Problems in our manufacturing process or facilities also could restrict our ability to meet market demand for our products.

3.3.2 WE RELY, AND EXPECT TO CONTINUE TO RELY, ON Brammer Bio, CATALENT AND OTHER THIRD PARTIES TO CONDUCT, SUPERVISE AND MONITOR MANUFACTURING FOR OUR PRECLINICAL STUDIES AND CLINICAL TRIALS. IF THESE THIRD PARTIES DO NOT MEET OUR DEADLINES, SUCCESSFULLY CARRY OUT THEIR CONTRACTUAL DUTIES OR OTHERWISE CONDUCT THE MANUFACTURING FOR THESE STUDIES AND TRIALS AS REQUIRED, WE MAY NOT BE ABLE TO OBTAIN REGULATORY APPROVAL FOR OR COMMERCIALIZE OUR PRODUCT CANDIDATES WHEN EXPECTED OR AT ALL.

We currently rely and expect to continue to rely to a significant degree, on Brammer Bio, Catalent and other third parties to carry out the production of our preclinical study, clinical trial and commercial materials (see Section 20.3 “Manufacturing Agreement”). We can control only certain aspects of these third-party activities.

Under certain circumstances, Brammer Bio and Catalent are entitled to terminate their engagements with us. If we need to enter into alternative arrangements, it could delay our product development activities. Our reliance on Brammer Bio and Catalent for certain manufacturing activities will reduce our control over these activities but will not relieve us of our responsibility to ensure compliance with all required regulations. If Brammer Bio or Catalent does not successfully carry out their contractual duties, meet expected deadlines or manufacture our clinical trial materials in accordance with regulatory requirements, or if there are disagreements between us and Brammer Bio and/or Catalent, we will not be able to complete, or may be delayed in completing, the preclinical studies required to support future IND submissions and the clinical trials required for approval of our product candidates. In such instances, we would need to find an appropriate replacement third-party relationship, which may not be readily available or on acceptable terms, causing additional delay or increased expense prior to the approval of our product candidates.

In addition to Brammer Bio and Catalent, we rely on additional third parties to manufacture ingredients of our product candidates and to perform quality testing, and reliance on these third parties rather than manufacturing the product candidates ourselves, exposes us to additional risks, including:

•reduced control for certain aspects of manufacturing activities;

•termination or non-renewal of such manufacturing agreements in a manner or at a time that is costly or damaging to us; and

•disruptions to the operations of our third-party manufacturers caused by conditions unrelated to our business or operations, including the bankruptcy of the manufacturer or service provider.

Any of these events could lead to clinical trial delays or failure to obtain regulatory approval, or impact our ability to successfully commercialize future product candidates. Some of these events could be the basis for FDA, EMA or other regulatory authority action, including injunction, recall, seizure or partial or total suspension of product manufacture.

3.3.3 WE RELY ON THIRD PARTIES TO CONDUCT, SUPERVISE AND MONITOR OUR PRECLINICAL STUDIES AND CLINICAL TRIALS. IF THESE THIRD PARTIES DO NOT MEET OUR DEADLINES OR OTHERWISE CONDUCT THE STUDIES AND TRIALS AS REQUIRED, OUR CLINICAL DEVELOPMENT PROGRAMS COULD BE DELAYED OR UNSUCCESSFUL AND WE MAY NOT BE ABLE TO OBTAIN REGULATORY APPROVAL FOR OR COMMERCIALIZE OUR PRODUCT CANDIDATES WHEN EXPECTED OR AT ALL.

We do not have the ability to conduct all aspects of our preclinical studies or clinical trials ourselves. We rely, and expect to continue to rely, on medical institutions, clinical investigators, CROs, contract laboratories and collaborators to carry out our preclinical studies and clinical trials and to perform data collection and analysis. Such third parties play a significant role in the conduct of these studies and trials and the subsequent collection and analysis of data. While we have agreements governing their activities, we have limited influence over their actual performance and will control only certain aspects of such third parties’ activities. Nevertheless, we are responsible for ensuring that each of our preclinical studies and clinical trials is conducted in accordance with the applicable legal, regulatory, ethical and scientific standards, and our reliance on the third party does not relieve us of our regulatory responsibilities.

We and our CROs are required to comply with the FDA’s, the EMA’s and other regulatory authorities’ GCP, cGMP, Good Laboratory Practice, or GLP, and other applicable requirements for conducting, recording and reporting the results of our preclinical studies and clinical trials to assure that the data and reported results are credible and accurate and that the rights, integrity and confidentiality of clinical trial participants are protected (See Section 9 “Regulatory Environment”). Regulatory authorities around the world, including the FDA and the EMA, enforce these requirements through periodic inspections of study sponsors, CROs, principal investigators and clinical trial sites. If we, our CROs, our investigators or trial sites fail to comply with applicable GCP, GLP and cGMP requirements, the clinical data generated in our future clinical trials may be deemed unreliable and the FDA, the EMA or other regulatory authorities around the world may require us to perform additional clinical trials before issuing any marketing authorizations for our product candidates. Upon inspection, the FDA or EMA may determine that our clinical trials did not comply with GCP and cGMP requirements, which may render the data generated in those trials unreliable or unusable for the purpose of supporting the marketing authorization applications for our products. In addition, our future clinical trials will require a sufficient number of study subjects to evaluate the safety and efficacy of our product candidates. Accordingly, if, for example, our CROs fail to comply with these regulations or if trial sites fail to recruit a sufficient number of patients, we may be required to repeat such clinical trials or incur delays in the performance of such trials, which would delay the regulatory approval process.

Therefore, the timing of the initiation and completion of trials is largely controlled by such third parties and may occur at times substantially different from our estimates. Our development activities, including preclinical studies and clinical trials conducted in reliance on third parties, may be delayed, suspended or terminated if:

•we are unable to negotiate agreements with third parties under reasonable terms;

•termination or nonrenewal of agreements with third parties occurs in a manner or at a time that is costly or damaging to us;

•the third parties do not successfully carry out their contractual duties or fail to meet regulatory obligations or expected deadlines; or

•the quality or accuracy of the data obtained by third parties is compromised due to their failure to adhere to clinical protocols, regulatory or ethical requirements, or for other reasons.

Third party performance failures in connection with our preclinical studies and clinical trials may increase our costs, delay our ability to obtain regulatory approval, delay or prevent starting or completion of clinical trials and delay or prevent commercialization of our product candidates. In the event of a default, bankruptcy or shutdown of, or a dispute with, a third party, we may be unable to enter into a new agreement with another third party on commercially acceptable terms. In addition, our third-party agreements usually contain a clause limiting such third party’s liability, such that we may not be able to obtain full compensation for any losses we may incur in connection with the third party’s performance failures. While we believe that there are numerous alternative sources to provide these services, in the event that we seek such alternative sources, we may not be able to enter into replacement arrangements without incurring delays or additional costs.

3.3.4 FUTURE INSURANCE COVERAGE AND REIMBURSEMENT STATUS OF OUR PRODUCT CANDIDATES IS UNCERTAIN.

We expect the cost of a single administration of our products candidates to be substantial, when and if they achieve regulatory approval. We expect that coverage and reimbursement by government and private payors will be essential for most patients to be able to afford these treatments. Accordingly, sales of our product candidates will depend substantially, in the United States and the European Union in particular, on the extent to which the costs of our product candidates will be paid or reimbursed by government authorities, private health coverage insurers and other third-party payors. The marketability of any products for which we receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our product candidates. Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Obtaining coverage and reimbursement for a product from third-party payors is a time-consuming and costly process that could require us to provide to the payor supporting scientific, clinical and cost-effectiveness data. We may not be able to provide data sufficient to gain acceptance with respect to coverage and reimbursement. If coverage and reimbursement are not available, or are available only at limited levels, we may not be able to successfully commercialize our product candidates. Even if coverage is provided, the approved reimbursement amount may not be adequate to realize a sufficient return on our investment.

There is significant uncertainty related to third-party coverage and reimbursement of newly approved products. In many countries outside the United States, product sales generally are subject to extensive government price controls and other market regulations (see Section 9 “Regulatory Environment”).

Therefore, it may be difficult to project the impact of these evolving reimbursement metrics on the willingness of payors to cover candidate products that we or our partners are able to commercialize. We expect to experience pricing pressures in connection with the sale of any of our product candidates due to the trend toward managed healthcare, the increasing influence of health maintenance organizations additional legislative changes and downward pressure on healthcare costs in general. As a result, increasingly high barriers are being erected to the entry of new products such as ours.

3.3.5 IF WE ARE UNABLE TO ESTABLISH SALES, MARKETING AND DISTRIBUTION CAPABILITIES FOR OUR PRODUCT CANDIDATES, WHETHER IT BE AN INTERNAL INFRASTRUCTURE OR AN ARRANGEMENT WITH A COMMERCIAL PARTNER, WE MAY NOT BE SUCCESSFUL IN COMMERCIALIZING THOSE PRODUCT CANDIDATES IF AND WHEN THEY ARE APPROVED.

In addition to the appointment of our Vice President of Marketing in 2017 and of our Senior Vice-President of Commercial Operations in 2022, the country leadership for the five major European markets (Germany, France, the UK, Italy and Spain) were recruited, with additional local positions filled for the first three markets. The teams began identifying and evaluating the potential network of treatment centers when LUMEVOQ® becomes available on the markets. In addition, they have begun assessing the network of Key Opinion Leaders who will drive treatment decisions and potentially support discussions with pricing and reimbursement authorities.

To successfully commercialize any of our product candidates, we will need to keep on developing these capabilities, either on our own or with others, which will be expensive and time-consuming and could delay any product launch. Moreover, we cannot be certain that we will be able to successfully develop this capability. We intend to commercialize our products, on our own or with strategic partners, in Europe and the United States and expect to seek partnership agreements in Asia for sales, marketing and distribution. If any current or future collaborators do not commit sufficient resources to commercialize our products, or we are unable to develop the necessary capabilities on our own, we will be unable to generate sufficient product revenue to sustain our business. We will be competing with many companies that have extensive, experienced and well-funded marketing and sales operations to recruit, hire, train and retain marketing and sales personnel. We also face competition in our search for third parties to assist us with the sales and marketing efforts of our product candidates. Without an internal team or the support of a third party to perform marketing, sales and distribution functions, we may be unable to compete successfully against more established companies.

3.3.6 THE COMMERCIAL SUCCESS OF ANY OF OUR PRODUCT CANDIDATES WILL DEPEND UPON THEIR DEGREE OF MARKET ACCEPTANCE BY PHYSICIANS, PATIENTS, THIRD-PARTY PAYORS AND OTHERS IN THE MEDICAL COMMUNITY.

Our efforts to educate the medical community and third-party payors on the benefits of our product candidates may require significant resources and may never be successful. Such efforts may require more resources than are typically required due to the complexity and uniqueness of our potential products. If LUMEVOQ® or any other product that we commercialize in the future is approved but fails to achieve market acceptance among physicians, patients or third-party payors, we will not be able to generate significant revenues from such product.

The degree of market acceptance of our product candidates, if approved for commercial sale, will depend on several factors, including:

•the potential and perceived advantages of product candidates over alternative treatments;

•the cost of treatment relative to alternative treatments;

•patient awareness of genotyping;

•the willingness of physicians to prescribe new therapies;

•the willingness of the target patient population to try new therapies;

•the prevalence and severity of any side effects;

•product labeling or product insert requirements of the FDA, the EMA or other regulatory authorities, including any limitations or warnings contained in a product’s approved labeling;

•relative convenience and ease of administration;

•the strength of marketing and distribution support;

•the timing of market introduction of competitive products;

•publicity concerning our products or competing products and treatments; and

•sufficient third-party payor coverage and adequate reimbursement.

Even if a potential product displays a favorable efficacy and safety profile in preclinical studies and clinical trials, market acceptance of the product will not be fully known until after it is launched.

3.4Risks related to our business operations

3.4.1 RISKS RELATED TO THE IMPACTS OF THE COVID-19.

The REVERSE and RESCUE Phase III trials of LUMEVOQ® for the treatment of Leber Hereditary Optic Neuropathy (LHON) are completed, and patients have been transferred to long-term follow-up for an additional 3-year period. Given the follow-up nature of these visits and the stability of patients with no safety concern, the Company confirms that the Covid-19 situation has no significant impact on the conduct of the trial.

The strategic manufacturing partner (CDMO) for LUMEVOQ®, ThermoFischer Scientific (TFS) in Boston, USA, informed the Company that, as a consequence of the US Defense Production Act (DPA), American suppliers have had to redirect certain consumables towards the manufacture of Covid vaccines in the US. This has resulted in extended timelines for the availability of some items required for manufacturing LUMEVOQ®. Accordingly, the Company anticipated delays in providing data from the planned validation batches to the EMA and, after discussions with the European Agency, agreed upon an extended clock-stop period.

The REFLECT Phase III trial of LUMEVOQ® is fully recruited with a primary endpoint at 78 weeks. Although some on-site visits had to be postponed due to Covid-19 travel restrictions, the Company closely partnered with clinical sites and properly documented and reported delays to regulators, as well as pre-specified them in the Statistical Analysis Plan (SAP), in agreement with biostatisticians, before database lock. Consequently, GenSight Biologics was able to collect data from 95 out of 98 patients with no consequence on the primary endpoint, other than a delay in the 78-week read out from Q1 initially to June 2021.

In order to protect patients, the Company and investigators together decided to delay recruiting new patients into the 3rd cohort of the PIONEER Phase I/II clinical trial of GS030 until the Covid-19 situation had improved, as RP is a chronic disease and does not require urgent treatment. The use of corticosteroids pre- and post-gene therapy injection, performed as part of the protocol to minimize inflammatory response, was deemed by GenSight and investigators to expose patients to a higher risk of Covid-19 infection. In the interim, the six patients in the first two cohorts were remotely monitored for safety aspects by investigators. Consequently, recruitment took longer than originally planned. PIONEER, combining gene therapy and optogenetics for the treatment of RP, has now fully completed recruitment of the 3rd cohort.

Patients continued to benefit from the Temporary Authorization of Use (ATU) granted by the French National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM).

The Company has implemented measures to protect its staff against Covid-19 by encouraging remote working for all employees.

3.4.2 OUR FUTURE SUCCESS DEPENDS ON OUR ABILITY TO RETAIN KEY EMPLOYEES, CONSULTANTS AND ADVISORS AND TO ATTRACT, RETAIN AND MOTIVATE QUALIFIED PERSONNEL, AND MEMBERS OF OUR MANAGEMENT TEAM MAY BE AFFECTED BY CONFLICTS OF INTEREST TO THE EXTENT THAT THEY SERVE IN MANAGEMENT OR DIRECTORSHIP CAPACITIES AT OUR COMPETITORS.

We are highly dependent on members of our executive team, the loss of whose services may adversely impact the achievement of our objectives. While we have entered into employment agreements with each of our executive officers, any of them could leave our employment at any time, as all of our employees are “at will” employees. We currently do not have “key person” insurance on any of our employees. The loss of the services of one or more of our current employees might impede the achievement of our research, development and commercialization objectives.

Recruiting and retaining other qualified employees, consultants and advisors for our business, including scientific and technical personnel, will also be critical to our success. There is a shortage of skilled individuals with substantial gene therapy experience, which is likely to continue. As a result, competition for skilled personnel, including the area of gene therapy research and vector manufacturing, is intense and the turnover rate can be high. We may not be able to attract and retain personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies and academic institutions for individuals with similar skill sets. In addition, failure to succeed in preclinical studies or clinical trials or applications for marketing approval may make it more challenging to recruit and retain qualified personnel. The inability to recruit, or the loss of services of certain executives, key employees, consultants or advisors, may impede the progress of our research, development and commercialization objectives and could have a material adverse effect on our business, financial condition, results of operations and prospects.

3.4.3 WE MAY NOT BE SUCCESSFUL IN OUR EFFORTS TO IDENTIFY OR DISCOVER ADDITIONAL PRODUCT CANDIDATES AND MAY FAIL TO CAPITALIZE ON PROGRAMS OR PRODUCT CANDIDATES THAT MAY BE A GREATER COMMERCIAL OPPORTUNITY OR FOR WHICH THERE IS A GREATER LIKELIHOOD OF SUCCESS.

Because we have limited resources and access to capital to fund our operations, we must decide which product candidates to pursue and the amount of resources to allocate to each. Our decisions concerning the allocation of research, collaboration, management and financial resources towards particular product candidates may not lead to the development of viable commercial products and may divert resources away from more promising opportunities. Similarly, our potential decisions to delay, terminate or collaborate with third parties with respect to some of our product development programs may also prove not to be optimal and could cause us to miss valuable opportunities. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights. If we make incorrect determinations regarding the market potential of our product candidates or misread trends in the pharmaceutical industry, our business prospects could be harmed.

The success of our business currently depends primarily upon our ability to identify, develop and commercialize our lead product candidates, LUMEVOQ® and GS030, as well as to identify other product candidates based on our MTS and optogenetics technology platforms. However, we may be unsuccessful in identifying potential product candidates for development. Alternatively, our potential product candidates may be shown to have harmful side effects or other characteristics that could make the products unmarketable or unlikely to receive marketing approval. If we are forced to abandon our development efforts for a program or programs, this would likely have a material adverse effect on our business and could potentially cause us to cease operations.

3.4.4 WE MAY BE SUBJECT TO PRODUCT LIABILITY LAWSUITS.

We face an inherent risk of product liability exposure related to the testing of our product candidates in clinical trials and may face an even greater risk if we commercialize any products that we may develop. If we cannot successfully defend ourselves against claims that our product candidates caused injuries, we could incur substantial liabilities. Regardless of merit or eventual outcome, liability claims may result in:

•decreased demand for any product candidates that we may develop;

•loss of revenue;

•substantial monetary awards to trial participants or patients;

•significant time and costs to defend the related litigation;

•withdrawal of clinical trial participants;

•the inability to commercialize any product candidates that we may develop; and

•injury to our reputation and significant negative media attention.

3.5Legal risks and risks related to our intellectual property

3.5.1 WE DO NOT OWN ANY ISSUED PATENTS AND OUR RIGHTS TO DEVELOP AND COMMERCIALIZE OUR PRODUCT CANDIDATES ARE SUBJECT TO THE TERMS AND CONDITIONS OF INTELLECTUAL PROPERTY LICENSES GRANTED TO US BY OTHERS.

Although since 2016 we have in-licensed at least 10 U.S. and foreign patent applications and at least 22 U.S. and foreign patents, we do not currently own any issued patents, and we are heavily reliant upon licenses to certain patent rights and other third party intellectual property rights that are important or necessary to the development and commercialization of our technology and products, including technology related to our manufacturing process and our gene therapy product candidates. Any of our patent applications may not be granted, and these intellectual property licenses and any patents that issue from these applications may not provide us with rights to use such intellectual property and technology in all relevant fields of use and in all territories in which we may wish to develop or commercialize our technology and products in the future. In particular, there may be unforeseen areas of technology over which the licensed rights, or any patents that issue from our pending applications, may not extend and for which we may be unable to obtain rights in the future. To the extent our licenses do not cover a relevant field or territory, the third-party licensor of applicable intellectual property rights may block our ability to develop or commercialize our technology and products in such field or territory unless we are able to extend our license to cover such field or territory. Further, our licenses may not provide us with exclusive rights to use such intellectual property in all relevant fields of use and in all territories in which we may wish to develop or commercialize our technology and products in the future. As a result, we may not be able to prevent competitors from developing and commercializing competing products in fields and/or territories included in our licenses.

In some circumstances, we may not have the right to control the preparation, filing and prosecution of patent applications, or to maintain or enforce the patents, covering technology licensed to us by third parties. For example, pursuant to our intellectual property license agreement with Adverum Biotechnologies, Inc., or Adverum, Adverum retains control of such activities. Therefore, we cannot be certain that the Adverum patent applications will be prosecuted, maintained and enforced in a manner consistent with the best interests of our business. If our licensors fail to prepare, file, maintain or enforce such patents or patent applications, or lose rights to such patents or patent applications, the rights licensed to us may be reduced or eliminated and our right to develop and commercialize any of our product candidates that are the subject of such licensed rights could be adversely affected. In addition, we face similar risks and uncertainties regarding our pending patent applications and any other patent rights that we may own in the future.

In some circumstances, our license agreements provide that we must grant, on a non-exclusive royalty-free basis, a license to the licensor to exploit technological improvements we have made to the licensed technology. Such “grant-back” provisions may limit our exclusive rights in technology we develop in-house, and so may hinder the extent to which we can prevent competitors from developing and commercializing competing products relating to those technologies.

We also in-licensed certain patents owned by the Regents of the University of California as Head Licensor through our license agreement with Adverum and we in-license certain patent rights from the Massachusetts Institute of Technology, or M.I.T. Under applicable law, to the extent that the research giving rise to the patents or technology so licensed was funded by the U.S. government, the U.S. government may have certain rights, including (1) a non-exclusive, irrevocable, paid-up license to practice or have practiced such patents or technology on behalf of the United States and (2) “march-in rights” requiring the grant of licenses under such patent rights and technology to one or more third parties. When new technologies are developed with U.S. government funding, the U.S. government generally obtains certain rights in any resulting patents and inventions, including a non-exclusive license to practice or have practiced on behalf of the U.S. government such patents and inventions. These rights may further permit the U.S. government to disclose our confidential information to third parties and to exercise march-in rights to allow third parties to use our licensed technology. The U.S. government can exercise its march-in rights if it determines that action is necessary because we or our licensors fail to achieve practical application of the U.S. government-funded technology, or because action is necessary to alleviate health or safety needs, to meet requirements of federal regulations or to give preference to U.S. industry. In addition, our rights in such inventions may be subject to certain requirements to manufacture products embodying such inventions in the United States. Any exercise by the U.S. government of such rights could harm our business, financial condition, results of operations and prospects.

In addition, licenses to additional third-party technology and materials that may be required for our development programs, including additional technology and materials owned by any of our current licensors, may not be available in the future or may not be available on commercially reasonable terms, or at all, which could have an adverse effect on our business and financial condition.

3.5.2 WE OR OUR LICENSORS MAY BE UNABLE TO OBTAIN AND MAINTAIN ADEQUATE PATENT PROTECTION FOR OUR PRODUCT CANDIDATES AND TECHNOLOGY.

Our success depends, in large part, on our and our licensors’ ability to obtain and maintain patent protection in the United States, the European Union and other countries with respect to our proprietary product candidates and manufacturing technology. We or our licensors have sought and we intend to further seek, to protect our proprietary position by filing patent applications in the United States, the European Union and other jurisdictions related to many of our novel technologies and product candidates that are important to our business. If we or our licensors fail to obtain and maintain patent or other protection for this proprietary intellectual property, we could lose our rights to such intellectual property or our exclusivity with respect to those rights, and our competitors could market competing products using such intellectual property.

The patent prosecution process is expensive, time-consuming and complex and we or our licensors may not be able to, or may choose not to, file, prosecute, maintain or enforce in a timely manner, or at all, all issued patents or patent applications that we believe are necessary or desirable for our business. In addition, patents might not be issued or granted with respect to our patent applications that are currently pending, and any issued patents may be challenged, invalidated, circumvented or rendered unenforceable. We cannot assure that either we or our licensors will be successful should such patents be challenged. If our or our licensors’ patent claims are rendered invalid or unenforceable, or narrowed in scope, it could seriously impair our competitive position.

Consequently, we would not be able to assert any such patents to prevent others from using our technology for, and developing and marketing competing products to treat, our indications of interest. It is also possible that we will fail to identify patentable aspects of our research and development output in timely manner to obtain patent protection.

In some cases, the work of certain academic researchers in the gene therapy field has entered the public domain, which we believe precludes our ability to obtain patent protection for certain inventions relating to such work. Consequently, we will not be able to assert any such patents to prevent others from using our technology for, and developing and marketing competing products to treat, our indications of interest. It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection.

We may not be aware of all third-party intellectual property rights potentially relating to our current and future product candidates. Because patent applications in the United States and most other countries are confidential for a period of time after filing, and some remain so until issued, and because publication of discoveries in the scientific or patent literature often lags behind actual discoveries and filings of patent applications, we cannot be certain of the priority of inventions covered by any pending patent applications.

Accordingly, with respect to our current patent applications and any patent applications that we may file in the future in the European Union or the United States, we may not be the first to file patent applications covering such subject matter, meaning that we may be unable to protect or exploit the invention(s) concerned.

Furthermore, for U.S. patent applications in which all claims are entitled to a priority date before March 16, 2013, we may become subject to interference proceedings or derivation proceedings before the United States Patent and Trademark Office, or the USPTO, to determine priority of invention. For U.S. patent applications containing a claim not entitled to priority before March 16, 2013, there is a greater level of uncertainty in the U.S. patent laws in view of the passage of the Leahy-Smith America Invents Act, or the Leahy-Smith Act, signed into law on September 16, 2011, which brought into effect significant changes to these laws, including new procedures for challenging pending patent applications and issued patents.

Even if the patent applications that we own or license from third parties or may own in the future do issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors or other third parties from competing with us or otherwise provide us with any competitive advantage. Our competitors or other third parties may be able to design around or otherwise circumvent our or our licensors’ patents by developing similar or alternative technologies or products in a non-infringing manner.

The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, and our licensors’ patents, or any patents that we may independently seek may be challenged in the courts or patent offices in the United States, the European Union or elsewhere. Such challenges may result in loss of exclusivity or in patent claims being narrowed, invalidated or held unenforceable, which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and product candidates. Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our intellectual property rights may not provide us with sufficient protection to exclude others from commercializing product candidates similar or identical to ours.

3.5.3 WE MAY FAIL TO COMPLY WITH OUR OBLIGATIONS UNDER THE AGREEMENTS UNDER WHICH WE IN–LICENSE INTELLECTUAL PROPERTY AND COULD THEREBY LOSE LICENSED RIGHTS THAT ARE IMPORTANT TO OUR BUSINESS.

We are a party to a number of intellectual property license agreements, including agreements with Inserm Transfert S.A., Adverum and M.I.T. that are important to our business, and we expect to enter into additional license agreements in the future. Our existing license agreements impose, and we expect that any future license agreements will impose, various diligence, development and commercialization timelines, milestone payments, royalties and other obligations on us. See Section 5.5.5 “Intellectual Property” and Section 20.2 “In-License Agreements” of this Universal Registration Document for a description of our license agreements. If we fail to comply with our obligations under these agreements, or are subject to a bankruptcy or certain other specified events, the licensor may have the right to terminate the license, in which event we would not be able to market products covered by the license. Further, in certain of our license agreements, we have the first right to bring actions against any third party infringers of the patents licensed to us. Certain of our license agreements also require us to meet development thresholds to maintain the license, including establishing a set timeline for developing and commercializing product candidates and minimum yearly diligence obligations in developing and commercializing the product. Disputes may arise regarding intellectual property subject to a licensing agreement, including:

•the scope of rights granted under the license agreement and other interpretation-related issues;

•the extent to which our technology and processes infringe any intellectual property of the licensor that is not subject to the licensing agreement;

•the sublicensing of intellectual property and other rights under our collaborative development, manufacturing and other third-party relationships;

•our diligence obligations under the license agreement and what activities satisfy those diligence obligations;

•the inventorship or ownership of intellectual property resulting from the joint creation or use of intellectual property by our licensors, consultants, contractors, collaborators or partners and us; and

•the priority of invention of patented technology.

If disputes over intellectual property that we have in-licensed prevent or impair our ability to maintain our current licensing arrangements on acceptable terms, we may be unable to successfully develop and commercialize the affected product candidates.

3.5.4 WE MAY NOT BE ABLE TO PROTECT OUR INTELLECTUAL PROPERTY RIGHTS THROUGHOUT THE WORLD.

Our patent applications and in-licensed patent rights may not have corresponding patents or patent applications in other countries. In addition, the laws of some other countries do not protect intellectual property rights to the same extent as federal and state laws in the United States or patent laws in Europe. Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States and Europe, or from selling or importing products made using our inventions in and into the United States or in Europe or other jurisdictions. Competitors may use our technologies in jurisdictions where we have not obtained patent protection or may export otherwise infringing products to territories where we have patent protection, but enforcement is not as strong as in the United States or in Europe. These products may compete with our products, patents or other intellectual property rights that we license from third parties.

Proceedings to enforce our intellectual property rights in other jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our in-licensed patents, or patents we may own, at risk of being invalidated or interpreted narrowly and our in-licensed patent applications, or patent applications we own or may own in the future, at risk of not issuing and could provoke third parties to assert claims against us. We may not prevail in any lawsuits that we initiate and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or in-license.

3.5.5 THIRD PARTIES MAY INITIATE LEGAL PROCEEDINGS ALLEGING THAT WE ARE INFRINGING THEIR INTELLECTUAL PROPERTY RIGHTS, THE OUTCOME OF WHICH WOULD BE UNCERTAIN AND COULD HAVE A MATERIAL ADVERSE EFFECT ON THE SUCCESS OF OUR BUSINESS.

Our commercial success depends upon our ability and the ability of our existing or future collaborators and third-party service providers to develop, manufacture, market and sell our product candidates and use our proprietary technologies without infringing the proprietary rights and intellectual property of third parties. The biotechnology and pharmaceutical industries are characterized by extensive and complex litigation regarding patents and other intellectual property rights. We may in the future become party to, or be threatened with, adversarial proceedings or litigation regarding intellectual property rights with respect to our product candidates and technology, including interference proceedings, post-grant review and inter partes review before the USPTO, the EPO or equivalent measures outside the United States and the European Union.

Third parties may assert infringement claims against us based on existing patents or patents that may be granted in the future, regardless of their merit. We are aware of certain third-party patents relating to gene delivery to ocular cells and certain vector manufacturing methods that may relate to, and potentially could be asserted to encompass our product candidates. There is a risk that third parties may choose to engage in litigation with us to enforce or to otherwise assert their patent rights against us. A court of competent jurisdiction could hold that these third-party patents are valid, enforceable and infringed by us, which could materially and adversely affect our ability to commercialize our LUMEVOQ® or GS030 product candidates or any other of our product candidates or technologies covered by the asserted third-party patents. In several major territories, including the United States, in order to successfully challenge the validity of any such U.S. patent in federal court, we would need to overcome a presumption of validity. As this is a high burden requiring to present clear and convincing evidence as to the invalidity of such U.S. patent claim, there is no assurance that a court of competent jurisdiction would invalidate the claims of any such U.S. patent. In addition, even if we were to prevail in any such litigation, the cost and diversion of management and employee attention could be significant and could adversely affect our business. Where a patent issued by the EPO, otherwise known as a European Patent, is concerned, it may be necessary to do this on a country-by-country basis, leading to increased litigation costs and diversion of management and employee attention. The risks of such third-party action equally apply outside the United States or the European Union, where it may also be necessary to establish, through a court or other procedure, that a patent is invalid.

If we are found to infringe a third party’s valid and enforceable intellectual property rights, we could be forced, including by court order, to cease developing, manufacturing and commercializing the infringing technology or product candidates. In addition, we could be found liable for monetary damages, including treble damages and attorneys’ fees if we are found to have willfully infringed a patent or other intellectual property right. A finding of infringement could prevent us from manufacturing and commercializing our product candidates or force us to cease some of our business operations. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business, financial condition, results of operations or prospects. We may be able to avoid such an outcome by obtaining a license from such third party to continue developing, manufacturing and marketing our product candidates and technology; however, we may not be able to obtain such a license on commercially reasonable terms or at all. Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors and other third parties access to the same technologies licensed to us, and it could require us to make substantial licensing and royalty payments.

3.6Insurance and risk management

We have implemented a policy to cover the main insurable risks with coverage amounts that we deem compatible with the nature of our operations. The total amount of premiums booked for all of our insurance policies for the fiscal year ended December 31, 2021 amounted to €76 K.

As a development-stage business, we are unable to quantify risk to determine a coverage amount, in particular with respect to civil liability. However, we consider that the insurance policies described below adequately cover the risks inherent to our operations and that our insurance policy is consistent with practice in our sector. We do not envisage any particular difficulty in maintaining appropriate levels of insurance in the future subject to market conditions and capacities.

Please note that as of the date of this Universal Registration Document, the insurance policies related to RESCUE, REVERSE, REALITY and CLIN01 trials have been terminated, as the trials they covered are finished.

Our insurance policies are summarized below:

Risks covered | Insurer | Amount | Excess per claim
Comprehensive professional insurance | GENERALI (N° AT060531) | Globally capped at €5,900 K (2021 amounts) |
Sub-limits for operating direct damages and additional costs combined: |  |  |
•Climate events (excluding natural disasters) |  | €1,000 K |
•Electrical damages |  | €300 K |
•Machinary breakdown |  | €900 K |
•Costs and losses |  | €1,000 K |
•Liability, including use of third parties |  | €4,500 K |
•Automatic guarantee |  | €500 K |
•Error or omissions |  | €500 K |
•Other damages |  | €2,000 K |
Sub-limits for direct damages |  |  |
•Theft |  | €100 K |
•Computer equipment breakdown |  | €700 K |
•Asset in travel status and/or transport for own account |  | €100 K |
•Asset in deposit with third parties, limited to fire and assimilated events |  | €2,000 K |
•Glass breakage |  | €20 K |
•Research and Development expenses |  | €250 K |
Directors & Officers civil liability insurance: claims made or pursued worldwide | AIG (7.919.283) | Capped at €5,000 K except for: (per “insured year”) |
Reputation damage |  | €100 K |
Psychological support |  | €50 K |
Consulting fees in case of extradition |  | €50 K |
Support expenses in case of property restrictive measures |  | €60 K per insured person with a maximum amount of €200 K per insured year |
Risk mitigation expenses |  | €500 K per insured year, with a maximum amount of €1,000 K for all insured persons |
Consulting fees related to a judicial liquidation |  | €50 K |
Preliminary investigation expenses following a social action ut singuli |  | €250 K |
Non-separable fault |  | €5,000 K |
Fund for prevention for financial difficulties |  | €30 K |
Consulting fees on the WCAM regulation within the framework of a group action related to financial securities |  | €50 K |
Emergency fees |  | €1,000 K |
Independent Director |  | €1,000 K |
Claim related to a pollution |  | €1,000 K |
Civil Liability | CHUBB (N° RC0099500275) |  |
Civil operating liability: |  |  |
All damage taken together including bodily harm: |  | €7,500 K per “claim” |
•Inexcusable fault |  | €1,000 K per victim capped at €3,000 K per “insured year” |
•All “material” and “non-material” damage including: |  | €1,500 K per “claim” |
—“non-consecutive non-material damage” |  | €200 K per “claim” | €1,500
—“property damage” |  | €50 K per “claim” | €1,500
—“any damage resulting from accidental pollution” |  | €300 K per “insured year” | €1,500
Criminal defense-Appeal |  | €30 K per dispute | €1,500
Civil product liability: |  |  |
All damage taken together including bodily harm: |  | €5,000 K | €10 K
•“Non-consecutive non-material damage” |  | €200 K except for professional civil liability €1,000 K | €10 K
Employee Travel Insurance | CHUBB (N° FRBBBA22378) |  |
Death or total permanent invalidity |  | Up to €500 K depending on the person insured |
Assistance (for individuals and legal assistance abroad, business assistance, travel incident assistance) |  | Travel incidents: up to €15 K, Legal assistance: up to €20 K |
Medical insurance and luggage and professional equipment insurance |  | No limitation for medical insurance out of the country of residence and €5 K for luggage and professional equipment |
Civil responsibility |  | Up to €7,500 K |
Homeworkers Policy | RSA |  |
•Employer’s liability |  |  |
Limit of Indemnity any one Event (excluding liability arising directly or indirectly out of Terrorism) |  | £10,000 K |
Limit of Indemnity any one Event arising directly or indirectly out of Terrorism |  | £5,000 K |
•Public Liability / Product Liability |  |  |
Limit of Indemnity any one Event |  | £2,000 K |
Limit of Indemnity any one Period of Insurance in respect of Products |  | £2,000 K |
Limit if Indemnity any one Period of Insurance in respect of Pollution |  | £2,000 K |
•Legal Defense Costs |  |  |
Limit of Indemnity in any one Period of Indemnity |  | £250 K |
•Legal Expenses Insurance |  |  |
Limit any One Claim |  | £100 K |
Limit in total for all claims in any one Period of Insurance |  | £1,000 K |
Personal Accident and Travel Policy |  |  |
•Personal Accident Cover | AIG | £25 K |
•Travel |  | Up to £5,000 K |
Research sponsor’s civil liability insurance |  |  |
Study GS-LHON-CLIN-03A in mainland France and its overseas departments and territories: | HDI Gerling |  |
•Victim |  | €1,000 K | €1,500 per victim capped at €16 K per protocol
•Research protocol |  | €6,000 K |
•Claims made during an insurance year by one and the same sponsor for several research protocol |  | €10,000 K |
Study GS-LHON-CLIN 03A in Italy, U.K. and USA: | ALLIANZ |  |
•ITALY |  |  |
—Per victim |  | €1,500 K |
—Per research protocol |  | €5,000 K |
•UNITED KINGDOM |  |  |
—Per research protocol |  | £5,000 K |
•UNITED STATES |  |  |
—Per research protocol |  | $5,000 K |
Study GS-LHON-CLIN-03A in Germany | ALLIANZ |  |
•Per victim |  | €500 K |
—if up to 1,000 patients participate in this trial |  | €5,000 K |
—if more than 1,000 patients and up to 3,000 participate in this trial |  | €10,000 K |
—if more than 3,000 patients participate in this trial |  | €15,000 K |
Study GS-LHON-CLIN-03B in France métropolitaine and DOM-TOM: | HDI Gerling |  |
•Per victim |  | €1,000 K | €1,500 per victim capped at €16 K per protocol
•Per research protocol |  | €6,000 K |
•Claims made during an insurance year by one and the same sponsor for several research protocol |  | €10,000 K |
Study GS-LHON-CLIN-03B in Italy, U.K. and USA | ALLIANZ |  |
•ITALY |  |  |
—Per victim |  | €1,500 K |
—Per research protocol |  | €5,000 K |
•UNITED KINGDOM |  |  |
—Per research protocol |  | £5,000 K |
•UNITED STATES |  |  |
—Per research protocol |  | $5,000 K |
Study GS-LHON-CLIN-03B in Germany | ALLIANZ |  |
•Per victim |  | €500 K |
—if up to 1,000 patients participate in this trial |  | €5,000 K |
—if more than 1,000 patients and up to 3,000 participate in this trial |  | €10,000 K |
—if more than 3,000 patients participate in this trial |  | €15,000 K |
GS-LHON-CLIN-05 | HDI Global SE |  |
•FRANCE |  |  |
—Per victim |  | €1,000 K | €1,500 per victim capped at €16 K per protocol
—Per research protocol |  | €6,000 K |
—Claims made during an insurance year by one and the same sponsor for several research protocol |  | €10,000 K |
•ITALY | ALLIANZ |  |
—Per victim |  | €1,500 K |
—Per research protocol |  | €5,000 K |
•UNITED KINGDOM | ALLIANZ |  |
—Per research protocol |  | £5,000 K |
•UNITED STATES | ALLIANZ |  |
—Per research protocol |  | $5,000 K |
•BELGIUM | HDI Global SE |  |
—Per victim |  | €650 K |
—Per research protocol |  | €5,000 K |
•TAIWAN | Allianz GCS |  |
—Per victim |  | €500 K |
—Per research protocol |  | €2,000 K |
•SPAIN | HDI Global SE |  |
—Per victim |  | €250 K |
—Per research protocol |  | €2,500 K | Per protocol and annually
GS-LHON-CLIN-06 |  |  |
•FRANCE | HDI Global SE |  |
—Per victim |  | €1,000 K | €1,500 per victim capped at €16 K per protocol
—Per research protocol |  | €6,000 K |
—Claims made during an insurance year by one and the same sponsor for several research protocol |  | €10,000 K |
•ITALY | CNA |  |
—Per victim |  | €1,000 K |
—Per research protocol |  |  |
▪If # subject less than or equal to 50 |  | €5,000 K |
▪If # subject more than 50 but less than 200 |  | €7,500 K |
▪If # subject more than 200 |  | €10,000 K |
•UNITED KINGDOM | CNA |  |
—Per victim |  | £5,000 K |
—Per research protocol |  | £5,000 K |
•UNITED STATES | CNA |  |
—Per victim |  | $5,000 K |
—Per research protocol |  | $5,000 K |
•GERMANY | HDI Global SE |  |
—Per victim (for death) |  | €50 K for patient of 18 up to 64 €37.5 K for patient of 65 up to 69 €25 K for patient of 70 up to 74 |
—Per victim (for disability) |  | €100 K for patient of 18 up to 64 €75 K for patient of 65 up to 69 €50 K for patient of 70 up to 74 |
GS030-CLIN-001 | HARDY |  |
•UNITED STATES |  |  |
—Per claim, per research subject |  | $5,000 K |
—Per clinical trial |  | $7,500 K |
—Globally during the period of insurance |  | $7,500 K |
•FRANCE | HDI Global SE |  |
—Per victim |  | €1,000 K | €1,500 per victim capped at €16 K per protocol
—Per research protocol |  | €6,000 K |
—Claims made during an insurance year by one and the same sponsor for several research protocol |  | €10,000 K |
•UNITED KINGDOM | CAN/HARDY |  |
—Per victim |  | £5,000 K |
—Per research protocol |  | £5,000 K |

Although we maintain insurance coverage for our clinical trials in the amount of €1 million per victim, €6 million per protocol and €10 million in the aggregate over a one-year period, this insurance may not be adequate to cover all liabilities that we may incur. We anticipate that we will need to increase our insurance coverage each time we commence a clinical trial and if we successfully commercialize any product candidate. Insurance coverage is increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise.

3.7Internal control and risk management procedures

As part of its listing on Euronext Paris, the Company has implemented an internal control policy and a certain number of procedures. Over time, the Company seeks to conform to AMF recommendations for small and medium-sized companies with regard to internal control.

The internal control procedures implemented by the Company are intended to:

•ensure control over operations, employee behavior and optimal resource management, in accordance with the framework defined by management, laws and applicable regulations;

•anticipate and control the risks inherent to the Company’s activities, whether operational, industrial or financial.

3.7.1 GENERAL INTERNAL CONTROL ORGANIZATION.

Internal control within the Company is handled, in fine, by the Board of Directors, assisted by the Audit and Compensation Committees. The Company is managed operationally by two internal committees, the Executive Committee and the Management Committee.

Executive Committee

Upstream of the Board of Directors, and more operationally, an Executive Committee (ComEx) ensures compliance with current procedures. This Committee meets once a week, and consists of the chief financial officer, chief medical officer, SVP commercial head and chief executive officer, who chairs it.

The Executive Committee assists the chief executive officer in the Company’s strategic and operational management.

Management Committee

The Executive Committee is supported by a Management Committee (CoDir), which is the operational review body for the Company’s projects. The Management Committee meets once a week and consists of the members of the Executive Committee and the Company’s principal managers. It meets to monitor performance and adjust the operational orientation, if needed. The Company’s Management Committee is a true place for exchange and reflection and plays a role in controlling and coordinating all operational teams. The Management Committee is responsible for meeting the Company’s annual corporate objectives.

3.7.2 INTERNAL CONTROL AND RISK MANAGEMENT PROCEDURES.

The procedures implemented by the Company as part of its internal control are reviewed and evaluated by the statutory auditors during their annual reviews of half-year and annual consolidated financial statements. The findings of these tasks are shared with the Company’s financial management, allowing it to take corrective measures and improve the Company’s internal control. These findings are also shared with the Audit Committee.

3.7.2.1Financial risk management

Accounting and financial information

The Company’s accounting is operated by both the financial department and an independent accounting firm using a dedicated ERP system.

The recording of accounting items, preparation of accounting information, reporting and corporate reports and documentation are provided internally, while the independent firm provides monthly controls, calculation of the research tax credit (CIR) and tax returns.

The work is reviewed and analyzed within the Company’s finance department, which prepares quarterly management reports for operations. These reports enable management to assess current expenses, with respect to the budget and various quarterly forecasts, and to take corrective measures if needed.

As of the date of this Universal Registration Document, the Company has implemented the following internal control procedures related to accounting and financial information, as well as the preparation of consolidated financial statements:

•the Company maintains, internally, a separation between the production and the control of financial operations, accounting procedures and the preparation of consolidated financial statements;

•an independent certified public accounting firm provides payroll management, as well as social security and tax returns;

•valuation and assessment of specific financial items, either complex or relying on subjective assumptions, are subcontracted to third-party experts. These items include notably the CIR, the provisions for compensation payable to employees on their retirement, the evaluation of derivative financial instruments and their accounting treatment under IFRS and the expense related to share-based payments;

•the Company has implemented an integrated system that provides for book keeping and securing the purchase-to-pay workflow, including electronic approvals, as well as automated entries and payments;

•the Company has implemented monthly closing procedures and key controls (Cut-off entries, Bank statement reconciliations, Manual journal entries review, Balance sheet substantiation, Payroll reconciliation, etc.) in order to ensure the reliability of the financial information; and

•the Company has also implemented expense-control measures, using an electronic purchase order system. Invoice payments are prepared by the “accounting” function, automatically and electronically transmitted to the bank for payment, and validated by the “controlling” function.

Payroll management

Payroll is also subcontracted in its entirety to an accounting firm. We performed a monthly three-way reconciliation control (reconciliation between the payroll journal, accounting entries and bank statement) over the documentation received by the third-party provider.

3.7.2.2Operational risk management

Given its stage of development, the Company’s operations are primarily:

•preclinical and toxicity studies of drug candidates;

•pharmaceutical and clinical development of drug candidates.

3.7.2.2.1Preclinical research and toxicity studies of drug candidates

These activities are subcontracted to top-tier, specialized international providers operating in accordance with Good Laboratory Practices (GLP) and certified by AAALAC International, a private non-profit organization that is an international reference in assessing the humane animal treatment in experimentation.

3.7.2.2.2Pharmaceutical and clinical development of drug candidates

These activities are subcontracted to top-tier, specialized international providers operating in accordance with both Good Laboratory Practices (GLP) and Good Clinical Practices (GCP).

The manufacturing of clinical supply is subcontracted to Contract Manufacturing Organizations (CMOs).

3.7.2.3Our internal controls, procedures and policies may fail to ensure adherence to applicable regulations

Our internal controls, disclosure controls and procedures and corporate governance policies and procedures are periodically reviewed and updated. Any system of controls, however, is based in part on certain assumptions and can provide only reasonable, rather than absolute, assurances that the objectives of the system are met. Any failure or circumvention of our controls and procedures or failure to comply with regulations related to controls and procedures could have a material adverse effect on our business, financial condition, results of operations and prospects.

4

INFORMATION ABOUT THE ISSUER

4.1 Legal and commercial name

Our corporate name is “GenSight Biologics S.A.”

4.2 Place of registration, registration number and legal entity identifier (“LEI”)

We are registered with the Paris Trade and Companies Register under number 751 164 757.

The Company is identified under the Legal Entity Identifier (LEI) 549300NK4AB8OUEX1F54.

4.3Date of incorporation, length of life of the issuer

We were incorporated on April 17, 2012.

The Company’s duration is 99 years from the date of its with the Paris Trade and Companies Register except in the event of early dissolution or extension.

4.4 Domicile, legal form, legislation, country of incorporation, address, telephone number and website

Our registered office is located at 74, rue du Faubourg Saint-Antoine – 75012 Paris, France (Tel.: +33 (0)1 76 21 72 20).

We are a French limited liability corporation (société anonyme) with a Board of Directors, governed by French law, including, in particular, Book II of the French Commercial Code.

Our website address is www.gensight-biologics.com

The information on the website does not form part of this Universal Registration Document unless that information is incorporated by reference into it.

5

BUSINESS OVERVIEW

5.1Overview

We are an innovative clinical-stage gene therapy company with an initial 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 a long-lasting cure for severe inherited retinal diseases for which there are no currently approved treatments. 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 and drug 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 lead product candidate, LUMEVOQ®, is a recombinant AAV2-based gene therapy for the treatment of Leber Hereditary Optic Neuropathy, or LHON, and is currently in the registration phase in Europe and in Phase III clinical trials in the United States. 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. 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. Our second most advanced product candidate, GS030, for the treatment of Retinitis Pigmentosa, or RP, is currently in an open-label, dose escalation 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.

LUMEVOQ® for the Treatment of LHON

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.

Our lead product candidate, LUMEVOQ®, was developed using our MTS technology platform and is designed to treat LHON by restoring the function of NADH dehydrogenase resulting from 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, internalization and proper localization 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.

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 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 less than 12 months.

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 fiber 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 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 Week 72, compared to the Week 48 improvement of +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).

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.

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 non-injected eye after unilateral IVT. LUMEVOQ® vector DNA was detected or quantified in the contralateral non-injected eyes for 5 of the 6 animals in the treatment group. In addition, vector DNA was detected or quantified in the optic chiasm of all 6 animals. The results of the non-human primate study were published in the journal Molecular Therapy – Methods and Clinical Development in December 2021.

In September 2020, a new meta-analysis of the natural history of Leber Hereditary Optic Neuropathy (LHON) was published in the Journal of Neuro-Ophthalmology, the official journal of the North American Neuro-Ophthalmology Society (NANOS). The paper, written by leading global authorities on LHON, confirms the low rate of spontaneous visual recovery in patients with a mutated ND4 gene, the most common cause of the disease. For those 15 years or older at onset of visual loss, only an estimated 11.3% experienced some degree of visual recovery.

To contrast the results from RESCUE and REVERSE against the observed natural progression of the disease, we also undertook a statistical analysis comparing the trial results to outcomes from published natural history studies and the registry study REALITY, which the Company conducted in 2018-2020. The statistical comparison showed a significant difference in the evolution of visual acuity among patients treated with LUMEVOQ® versus that of those who were not treated. Treated eyes showed progressive and sustained improvement from Month 12 to Month 52, in contrast to the absence of recovery over the same period for untreated eyes. At Month 18, the difference became statistically significant (p = 0.01). By Month 48, the difference between the mean visual acuity in treated patients and that in untreated patients was both statistically significant (p < 0.01) and clinically meaningful (-0.33 LogMAR, or +16.5 ETDRS letters equivalent, in favor of treated eyes). These findings were published in the journal Frontiers in Neurology in May 2021.

The complete results at 96 weeks of our Phase III REVERSE trial and RESCUE trial formed the core body of evidence, along with an indirect comparison against natural history, that supported our filing for marketing authorization in the European Union on September 14, 2020. We believe that the benefits of LUMEVOQ® treatment may prevent further vision loss and/or restore vision, leading to increased autonomy and overall quality of life for affected individuals.

Review of the MAA for LUMEVOQ® is ongoing. The Company received an initial set of questions from the EMA at the Day 120 clock stop of the procedure. Initially planned to end in May 2021, the D120 clockstop was extended three times by the EMA for a total of 17 months, following operational issues in producing validation batches (PPQ) at the Company's contract manufacturing partner in the US.

GenSight Biologics is working with its partner to implement targeted corrections around enhanced process control and more rigorous supervision inside the manufacturing suites. In addition, engineering lots will be used to confirm the robustness of the corrective actions.

GenSight targets the restart of the PPQ campaign in Q3 2022 and to submit responses to the Day 120 questions in October 2022, as agreed with the EMA. The responses will incorporate updates based on the trials that were ongoing when the MAA was filed.

•One trial was REFLECT, which was a multi-center, randomized, double-masked, placebo-controlled Phase III study to evaluate the safety and efficacy of bilateral injections of LUMEVOQ® in 98 subjects and which was designed under a Special Protocol Assessment with the FDA. The study reported topline results at the time point of its primary efficacy endpoint (1.5 year after treatment) in June 2021 and 2 years results in December 2021. At 1.5 year after injection, mean best-corrected visual acuity (BCVA) in LUMEVOQ®-treated eyes was statistically significantly better than baseline, whereas the improvement from baseline was not statistically significant in placebo eyes. Consistent with REVERSE and RESCUE, unilaterally treated subjects showed a contralateral effect in their placebo-treated eye. The contralateral effect reduced the difference in the outcomes among LUMEVOQ®- and placebo-treated eyes, and consequently, the trial did not meet the pre-defined primary endpoint. Responder analyses showed that most of the subjects responded to treatment and confirmed that bilateral injections provide better efficacy. Comparison against the worst observed visual acuity (the “nadir”) demonstrated the treatment effect even more strongly. Finally, the favorable safety profile of LUMEVOQ® was again confirmed. A subsequent Year 2 readout demonstrated that the visual improvements were maintained.

The year 2 analysis showed that the mean BCVA for bilaterally and unilaterally treated subjects reached 1.32 and 1.44 LogMAR respectively, with an absolute difference between treatment arms of +6 ETDRS letters favoring bilaterally treated subjects. This efficacy was demonstrated more clearly in visual acuity improvements from nadir (worst BCVA recorded from baseline to year 2). Subjects treated bilaterally with LUMEVOQ® saw an improvement in BCVA of (-0.39 LogMAR [+20 ETDRS letters equivalent] and ‑0.34 LogMAR [+17 ETDRS letters equivalent]) in the first-affected eye and second-affected/not-yet-affected eye respectively. Subjects treated unilaterally with LUMEVOQ® showed an improvement of (-0.38 LogMar [+19 ETDRS letters equivalent] and -0.27 LogMAR [+14 ETDRS letters equivalent] in the first-affected eye and placebo-treated eye respectively. The results in the placebo-treated eyes confirm the contralateral effect observed in the three previous Phase III clinical trials.

•The second trial that will inform the Day 120 responses is RESTORE, the long-term follow-up study to which subjects in RESCUE and REVERSE were invited. Study results at Year 3 showed sustained treatment effect from a unilateral injection of LUMEVOQ® three years after injection in the RESCUE and REVERSE trials; steady improvement of visual acuity meant that the average visual acuity of the subjects was at an on-chart level at Year 3. The improved vision was matched by increased Quality of Life (QoL) self-reported scores from the subjects. The findings were published in the Journal of Neuro-Ophthalmology (JNO) in August 2021. Year 4 results became available in January 2022 and confirm the durability of the Year 3 results.

In the United States, the FDA advised in a Type-C meeting in January 2022 that the Company conduct an additional placebo-controlled trial to bolster the demonstration of LUMEVOQ® efficacy in view of the unexpected bilateral effect observed in unilaterally treated patients in the RESCUE, REVERSE and REFLECT trials. The Company is engaging with the FDA on the design of such a trial and aims to initiate it as soon as product from the PPQ campaign becomes available towards the end of 2022.

On September 6, 2021 the Company announced that Lumevoq® had been granted Promising Innovative Medicine (PIM) designation by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of vision loss due to LHON caused by a confirmed m.11778G > A mutation in the ND4 mitochondrial gene.

A PIM designation is an early indication that a medicine is a promising candidate for the MHRA’s Early Access to Medicines Scheme (EAMS) for the treatment, diagnosis, or prevention of life-threatening or seriously debilitating conditions with an unmet need. The EAMS is similar to the Cohort ATU (Autorisation Temporaire d’Utilisation de Cohorte [Cohort Temporary Authorization for use]) program in France.

For more information on clinical trials protocols, see Section 5.2.2 “Our Lead Product Candidate: LUMEVOQ® for the Treatment of LHON”, of this Universal Registration Document.

GS030 for the Treatment of RP

We are developing GS030 for the treatment of diseases of photoreceptor degeneration that include RP and dry age-related macular degeneration, or AMD, with and without geographic atrophy, or GA. We initially focused our studies on the treatment of RP, which is an orphan family of diseases caused by multiple mutations in over 100 genes involved in the visual cycle. On average, RP patients begin experiencing vision loss as young adults, eventually becoming blind around the age of 40 to 45. RP is the most widespread hereditary cause of blindness in developed nations, with a prevalence of about 1.5 million people throughout the world. In Europe and the United States, the prevalence of RP is approximately one in 3,500 and one in 4,000 and the incidence of new patients each year is 15,000 and 20,000. There is currently no existing treatment for RP.

GS030 utilizes our novel optogenetics technology platform. Optogenetics is a biologic technique that involves the transfer of a gene that is encoding for a light-sensitive protein to cause neuronal cells to respond to light stimulation. Our platform of optogenetics targets retinal ganglion cells, or RGCs, and modifies them into becoming true photoreceptors. This allows us to confer a photoreceptive function to the healthy and preserved RGCs independent of any specific underlying genetic mutation that caused the original degeneration of photoreceptor cells. Light stimulation, which activates the protein, is amplified and enhanced by an external wearable device designed as goggles. We developed these goggles to amplify the light stimulation upon the transduced neuronal cells and expand vision restoration. We believe our technology would be immediately transferable to any disease in which photoreceptors are lost while RGCs remain, such as dry AMD and GA. Approximately 15 million people are affected with AMD in the United States, with a global prevalence of 170 million, and dry AMD accounts for approximately 80% of all cases of late-stage AMD. Given this, we expect to initiate clinical trials of GS030 for the treatment of dry AMD and GA.

GS030 received orphan drug designation for the treatment of RP in the United States and the European Union and advanced therapy medicinal product, or ATMP, classification for the treatment of RP in the European Union. Our preclinical proof-of-concept studies have demonstrated that GS030 can restore light sensitivity in the retina of blind mice and non-human primates. In other preclinical studies, we have also restored visual behaviors in vivo in blind rats using GS030 with demonstrable effects upon their visual cortex. We received approval in December 2017 from the UK’s Medicines and Healthcare Products Regulatory Agency, or MHRA, followed by the French Agence nationale de sécurité du médicament et des produits de santé, or ANSM, in May 2018 and the U.S. FDA in August 2018, to conduct a Phase I/II clinical trial in severely affected RP subjects and treated the first subject in October 2018.

The Data Safety Monitoring Board (DSMB) completed all safety reviews of the ongoing PIONEER Phase I/II clinical trial of GS030, GenSight’s novel product combining gene therapy and optogenetics for the treatment of Retinitis Pigmentosa (RP).

The DSMB found no safety issue in the third cohort of patients, who received an intravitreal injection with the highest dose (5e11 vg) among the three cohorts studied to date, followed by the use of a wearable optronic visual stimulation device. Based on GS030’s safety profile, the DSMB recommended selecting this dose for the extension cohort and using the protocol without any modification in the cohort. Recruitment of this cohort is ongoing.

A case report of a patient, who was treated with a low dose (5e10 vg) of the gene therapy and subsequently experienced visual recovery, was published in Nature Medicine in June 2021. In November 2021, the company reported a second case of a patient with late-stage retinitis pigmentosa (RP), who partially recovered her visual function after treatment with GS030 optogenetic therapy. The second patient had been treated with the medium dose (1.5E11 vector genomes) in her worse-seeing eye.

The U.S. Food & Drug Administration (FDA) has granted Fast Track Designation to GS030 in October 2021.

Our Technology Platforms and Other Applications

We believe our integrated technology, which combines gene therapy with our core MTS and optogenetics technology platforms, has the potential to replace or restore the function of retinal cells, either RGCs or photoreceptors that have degenerated in order to regain vision for patients, thereby improving the quality of their lives. Beyond our initial product candidate, LUMEVOQ® for the treatment of LHON, we believe that our MTS technology platform can be applied to treatments for LHON caused by other single mutations, including our second LHON product candidate, GS011, to treat LHON due to mutation in the ND1 gene. Similarly, we believe that GS030 using our optogenetics platform can address any disease of photoreceptor degeneration regardless of the etiology and be entirely transferable to dry AMD or GA, offering a meaningful benefit to these diseases that have significant unmet medical needs.

In addition, our MTS and optogenetics technologies have potential applicability outside of our initial focus on severe retinal diseases. We believe our MTS technology platform, given its unique ability to actively shuttle mitochondrial proteins into the mitochondrion, enables the development of treatments for the many indications involving defects of the mitochondrion, including such rare diseases as Kearns-Sayre syndrome and Alpers disease, and possibly more common disorders such as Parkinson’s disease and amyotrophic lateral sclerosis, or ALS. Similarly, we believe this gene therapy approach of our optogenetics platform that permits the introduction of proteins sensitive to light stimulation has broad applicability to indications outside ophthalmology that are receptive to light stimulation, such as congenital deafness, pain treatment and vagus nerve stimulation.

We own or have exclusively in-licensed all intellectual property rights covering our MTS and optogenetics platform technologies and our current product candidates. In addition, we hold worldwide commercialization rights to our technology platforms, product candidates and development programs. Because of the orphan nature of LHON and RP, we believe a limited and targeted sales and marketing organization would be able to reach specialized ophthalmology centers and their patients.

Our Management and Scientific Team

We believe that we have a significant competitive advantage as a result of the collective experience of our management and scientific team in the biotechnology industry, specifically in the areas of ophthalmology and gene therapy. Our Chief Executive Officer and co-founder, Bernard Gilly Ph.D., has over 20 years of experience in the pharmaceutical sector and as an entrepreneur. Other members of our executive management team have significant experience in the discovery and development of gene therapy and ophthalmology drug products. Our co-founder, José-Alain Sahel M.D. Ph.D., is Chairman of Departments of Ophthalmology at the Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts and the Rothschild Ophthalmology Foundation in Paris, France. He was the Director of Institut de la Vision until 2021. Since July 2016, Dr. Sahel has also been appointed Chairman of the Department of Ophthalmology at the University of Pittsburgh Medical Center. Such experience plays a critical role in our core MTS and optogenetics technology platforms and reflects substantial cross-disciplinary knowledge.

5.2Our Product Development Pipeline

Our pipeline is comprised of two lead product candidates for the treatment of sight-threatening retinal degenerative diseases, together with preclinical development programs targeting ophthalmic and neurodegenerative diseases. Below is a table summarizing our development programs:

We filed for regulatory approval of LUMEVOQ® with the EMA in Europe as planned in September 2020. Depending on the progress of our interactions with regulatory authorities, LUMEVOQ® could then potentially be in a position to be approved in Europe in Q3 2023, subject however to a variety of factors, including changes in regulatory requirements, evolutions in guidance from the FDA, the EMA or other European regulatory authorities, and the occurrence of unexpected events in the approval process, preparation for commercialization or otherwise, any of which could impact our anticipated timeline and our ability to obtain regulatory approval and commercialize LUMEVOQ®. For a description of such factors, see Section 3 “Risk Factors” of this Universal Registration Document.

5.2.1 GENE THERAPY IN THE EYE: A WELL-VALIDATED APPROACH.

The eye is a validated target organ for gene therapy due to its accessibility, small size, compartmentalization and relative immune privileged status. In addition to having a validated manufacturing process, vectors based on adeno-associated virus, or AAV, are believed to be especially well suited for treating severe retinal diseases because AAV is a small, replication-deficient virus that is non-pathogenic and has a well-documented safety profile. The vectors can be directly injected into the diseased tissue and their effects can be non-invasively observed for efficacy and safety. The blood-ocular barrier prevents the widespread dissemination of locally administered vectors throughout the body. Given the small volume of the eye, the amount of vector needed to achieve a therapeutic effect is low, reducing the amount of vector required to be administered to the patient and reducing potential systemic side effects or immune response. In addition, the reduced volume requirement provides us with the advantage of small-scale manufacturing requirements for clinical trials and potential commercialization.

Our Gene Therapy Approach

Building on our scientific expertise and clinical experience of our team, we have developed two proprietary technology platforms, MTS and optogenetics. These technologies are combined with a gene therapy-based approach and have the potential to reverse vision loss, thereby improving the quality of their lives.

•Our MTS technology platform allows for efficient expression of a mitochondrial gene by active delivery of mRNA to polysomes located at the mitochondrial surface. This allows for the synthesis, translocation, internalization and proper localization of the 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, to enable the restoration of mitochondrial function necessary to potentially treat a variety of diseases involving defects of the mitochondrion.

•Our novel optogenetics technology platform permits the introduction of proteins sensitive to light stimulation and may have broad applicability to indications within ophthalmology and others that are receptive to light stimulation, such as congenital deafness, pain treatment and vagus nerve stimulation.

5.2.2 OUR LEAD PRODUCT CANDIDATE: LUMEVOQ® FOR THE TREATMENT OF LHON.

We are leveraging our MTS technology platform to develop LUMEVOQ® as a treatment for LHON due to a mutation in the ND4 gene, a rare mitochondrial genetic disease that leads to blindness in teens and young adults. We believe that LUMEVOQ® has the potential to be the first therapy approved by the FDA for the treatment of LHON. We have received orphan drug designation for LUMEVOQ® in the United States and the European Union.

LHON Overview

LHON is a rare maternally inherited disease caused by defects in mitochondrial genes encoding for proteins called NADH dehydrogenase. LHON causes sudden and dramatic loss of vision, leading to bilateral blindness in less than a year, which reduces patients’ autonomy and greatly alters the patient’s ability to perform daily life activities, including recognizing facial features and expressions. In addition, LHON causes patients and their family’s trauma socially, emotionally and financially, and the quality of life of patients with LHON is generally poor. The onset of vision loss due to LHON typically occurs between 15 and 35 years of age. The following images are representative of the early onset of vision loss due to LHON, as described by patients.

LHON is caused by defects in mitochondrial genes encoding for proteins called NADH dehydrogenase. These proteins are part of a large enzyme complex known as the respiratory chain complex I, or complex I, which is active in the mitochondrion. Complex I is one of several enzyme complexes necessary for the creation of adenosine triphosphate, or ATP, which is the main energy source within the cell. Three different genes encoding for three NADH dehydrogenases have been linked to LHON and are considered to be the primary mutations for the disease to manifest: ND1, ND4 and ND6.

Although the genetic mutation is present throughout the body, LHON symptoms are almost uniquely limited to retinal ganglion cells, or RGCs. RGCs receive visual information from photoreceptors, and collectively transmit visual information from the retina to the brain via the optic nerve. Over the months after onset, LHON is associated with a significant thinning of the RGC layer. Once the RGCs degenerate, signals can no longer be transmitted to the brain.

Patients with LHON typically suffer vision loss over a period of weeks and overwhelmingly both eyes are ultimately affected. Commonly, vision loss is sequential, although some patients report simultaneous bilateral onset. Within 6 months after onset, there is atrophy of the optic nerve. Although maintaining some small element of peripheral vision, the majority of patients with the ND4 mutation become legally blind. For most patients with the ND4 mutation, vision is not recovered.

For ND4 patients, studies have shown that the delay between the first affected and second affected eye averages 1.8 month and the duration of progression of vision loss averages 3.2 months. The mean Early Treatment Diabetic Retinopathy Study, or ETDRS, score at 12 months is 14.4 letters in patients. The normal visual acuity score is 20/20 or 20/25, equivalent to an ETDRS score of 85 and 80 letters, respectively.

For patients with the most severe vision loss, specifically those who cannot count the fingers of the examiner held very close to their face, even small improvements such as going from off-the ETDRS chart to on the-chart or an improvement by five to 10 ETDRS letters can have a positive impact on functionality and quality of life.

The following close-up image depicts a cross-section of the human retina:

The layers of the retina are visible in the right panel, and the left panel is a cross-section of the eye including unlabeled viral particles.

No Effective Existing Therapies for the Treatment of LHON

No treatments for LHON have been approved in the United States. In the European Union, the European Medicines Agency, or EMA, granted Marketing Authorization, or MAA, for Raxone/Idebenone under “exceptional circumstances” as a treatment for LHON in September 2015, though no clinically significant effect of this agent has been demonstrated or studied in randomized clinical trials. A MAA under exceptional circumstances is when comprehensive data cannot be provided, and therefore the MAA is reviewed annually to re-assess the risk-benefit balance, in an annual re-assessment procedure.

Market Opportunity for LHON

LHON is the most common illness caused by mitochondrial DNA mutations. We estimate the incidence of LHON to be approximately 1,400 to 1,500 new patients who lose their sight every year in the United States and Europe. LHON is estimated to have a prevalence of between one in 31,000 and one in 40,000 in Northern Europe. European and North American studies of LHON patients indicate that the ND4 mutation accounts for up to 70% of LHON cases. In Asian countries, the proportion of ND4 mutation is higher, ranging from 80% to 85%.

Our Solution: LUMEVOQ® for the Treatment of LHON

LUMEVOQ® is developed through our MTS technology platform and is designed to restore the function of NADH dehydrogenase and therefore improves vision. Our LUMEVOQ® product candidate is a recombinant AAV vector, serotype 2, or AAV2, containing the human wild-type mitochondrial ND4 gene combined with our proprietary MTS technology. We are developing LUMEVOQ® for the treatment of LHON due to the ND4 gene mutation with visual loss of less than one year.

Our novel, proprietary MTS platform technology has enabled us to develop LUMEVOQ® with potential advantages, including:

•IVT administration, a straightforward and common approach well-accepted by ophthalmologists, in contrast to subretinal injections;

•use of the AAV2 vector, which is the most studied of all AAVs, with a demonstrated safety profile and validated manufacturing process; in addition, there are currently no IP rights attached to AAV2 and thus no royalty payments associated with its use;

•small viral load administered, decreasing the risk of systemic immunologic response;

•injection of small volumes, reducing the likelihood of ophthalmic complications; and

•small required volumes, resulting in ease of manufacturing.

The following image depicts the schematic design of LUMEVOQ®, which includes the steps listed below the image. LUMEVOQ® allows an efficient expression in the cell nucleus of a mitochondrial wild-type ND4 gene, encoding for a protein which is normally produced in the mitochondrion.

ITR: Inverted Terminal Region; PCMV: Promoter cytomegalovirus; cDNA: complementary DNA; ND4: NADH Dehydrogenase Subunit 4.

•The ND4 transgene is flanked by two oligonucleotide sequences, referred as MTS1 and MTS2 in the above diagram.

•MTS2 allows the ND4 mRNA to be addressed to polysomes that are attached to the outer mitochondrial membrane, where it is translated into ND4 protein.

•MTS1, in turn, allows the ND4 protein to be transported through the mitochondrion membrane into the matrix where it integrates the complex I of the respiratory chain in order to restore normal function.

Our construction of LUMEVOQ®, that includes the two MTSs and the functional transgene, is what actively drives this into the mitochondrial matrix, and characterizes the unique nature of our MTS platform, as depicted in the following image.

Clinical Development Program for LUMEVOQ®

We have completed REVEAL, a Phase I/II clinical trial for LUMEVOQ® and our two most advanced Phase III clinical trials, RESCUE and REVERSE, reported top-line results in 2018 and 2019. Both of these Phase III trials are designed as randomized, double-masked, sham-controlled, multi-center clinical trials in Europe and the United States, of LHON subjects with the ND4 mutation with vision loss. RESCUE has enrolled 39 subjects with an onset of vision loss of less than 6 months in duration and REVERSE has enrolled 37 subjects with an onset of vision loss between 6 and 12 months. Based on our regulatory interactions, subjects as young as 15 are included in our Phase III clinical trials.

Time since onset of vision loss is considered a major factor in the ability to intervene therapeutically due to the neuro-degenerative nature of LHON and the cell death of the RGCs. We have therefore chosen to evaluate two subject groups in these two Phase III clinical trials based on the onset of vision loss of less than one year. This will allow us to define the efficacy of LUMEVOQ® in early affected populations of subjects at different stages of the disease and to compare an otherwise homogeneous patient population.

Our Phase III clinical trials are intended to determine if LUMEVOQ® is an effective treatment in halting or reversing vision loss associated with LHON due to the ND4 mutation. A dose level of 9E10 vg/eye was administered once by IVT injection in both trials to a randomly chosen single eye of each subject. The dose level of LUMEVOQ® in our Phase III clinical trials was determined based on outcomes of the safety and tolerability in our Phase I/II clinical trial.

The primary endpoint of the RESCUE and REVERSE clinical trials is based on Best Corrected Visual Acuity, or BCVA, as measured with the ETDRS at 48 weeks post-injection relative to baseline. The patients’ log of the Minimal Angle of Resolution, or logMAR, scores, which are derived from the number of letters they read on the ETDRS chart, will be used for statistical analysis. Both trials have been adequately powered to evaluate a clinically relevant difference of at least 15 ETDRS letters between treated and untreated eyes adjusted to baseline.

The secondary efficacy endpoints compare the best seeing eyes that received LUMEVOQ® to those that received sham, and compare worse seeing eyes that received LUMEVOQ® to those that received sham. We will evaluate the proportion of subjects who maintain vision (< ETDRS 15L loss), the proportion of subjects who gain 15 ETDRS letters from baseline, and the proportion of subjects with Snellen acuity of > 20/200. Complementary vision metrics will include automated visual fields, optical coherence tomography, or OCT, and color and contrast sensitivity, in addition to quality of life scales, bio-dissemination and the time course of immune response.

Full results of REVEAL were published in BioDrugs in February 2021.

REVERSE: Results at 48, 72 and 96 weeks

In April 2018, we reported top-line results from REVERSE, our first Phase III clinical trial evaluating the safety and efficacy of a single intravitreal injection of LUMEVOQ® (rAAV2/2-ND4) in 37 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) commenced between 6 and 12 months prior to study treatment.

Top-line results highlight the favorable safety and tolerability profile of LUMEVOQ®, and demonstrate a clinically meaningful improvement of +11 ETDRS letters (-0.218 LogMAR) in treated eyes at 48 weeks as compared to baseline in all 37 patients. Unexpectedly, untreated contralateral eyes (treated with a sham injection) show a similar improvement of +11 ETDRS letters (-0.211 LogMAR). Due to this improvement in untreated eyes, the trial did not 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 weeks in October 2018 and 96 weeks in May 2019, showing a continued clinically meaningful improvement of visual acuity of +15 ETDRS letters (-0.308 LogMAR) in treated eyes, and of +13 ETDRS letters (-0.259 LogMAR)(2) in untreated eyes. This improvement, which extends the positive trend that had been reported at Weeks 48 and 72, points to a sustained functional outcome for the trial subjects.

The improvement of visual acuity in sham-treated eyes was unexpected based on the natural history of LHON, for which limited partial spontaneous recovery is reported in only 8 to 22% of patients with the G11778 ND4 mutation (Lam et al. 2014, Riordan-Eva et al. 1995).

The graph below shows the mean change from baseline in visual acuity, in both treated (LUMEVOQ®) and untreated (sham) eyes, over time in LogMAR:

Continued bilateral improvement was also observed in contrast sensitivity as determined by Pelli-Robson low-contrast testing. At 96 weeks, LUMEVOQ®-treated eyes and sham-treated eyes gained on average +0.22 LogCS and +0.12 LogCS versus baseline, respectively.

In a natural history study conducted by Santhera(3), 15% of subjects who had the 11778A mutation achieved the following definition of spontaneous “clinically relevant recovery” (CRR) from baseline in at least one eye:

•Improved by at least 10 ETDRS letters from on-chart visual acuity, or

•Improved from off-chart visual acuity to being able to read at least 5 ETDRS letters.

By comparison, 68% of REVERSE subjects achieved this definition of CRR in at least one eye at Week 96, with LUMEVOQ®-treated eyes significantly more likely to achieve this than sham-treated eyes (62% vs. 43%, p = 0.0348).

The objectively measured endpoints were the effects of LUMEVOQ® on parameters measured with high resolution Spectral-Domain Optical Coherence Tomography (SD-OCT). The trial demonstrated relative preservation of the structure of the retina in both treated and untreated eyes, specifically the volume of the retinal ganglion cells and the thickness of the nerve fiber layers. The critical secondary endpoint of the change in retinal ganglion cell macular volume measured from baseline to Week 96 demonstrated a reduced loss of volume of –0.018 mm3 for LUMEVOQ® eyes and -0.031 mm3 for sham eyes.

The secondary endpoint of change in thickness of the papillo-macular bundle of the retinal nerve fiber layer from baseline to Week 96 demonstrated preservation of retinal nerve fibers LUMEVOQ®-treated eyes showing a change in thickness of +1.3 µm and sham eyes showing change in thickness equal to +0.6 µm. The change in thickness of the temporal quadrant of the retinal nerve fiber layer from baseline to Week 96 demonstrated reduced loss of retinal never fibers, with LUMEVOQ® eyes showing a change in thickness of -1.5 µm and sham eyes –2.4 µm.

In May 2019, we reported continued quality of life improvements at 96 weeks. All 37 patients in REVERSE were asked to complete the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), a reliable and valid vision-specific quality-of-life instrument that measures patients’ perception of their ability to perform daily activities requiring high-acuity vision and their general sense of well-being. The test defines sub-scales for functions such as near-distance vision and vision-related dependency as well as measures of well-being such as ocular pain and vision-related mental health. These sub-scale scores are aggregated into a composite score, excluding the general health rating question.

Well-accepted as a source of patient-reported measures of vision-related function, the questionnaire has been used in many clinical trials. A study in neovascular AMD – which, like LHON, leads to loss of central vision – showed that a clinically meaningful 15-letter change in BCVA was associated with a 4- to 6-point change in the NEI VFQ-25 composite score and in sub-scores in three pre-specified areas (near activities, distance activities, and vision-specific dependency).

At Week 96, REVERSE patients reported mean improvement from baseline for NEI VFQ-25 scores in domains important to patients with loss of central vision: near activities, distance activities, vision-specific dependency and composite score. An improvement had already been observed at Week 48, confirming sustained enhancement of ability to perform activities of daily living. In addition, large improvements were also noted in other domains relevant to LHON patients: role difficulties, general vision, and overall mental health. Again, the improvements observed at Week 48 were sustained at Weeks 72 and 96. The relevant comparison in REVERSE is against patients’ own baseline, because the NEI VFQ-25 is assessed by patient; by design, all REVERSE patients received an injection in one eye.

NEI VFQ-25 Results from REVERSE

Mean change from baseline (absolute score and percent)

| Composite Score** | Near Activities | Distance Activities | Dependency | Role Difficulties | General Vision
Week 48 | +7.2 | +10.4 | +9.6 | +12.4 | +14.5 | +10.3
23.2% | 65.1% | 49.8% | 100.6% | 65.0% | 50.9%
Week 72 | +8.1 | +9.5 | +8.2 | +18.9 | +15.2 | +11.9
25.2% | 58.1% | 42.5% | 130.2% | 70.9% | 54.1%
Week 96 | +9.5 | +13.3 | +10.7 | +18.5 | +15.9 | +6.5
28.8% | 78.1% | 47.4% | 130.2% | 78.9% | 32.4%

* Suñer et al. (2009): clinically relevant score differences based on a clinically significant 15-letter BCVA improvement at 12 months.

** The composite score is an average of the vision-targeted sub-scale scores, excluding the general health rating question.

Full results of REVERSE were published in Science Translational Medicine in December 2020.

RESCUE: Results at 48, 72 and 96 weeks

In February 2019, we reported top-line results from RESCUE, our second Phase III clinical trial evaluating the safety and efficacy of a single intravitreal injection of LUMEVOQ® (rAAV2/2-ND4) in 39 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) commenced up to 6 months prior to study treatment.

Visual loss in LHON usually progresses such that vision reaches a nadir in 3 to 5 months, before stabilizing; the duration and severity of this progression to nadir varies from patient to patient. In RESCUE, mean best-corrected visual acuity (BCVA) of LUMEVOQ®-treated eyes and sham-treated eyes evolved with similar trajectories, worsening to a low point before showing an improvement at Week 48. At Week 48, change from baseline for LUMEVOQ®-treated eyes was +0.380 LogMAR (–19 ETDRS letters), while that for sham-treated eyes was +0.392 LogMAR (-20 ETDRS letters). These figures incorporate a recovery from the nadir of vision loss for drug- and sham-treated eyes: mean improvement from nadir was +13 ETDRS letters equivalent in LUMEVOQ®-treated eyes and +12 ETDRS letters equivalent in sham-treated eyes. Due to this bilateral improvement, the primary efficacy endpoint, defined as a +15‑letter difference in visual acuity improvement for LUMEVOQ®-treated eyes compared to sham-treated eyes at 48 weeks, was not met.

Planned analysis of other visual functions and anatomic measures showed results broadly consistent with the direction of BCVA evolution: similar trajectories for LUMEVOQ®-treated and sham-treated eyes with the difference in change from baseline not being statistically significant at Week 48.

We reported follow-up results at 72 weeks in April and 96 weeks in September 2019, showing sustained recovery from the lowest point, or nadir, experienced in the acute phase of the disease. By Week 96, LUMEVOQ®-treated eyes improved by -0.526 LogMAR (+26 ETDRS letters) from nadir, compared to the Week 48 improvement of -0.257 LogMAR (+13 ETDRS letters) and the Week 72 improvement of -0.413 LogMAR (+21 ETDRS letters). This sustained at Week 96 could not yet completely offset deterioration from baseline through the acute phase: LUMEVOQ®-treated eyes were still below baseline by 0.178 LogMAR (-9 ETDRS letters), compared to 0.380 LogMAR (-19 ETDRS letters) at Week 48. The U-shaped curve thus closely matched that of LUMEVOQ®-treated eyes, so a statistically significant difference in visual acuity between LUMEVOQ®- and sham-treated eyes could not be shown.

Time Course of Best-Corrected Visual Acuity (BCVA) in LogMAR

The strength of the bilateral recovery shifted the mean BCVA in both sets of eyes from off-chart values at Week 48 to on-chart values at Weeks 72 and 96. In addition, 61% of LUMEVOQ®-treated eyes improved by a clinically meaningful difference of at least -0.3 LogMAR (+15 ETDRS letters) from nadir. Similarly, 71% of LUMEVOQ®-treated eyes improved by a clinically meaningful difference of -0.2 LogMAR (+10 ETDRS letters) from nadir.

Contrast sensitivity (CS), a second visual function, evolved in a manner similar to BCVA: while values for LUMEVOQ®-treated eyes and sham-treated eyes remained below baseline, CS also recovered so that the gap to baseline diminished at Weeks 72 and 96 compared to Week 48. The two sets of eyes closely matched each other, so that the difference between their CS values was not statistically significant.

Full results of RESCUE were published in Ophthalmology, the journal of the NANOS, in January 2021.

In a natural history study conducted by Santhera, 28% of subjects who had the 11778A mutation achieved the following definition of spontaneous “clinically relevant recovery” (CRR) from nadir in at least one eye:

•Improved by at least 10 ETDRS letters from on-chart visual acuity, or

•Improved from off-chart visual acuity to being able to read at least 5 ETDRS letters.

By comparison, 68% of REVERSE subjects achieved this definition of CRR in at least one eye at Week 96, with LUMEVOQ®-treated eyes as likely to achieve this as sham-treated eyes (58% vs. 45%, p = 0.0956).

Change from in Best-Corrected Visual Acuity (LogMAR and ETDRS Letter Equivalents)

| Change from BASELINE
Week 48 | Week 72 | Week 96
LS Mean (SE) (a) | n | LogMAR | ETDRS Letters Equivalent | n | LogMAR | ETDRS Letters Equivalent | n | LogMAR
GS010 Eyes | 37 | -0.218 (0.055) | +11 | 37 | -0.294 (0.063) | +15 | 37 | -0.308 (0.068)

| Change from BASELINE
Week 48 | Week 72 | Week 96
LS Mean (SE) (a) | n | LogMAR | ETDRS Letters Equivalent | n | LogMAR | ETDRS Letters Equivalent | n | LogMAR
GS010 Eyes | 34 | +0.380 (0.129) | -19 | 34 | +0.192 (0.104) | -10 | 34 | +0.168 (0.132)

(a) Efficacy Endpoint was assessed using a mixed model of analysis of covariance (ANCOVA), with change from baseline at week of interest as the response, and subject, eyes of the subject as random factor, treatment and the baseline LogMAR value as covariates.

| Change from NADIR(a)
Week 48 | Week 72 | Week 96
Mean (SD) (b) | n | LogMAR | ETDRS Letters Equivalent | n | LogMAR | ETDRS Letters Equivalent | n | LogMAR
GS010 Eyes | 37 | -0.487 (0.426) | +24 | 37 | -0.553 (0.444) | +28 | 37 | -0.566 (0.450)

| Change from NADIR(a)
Week 48 | Week 72 | Week 96
Mean (SD) (b) | n | LogMAR | ETDRS Letters Equivalent | n | LogMAR | ETDRS Letters Equivalent | n | LogMAR
GS010 Eyes | 34 | -0.287 (0.377) | +14 | 34 | -0.509 (0.496) | +25 | 34 | -0.526 (0.479)

(a) Nadir was defined as the lowest Visual Acuity value from baseline up to Week of interest. LP/NLP vision was not included in the analysis.

(b) Mean change from nadir was calculated using observed values (no data were imputed).

REVERSE and RESCUE Safety

REVERSE and RESCUE studies demonstrated a consistent safety read-out: LUMEVOQ® was well-tolerated over 96 weeks. There were no serious adverse events in LUMEVOQ®-treated eyes, and no discontinuations due to ocular events. Most frequently seen ocular adverse events in the therapy group were mainly related to the injection procedure, except for the occurrence of intraocular inflammation, likely related to LUMEVOQ®, and responsive to conventional treatment and without sequelae. There were neither systemic serious adverse events nor discontinuations that were related to study treatment or study procedure.

Non-Human Primate Study

We conducted a non-clinical study in non-human primates to further investigate the bilateral effect observed in both REVERSE and RESCUE trials. In this study, we reported positive proof of LUMEVOQ® DNA transfer from one eye to the other eye following unilateral intravitreal injection of primates.Tissue samples from the non-injected eye of monkeys that had been unilaterally injected with LUMEVOQ® were found to contain LUMEVOQ® DNA three months after injection, indicating the expression of the therapeutic gene in the contralateral eye.

LUMEVOQ® is currently being investigated in an additional ongoing Phase III trial, REFLECT, while patients in REVERSE and RESCUE continue to be followed for a total period of 5 years.

REFLECT

REFLECT is a multi-center, randomized, double-masked, placebo-controlled Phase III study to evaluate the safety and efficacy of bilateral injections of LUMEVOQ® in subjects with LHON due to the NADH dehydrogenase 4 (ND4) mutation.

REFLECT is conducted under a Special Protocol Assessment with the FDA on request of the Agency.

The trial enrolled 98 patients with vision loss up to 1 year in duration and will be conducted in multiple centers in Europe and in the U.S.

In the active arm, LUMEVOQ® will be administered as a single intravitreal injection to both eyes of each subject. In the placebo arm, LUMEVOQ® will be administered as a single intravitreal injection to the first affected eye, while the fellow eye will receive a placebo injection.

The primary endpoint for the REFLECT trial is the BCVA reported in LogMAR at 1.5-Year post-treatment in the second-affected/not-yet-affected eye. The change from baseline in second-affected/not-yet-affected eyes receiving LUMEVOQ® and placebo will be the primary response of interest. The secondary efficacy endpoints include: BCVA reported in LogMAR at 2-Years post-treatment in the second-affected/not-yet-affected eye compared to both placebo and the first-affected eye receiving LUMEVOQ®, OCT and contrast sensitivity and quality of life scales. The first subject was treated in March 2018, and enrollment was completed in July 2019, ahead of schedule.

On June 30, 2021, the company reported the topline results from the REFLECT phase III clinical trial, confirming LUMEVOQ® efficacy including better efficacy with bilateral treatment.

On December 14, 2021, the company reported topline efficacy and safety results at 2 years post-treatment administration in the REFLECT Phase III clinical trial with LUMEVOQ®. The results show sustained efficacy and safety for bilateral intravitreal injection of the gene therapy, including better efficacy compared to unilateral injection.

Significant visual acuity improvement over baseline, with better results for bilaterally injected patients

At the primary time point of the analysis, 1.5 years after injection, mean best-corrected visual acuity (BCVA) in LUMEVOQ®-treated eyes was statistically significantly better than baseline, whereas the improvement from baseline was not statistically significant in placebo eyes.

Table 1: Change in Best-Corrected Visual Acuity (BCVA versus Baselin, 1.5 Year after Injection

| 1st-affected eye | 2nd-affected eye
Bilaterally injected subjects | LUMEVOQ 0.23 LogMAR (+12 ETDRS letters equivalent; p = 0.001**) | LUMEVOQ 0.15 LogMAR (+8 ETDRS letters equivalent; p < 0.05*)
Unilaterally injected subjects | LUMEVOQ 0.15 LogMAR (+8 ETDRS letters equivalent; p < 0.05*) | PLACEBO 0.08 LogMAR (+4 ETDRS letters equivalent; p = NS)

Consistent with REVERSE and RESCUE, unilaterally treated subjects showed a contralateral effect in their placebo-treated eye (Figure 1). The contralateral effect reduced the difference in the outcomes among LUMEVOQ®- and placebo-treated eyes, and consequently, the trial did not meet the pre-defined primary endpoint. The difference of the change from baseline in BCVA between the second affected LUMEVOQ® and placebo-treated eyes was -0.05 LogMAR (+3 ETDRS letters equivalent; p = 0.6080).

Figure 1: Best-Corrected Visual Acuity (BCVA) Change fom Baseline (LogMAR) – Eye Groups

Note: Differene from baseline LogMAR. LS mean are estimated by mixed models at the eye level, adjusted on baseline, with repeated values for each patient.

A dose effect, seen between bilaterally and unilaterally treated subjects, provides new evidence on LUMEVOQ® efficacy. In each group, the BCVAs of both eyes improved from baseline in tandem, but with a higher treatment effect for bilaterally treated subjects (Figure 2). The mean BCVA at 1.5 years for bilaterally and unilaterally treated subjects reached 1.35 and 1.45 LogMAR, respectively, with an absolute difference between arms of +5 letters in favor of bilaterally treated subjects.

Figure 2: Mean BCVA over time (LogMAR) – Eye Groups

Note: Mean LogMAR at each timepont.

Responder analyses show that most of the subjects responded to treatment and confirm that bilateral injections provide better efficacy. Most of the subjects had on-chart BCVAs at 1.5 year (able to read letters on a screen): 85% of bilaterally treated subjects and 72% of unilaterally treated subjects.

The REFLECT trial confirmed the favorable safety profile of LUMEVOQ®, with no study discontinuation related to systemic or ocular adverse events. The main ocular adverse event was intraocular inflammation which was mostly mild and responded to conventional treatment.

The safety and efficacy profile of LUMEVOQ® from the three phase III trials, RESCUE, REVERSE, and REFLECT is highly consistent across studies.

Based on the data from our Phase III trials, we plan to initiate preclinical studies of GS011, our product candidate for the treatment of LHON subjects with the ND1 mutation with vision loss.

Phase I/II Dose-Escalation Safety Trial for LUMEVOQ®

In 2014, we initiated a 15 subject Phase I/II safety trial of LUMEVOQ® (CLIN-01), which was designed to test the safety and tolerability profile of LUMEVOQ® with ascending doses in subjects with LHON due to the ND4 mutation. Each subject received a single IVT injection of LUMEVOQ® in the more severely affected eye. Subjects enrolled were required to have severe vision loss, with acuities of less than 20/200. The trial included four ascending dose cohorts each comprised of three subjects: 9E9 vector genome per eye, or vg/eye in cohort 1, 3E10 vg/eye in cohort 2, 9E10 vg/eye in cohort 3 and 1.8 E11 vg/eye in cohort 4. Once the maximum tolerated dose was established, according to the protocol, we included three additional subjects in the trial.

Overall, 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. The most common ocular side effects were elevated intraocular pressure, or IOP, and ocular inflammation. These side effects were mostly mild, transient and, when required, treatment responsive to standard therapies, without vision loss.

The secondary endpoints included immuno-monitoring and vector bio-dissemination, visual acuity, color and contrast vision as well as structural tests such as OCT and electrophysiological tests related to the functioning of the RGCs and the optic nerve.

The results of our Phase I/II clinical trial, which were released in June 2016, demonstrated that:

•all 15 subjects completed 48 weeks of follow-up;

•consistent with the protocol requiring treatment of the worst functioning eye, baseline mean logMAR, visual acuity was worse in the treated eyes than non-treated fellow eyes;

•the magnitude of the treatment effect was impacted by disease duration and baseline vision status at the time of treatment;

•a greater magnitude of treatment effect was observed when disease duration was less than two years compared to greater than two years; and

•the magnitude of treatment effect was greater when the baseline vision status was relatively better.

After talks with consultants, we designed our ongoing Phase III trials to target a more homogeneous patient population, with more recently diagnosed (less than 12 months) vision loss, to maximize the benefits and efficacy of treatment.

Visual Function Evolution: Trends of Improved Acuity at 2.5 Years of Follow-up

In December 2017, we reported results in 14 subjects after 2.5 years of follow-up (one subject withdrew its consent after 48 weeks of follow-up). As described in the following table, we continued to observe a greater magnitude of treatment effect when the disease duration was less than two years as compared to a disease duration that was greater than two years.

ETDRS letters (LogMAR) Visual Acuity change from baseline ∆ Treated Eye vs. Untreated Eye | 1.0 year | 1.5 year | 2.0 years
All subjects (n = 14) | +3 letters (-0.06) | +8 letters (-0.16) | +0 letters (-0.00)

Note (*) Excludes “hand motion” subjects, in accordance with the Phase III protocol.

In the following chart, five letters correspond to one line on the ETDRS chart. Therefore, a difference of 15 letters is equivalent to three lines on the ETDRS chart, the widely recognized standard of clinically significant improvement.

Evolution of visual acuity in the treated eye vs. untreated eye at 2.5 years of follow-up in subjects with vision loss duration ≤ 2 years and Baseline LogMAR ≤ 2.79 (n = 5)

(i.e., excludes “hand motion” subjects, in accordance with the Phase III protocol).

Long-term Safety at 5 Years of Follow-Up

In February 2021, we published in the journal BioDrugs full results of the REVEAL trial, demonstrating favorable safety and tolerability of LUMEVOQ® over a 5-year follow-up period.

Additional Studies

REALITY

REALITY is a retrospective and cross-sectional observational study of subjects with LHON, conducted in centers across Spain, Italy, France, United Kingdom, and the United States. The objective is to generate insights about the natural history of the disease based on an approach that would facilitate comparisons with REVERSE and RESCUE. The study seeks to enroll 50 subjects by the second quarter of 2020.

Interim analysis of REALITY reported in December 2019, based on the fifteen subjects with the ND4 mutation who were at least 15 years old at onset and who had enrolled in the study as of September 2019, shows the dramatic and usually irreversible decline in visual acuity that is the typical outcome for ND4 LHON patients. Unlike in subjects enrolled in REVERSE and RESCUE, who all received a unilateral injection of LUMEVOQ®, mean visual acuity in REALITY subjects did not recover after the initial decline. The results confirm LHON experts’ observations from their clinical practice.

Figure 1. LHON Natural History from Interim Analysis of REALITY vs. Time Course of Visual Acuity from REVERSE and RESCUE

Note: BCVA = best-corrected visual acuity. The LOWESS line for REALITY (n = 15 subjects) is based on a series of polynomial regressions around each data point. The regressions use a limited look back and look forward and give distant points less weight. The time course of BCVA for REVERSE and RESCUE uses the least-squares mean based on a mixed model ANCOVA analysis. The starting points of the curves are set to the average time from onset to time of treatment (16 weeks for RESCUE, 39 weeks for REVERSE).

A second set of results, derived from a pooled dataset of baseline readings from the REVERSE and RESCUE patient populations, shows that eyes farther along the progression of the disease, as measured by time since onset, had worse visual acuity.

Figure 2. Best-Corrected Visual Acuity (BCVA) Prior to Injection Among REVERSE and RESCUE Patients, by Time Since Onset

Note: Eyes of REVERSE and RESCUE patients were categorized according to the time between onset of vision loss and baseline reading (one day before injection). The n’s represent the number of eyes in each time grouping. By design, the maximum value for onset in the pooled data is 12 months. The average for each group represents the least-squares mean of BCVA values in LogMAR. The y-axis shows an inverted LogMAR scale to represent worse vision with lower vertical positions.

The picture of visual decline is based on cross-sectional data, yet remains consistent with the pattern revealed by the interim analysis for REALITY.

Statistical analysis of the visual acuity in 23 REALITY subjects aged 15 or older with a mutated ND4 gene shows that on average, vision failed to recover from an initial sudden decline, even several years after vision loss. The sharp deterioration followed by an extended period of low visual acuity stands in sharp contrast with the improvements observed in the LUMEVOQ® RESCUE and REVERSE trials.

The study aimed to enroll 50 subjects, but enrollment was curtailed due to measures taken to protect patients in the Covid-19 pandemic. Of the 44 subjects who were enrolled before the Covid-19 measures took effect, 23 were 15 years old or older at the time of vision loss due to their mutated ND4 gene. Of these 23 ND4 subjects, 15 had been treated with idebenone, the majority within 12 months of their vision loss.

The RESCUE and REVERSE pivotal trials evaluated the efficacy and safety of a single intravitreal injection of LUMEVOQ® in LHON subjects who were at 0-6 months and 6-12 months, respectively, from onset of vision loss due to carrying a mutated ND4 mitochondrial gene. 61 of the RESCUE and REVERSE subjects accepted the invitation for long-term follow-up in the CLIN06 trial, which recently reported initial results.

Indirect comparison to Natural History

In order to address the bilateral effect observed in RESCUE and REVERSE, the Company performed a statistical analysis of pooled data from LUMEVOQ® trials and natural history studies demonstrating a statistically significant and clinically meaningful difference between the visual outcomes in LUMEVOQ®-treated patients and untreated patients. Treated patients showed progressive and sustained improvement from Month 12 to Month 52, in contrast to the absence of recovery over the same period for untreated patients. At Month 18, the difference became statistically significant (p = 0.01). By Month 48, the difference between the mean visual acuity in treated patients and that in untreated patients was both statistically significant (p < 0.01) and clinically meaningful (–0.33 LogMAR, or +16.5 ETDRS letters equivalent, in favor of treated eyes).

Figure 1. Evolution of Visual Acuity in LUMEVOQ®-treated Patients (N = 76) versus Untreated Patients (N = 208)

Note: All patients had a confirmed G11778A mutation in the ND4 mitochondrial gene and were at least 15 years old. The diagram shows the Locally Estimated Scatterplot Smoothing (LOESS) curves for visual acuity in LUMEVOQ®-treated patients and untreated patients. The shaded areas represent the 95% confidence interval for the mean BCVA. “Treated” eyes refer to all eyes (LUMEVOQ® and sham) from the RESCUE, REVERSE and CLIN06 trials (N = 76 patients / 152 eyes). Untreated eyes refer to patient-level data from the REALITY study and a matched data set from two prospective and eight retrospective natural history studies (N = 208 patients / 408 eyes). LOESS curves were estimated using a non-parametric, local regression model that treated each eye as independent of the other. LOESS curves are shown from Month 12 to depict post-treatment progression among treated patients (93% of LUMEVOQ® patients had already been treated within 12 months from onset). *Statistically significant difference between mean visual acuity of treated and untreated eyes at M18, M24, M36 and M48, as illustrated by the non-overlapping confidence intervals.

The analysis compared data from the completed Phase III trials RESCUE and REVERSE studies and interim results from the long-term follow-up CLIN06 study to a matched sample created from the REALITY registry study and 10 other natural history studies. The natural history studies were identified from an extensive review of the scientific literature and selected based on specific inclusion criteria for their patient-level data. In all, the visual outcomes in 76 treated patients could be compared to the visual outcomes of 208 untreated patients.

Separate analysis of patients enrolled in RESCUE and REVERSE demonstrated similarly favorable results compared to untreated patients. Full findings from the indirect comparison were included in the European Marketing Authorization Application (MAA) for LUMEVOQ® and are being prepared for publication in a peer-reviewed journal.

In addition, a new meta-analysis of the natural history of Leber Hereditary Optic Neuropathy (LHON) was published in September 2020 in the Journal of Neuro-Ophthalmology, the official journal of the North American Neuro-Ophthalmology Society (NANOS). The paper, written by leading global authorities on LHON, confirms the low rate of spontaneous visual recovery in patients with a mutated ND4 gene, the most common cause of the disease. For those 15 years or older at onset of visual loss, only an estimated 11.3% experienced some degree of visual recovery.

The Journal of Neuro-Ophthalmology paper, entitled “Visual Outcomes in Leber Hereditary Optic Neuropathy Patients with the m.11778G>A (MTND4) Mitochondrial DNA Mutation”, overcame the challenge of small patient numbers by conducting a meta-analysis of 12 retrospective and 3 prospective studies, which were identified after an extensive review of the scientific and medical literature. Treatment with idebenone did not exclude patients from the sample. This approach enabled the authors to analyze the evolution of visual function in 695 patients with a mutated ND4 gene.

The estimate of the rate of spontaneous recovery in the paper provides important context for the bilateral improvement observed in the pivotal trials RESCUE and REVERSE for GenSight Biologics’ lead product, LUMEVOQ®, a gene therapy for patients with LHON caused by a mutated ND4 gene. In the trials, the rate of clinically meaningful improvement from nadir of at least 0.3LogMAR, or at least 3 lines on the Snellen chart, was 76% in REVERSE and 71% in RESCUE.

Non-clinical mechanistic study in primates

In 2019, we conducted a non-clinical study to investigate the local biodistribution of LUMEVOQ®. Tissue samples from the non-injected eye of monkeys that had been unilaterally injected with LUMEVOQ® were found to contain LUMEVOQ® DNA three months after injection, indicating the expression of the therapeutic gene in the contralateral eye.

Performed by CiToxLAB France, a leading CRO for preclinical research, the study was initiated by GenSight to investigate potential mechanisms behind the unexpected contralateral effect seen in two of LUMEVOQ®’s Phase III trials, REVERSE and RESCUE. Both trials documented sustained bilateral improvements in LogMAR mean visual acuity. The contralateral effect did not conform to expectations for gene therapies administered to only one eye.

The CiToxLAB study used a purpose-bred species of monkeys, which is favored by scientists and accepted by regulatory bodies due to physiological similarities with humans. For testing at three months, a control monkey was given an intravitreal injection of saline solution in its right eye and was not injected in its left eye. Three test monkeys were given an intravitreal injection of LUMEVOQ® in their right eyes and not injected in their left eyes. The dosage of LUMEVOQ® was calibrated to be the allometric equivalent of that used in the LUMEVOQ® Phase III trials. Three months after the injection, tissues from the right and left eyes were sampled and tested using a qPCR test which had been validated in a dedicated prior study. The highly sensitive and accurate test contains a protocol that specifically targets a portion of the LUMEVOQ® DNA and can detect the LUMEVOQ® DNA matrix.

As expected, the qPCR test did not detect the LUMEVOQ® DNA in any of the tissue samples from the control monkey unilaterally injected with saline solution. Also as expected, the test was able to detect, and in many cases, quantify the presence of LUMEVOQ® DNA in tissue samples from LUMEVOQ®-injected right eye. Remarkably the qPCR test was also able to detect, and even quantify, viral DNA vector in the contralateral eye, which had received no injection.

Presence of LUMEVOQ® DNA in the visual and cerebral systems of test monkeys

Note: qPCR test used to detect LUMEVOQ® DNA was validated in a dedicated study conducted prior to the monkey study. The graph depicts the number of monkeys whose tissues contained DNA that were within the sensitivity of the test to detect. In some cases, the levels were above the quantifiable threshold.

DNA was detected and quantified in the anterior segment, the retina, as well as the optic nerve of the non-injected contralateral eye. In addition, DNA was detected and quantified in the optic chiasm, suggesting that the anatomic route taken by the viral vector DNA from the treated eye to the non-treated eye could be via the optic nerves and chiasm.

RESTORE

The company reported in January 2022 the results of the RESTORE study, four years after injection. RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials.

When RESTORE subjects enrolled in the study, 2 years after the one-time injection, they had already experienced clinically meaningful improvements relative to the lowest point (the “nadir”) of their bestcorrected visual acuity (BCVA): +18.8 ETDRS letters equivalent* in their LUMEVOQ®-treated eyes and +17.3 letters equivalent in their sham-treated eyes. Four years after treatment, the bilateral improvement from nadir was sustained, with LUMEVOQ®-treated eyes achieving a mean improvement against nadir of +22.5 letters equivalent and sham-treated eyes demonstrating a mean improvement of +20.5 letters equivalent.

The impact of such results on patients is demonstrated by increases in the self-reported quality of life (QoL) scores at Year 4 vs. baseline. Mean overall QoL increased by a clinically meaningful magnitude relative to baseline, driven by clinically meaningful increases in the sub-scores corresponding to mental health and the ability to carry out activities autonomously (e.g., role difficulties, dependency, near and far activities, general vision).

RESTORE is one of the largest long-term follow-up studies for a rare disease treatment, with 62 subjects accepting the invitation to enroll. All subjects, who were affected by LHON caused by a mutated ND4 mitochondrial gene, were treated with an intravitreal injection of LUMEVOQ® in one eye and with sham injection in the other.

Table 1: BCVA Mean Improvement vs. Nadir* in LUMEVOQ® long-term follow-up (RESTORE)

| 2 Years post-injection | 3 Years post-injection | 4 Years post-injection
LOGMAR (Std Error) | Letters Equivalent** | LOGMAR (Std Error) | Letters Equivalent** | LOGMAR (Std Error) | Letters Equivalent**
LUMEVOQ®-treated eyes | -0.375 (0.306) | +18.8 | -0.410 (0.365) | +20.5 | -0.453 (0.440) | +22.5
Sham-treated eyes | -0.346 (0.291) | +17.3 | -0.367 (0.369) | +19.4 | -0.406 (0.361) | +20.5

Note: The RESTORE sample consists of the RESCUE and REVERSE participants who accepted to be followed in the long-term follow-up study. Year 4 values were the LogMAR readings nearest to 461 days post-treatment recorded between 1461+/- 273 days post-treatment. Missing values were imputed using the Last Observation Carried Forwad (LOCF) method.

* Nadir = worst best-corrected visual aculty recorded from baseline to Year4.

** Assessments of best-corrected visual aculty (BCVA) were recorded in LogMAR was converted to “letters equivalent” improvement by multiplying the LogMAR by -50 (ref. J.T. Holladay, J. Refrac Surgery, 1997; 13, 388-391).

Responder analyses at Year 4 indicate that improved BCVA was a benefit for a substantial proportion of the study participants. 71.0% of RESTORE subjects achieved Clinically Relevant Recovery (CRR)4 against nadir four years after treatment, and 80.7% of them had on-chart vision (BCVA ≤ 1.6 LogMAR) in one or both eyes. Viewed against the trend in vision typically seen in untreated patients5, the findings represent a significant departure from the natural progression of LHON.

Figure 1: Evolution of BCVA in LUMEVOQ®-treated Patients (RESCUE/REVERSE/RESTORE) vs. Untreated Patients

Note: The Locally Estimated Scatterplot Smooting (LOESS) curves show the evolution, from 12 months to 52 months after onset of vision loss, of the mean BCVA in all eyes (LUMEVOQ®- and sham-treated) from REVERSE/RESCUE/RESTORE studies and all eyes from a matched cohort of patients not treated with LUMEVOQ®. The shaded areas represent the 95% confidence interval for the mean BCVA. The values < 52 months were set to 52 months. The curve starts at 12 months after onset when 92.7% of eyes in RESCUE and REVERSE had received treatment, either with LUMEVOQ® or a sham injection. The untreated cohort consisted of 208 ND4-LHON patients that wre followed in the REALITY registry and from two prospective and eight retrospective natural history studies

Safety findings at 4 years post-injection were consistent with previous readouts, which concluded that LUMEVOQ® is well-tolerated: no serious adverse events were recorded among LUMEVOQ®-treated eyes, and no discontinuations occurred due to ocular events. There were no systemic serious adverse events or discontinuations related to study treatment or study procedure.

Regulatory Interaction for LUMEVOQ®

In October 2014, we initiated our first discussions with the FDA regarding the prerequisites for future initiation of clinical trials in the United States. In June 2015, we submitted an application in the United States, which was cleared by the FDA on August 19, 2015.

Following our meetings with the FDA in April and December 2016, the FDA made recommendations with respect to our RESCUE and REVERSE studies, as well as the bilateral treatment of LHON subjects. Based on these recommendations, a special protocol assessment, or SPA, of a bilateral clinical protocol was submitted to the FDA in July 2017 for subjects with vision loss due to the ND4 mutation. The design and planned analysis of the REFLECT protocol (GS-LHON-CLIN-05) testing the efficacy and safety of bilateral injections of LUMEVOQ® has been agreed to with FDA.

In December 2019, the French National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM), granted a named patient Temporary Authorization for Use (“ATU nominative”) for LUMEVOQ® to the CHNO of the Quinze-Vingts. Dr. Catherine Vignal, who as the prescribing physician originated the request, will be able to use LUMEVOQ® to treat a patient recently affected by Leber Hereditary Optic Neuropathy (LHON). GenSight Biologics committed to provide the drug for a bilateral injection.

The temporary authorization is the outcome of a close partnership between physicians and pharmacists from the CHNO of the Quinze-Vingts, the “Ouvrir les yeux” (Open the eyes) patient advocacy group and GenSight Biologics, to the benefit of patients affected by LHON.

In France, use of pharmaceutical products not yet approved with a Marketing Authorization (AMM) and not recruiting for a clinical trial requires first obtaining an ATU from the ANSM.

Named patient ATUs are granted by the ANSM under the following conditions:

•The product is meant to treat, prevent or diagnose a severe or rare disease,

•No other appropriate treatment is available in France,

•The product’s efficacy and safety are presumed in the state of scientific knowledge,

•The ATU is requested by and remains under the responsibility of the prescribing physician when the drug has the potential to benefit the patient.

On September 6, 2021 the company announced that LUMEVOQ® had been granted Promising Innovative Medicine (PIM) designation by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of vision loss due to LHON caused by a confirmed m.11778G > A mutation in the ND4 mitochondrial gene. A PIM designation is an early indication that a medicine is a promising candidate for the MHRA’s Early Access to Medicines Scheme (EAMS) for the treatment, diagnosis, or prevention of life-threatening or seriously debilitating conditions with an unmet need. The EAMS is similar to the Cohort ATU (Autorisation Temporaire d’Utilisation de Cohorte [Cohort Temporary Authorization for use]) program in France.

In the United States, the FDA advised in a Type-C meeting in January 2022 that the Company conduct an additional placebo-controlled trial to bolster the demonstration of LUMEVOQ® efficacy in view of the unexpected bilateral effect observed in unilaterally treated patients in the RESCUE, REVERSE and REFLECT trials. The Company is engaging with the FDA on the design of such a trial and aims to initiate it as soon as product from the PPQ campaign becomes available towards the end of 2022.

LUMEVOQ® submission for Marketing Authorization

On September 14, 2020, the Company has submitted LUMEVOQ® to the EMA for marketing authorization. The Company received an initial set of questions from the EMA at the Day 120 clock stop of the procedure. Initially planned to end in May 2021, the D120 clockstop was extended three times by the EMA for a total of 17 months, following operational issues in producing validation batches (PPQ) at the Company's contract manufacturing partner in the US.

GenSight Biologics is working with its partner to implement targeted corrections around enhanced process control and more rigorous supervision inside the manufacturing suites. In addition, engineering lots will be used to confirm the robustness of the corrective actions.

GenSight targets the restart of the PPQ campaign in Q3 2022 and to submit responses to the Day 120 questions in October 2022, as agreed with the EMA. Approval is now expected in Q3 2023.

5.2.3 OUR SECOND PRODUCT CANDIDATE: GS030 FOR THE TREATMENT OF PHOTORECEPTOR DEGENERATION.

We are leveraging our optogenetics technology platform to develop GS030 for the treatment of diseases of photoreceptor degeneration that include RP, dry AMD and GA. Our most advanced clinical program using our optogenetics platform is for the treatment of RP, which is an orphan family of diseases caused by multiple mutations in over 100 genes involved in the visual cycle. There is currently no existing treatment for RP. GS030 has received orphan drug designation for the treatment of RP in the United States and the European Union and advanced therapy medicinal product, or ATMP, classification for the treatment of RP in the European Union. We are currently conducting a Phase I/II clinical trial in end stage, non-syndromic RP subjects. The first subject was treated in October 2018, and we completed the recruitment of the first three cohort in Q3 2020. We anticipate receiving interim data in H2 2022. The U.S. Food & Drug Administration (FDA) has granted Fast Track Designation to GS030 in October 2021. Upon evidence of clinical proof of concept in RP and demonstration of our approach, we believe this technology would be immediately transferable to any disease in which photoreceptors are lost while RGCs remain, such as dry AMD and GA. Given this, we expect to initiate clinical trials of GS030 for the treatment of dry AMD and GA.

RP Overview

RP is the leading cause of hereditary blindness in developed countries. RP represents a group of related genetic eye disorders that clinically manifest in visual disability. The mutations that cause RP are heterogeneous and include recessive, dominant and X-linked forms of more than 100 genes.

RP causes progressive vision loss due to degeneration of rod photoreceptors resulting in the loss of peripheral vision followed by degeneration of cone photoreceptors resulting in loss of central vision. The first symptom of RP is usually difficulty with night vision, which may occur as early as childhood. The disease progresses over a period of years or decades and often ultimately leads to complete loss of vision. Some patients become blind as early as age 30, and the majority of patients become legally blind before the age of 60. RP reduces patients’ autonomy and greatly alters the patients’ ability to perform daily life activities. The following images illustrate a representation of the deterioration of normal vision to blindness in RP.

No Existing Therapies for the Treatment of RP

No treatments for RP have been approved in the United States or the European Union. Other gene therapy approaches under development to treat vision loss due to RP are focused on specific mutations and these therapies, if approved, would be limited to specific patient subpopulations. Another alternative to treat vision loss from RP involves medical devices in the form of retinal implants, certain of which products have received marketing approval in Europe and the United States. Retinal implants have proven to restore some visual perception in patients and are intended for patients with advanced RP who have lost their photoreceptors. Therefore, treatment of RP is considered a significant unmet medical need.

Market Opportunity in RP

RP is the leading cause of hereditary blindness in developed countries, with a prevalence of about 1.5 million people throughout the world. In Europe and the United States, about 265,000 to 350,000 patients suffer from RP, and every year an estimated 10,000 to 15,000 patients with RP lose their sight. Some studies of prevalence rates of RP may underestimate the number of severely visually impaired patients with RP because they are based on patients with active follow-up care in ophthalmology clinics. We believe that many patients stop seeing ophthalmologists within a few years after reaching blindness because of a perceived lack of treatment and difficulty in traveling to medical centers.

Our Solution: GS030 for the Treatment of Photoreceptor Degeneration

GS030 is developed through our optogenetics platform and is designed to confer light sensitivity to normally light insensitive retinal neurons, specifically RGCs, in order to restore vision. While there is significant loss of photoreceptor cells in these diseases, RGCs are preserved.

Our novel, proprietary optogenetics platform technology has enabled us to develop GS030 with potential advantages over other therapies currently in development, including:

•potential to address any photoreceptor degenerative disease independent of genotype;

•IVT administration, a straightforward and common approach well-accepted by ophthalmologists, in contrast to subretinal injections;

•small viral load administered, decreasing the risk of systemic immunologic response;

•injection of small volumes, reducing the likelihood of ophthalmic complications; and

•small required volumes, resulting in ease of manufacturing.

Our primary optogenetics strategy consists of introducing ChrimsonR, a light-sensitive protein belonging to the channel rhodopsin family into normally light insensitive cells present in the inner retinal layer, particularly RGCs, via a gene therapy product injected into the vitreous of an affected eye. Upon light stimulation, the ChrimsonR protein is activated leading to an electrical response of the cell, which in turn carries electrical signals encoding visual information through the optic nerve into the visual cortex of the brain. This process mimics the natural function of the retina without the need for the initial step of the transduction cascade, which normally occurs in the outer segments of the cone. By stimulating RGCs, partial restoration of retina performance allowing daily life tasks is expected.

The figure below illustrates our optogenetics strategy aimed at restoring vision in retinal degenerative diseases, which includes the following steps:

The photoswitch gene (gene encoding for ChrimsonR protein) is packaged into an AAV2 7m8 vector.

The AAV2 7m8 carries the transgene into RGCs, resulting in synthesis of ChrimsonR protein within the membrane of the RGCs.

When appropriate light (590nm wavelength) is shed onto the RGCs expressing ChrimsonR, it results in a depolarization of the cells, creating an action potential which is then transmitted to the visual cortex by the optic nerve.

The visual cortex will then assemble the signals to form a useful image.

Because cells expressing optogenetic protein are less light sensitive than normal photoreceptors, vision under regular daylight conditions is unlikely to be possible. However, amplifying the light source and mimicking the normal retinal activity of capturing visual information will then amplify the light signal at the appropriate wavelength to enable vision restoration.

Product Structure for GS030

GS030 consists of two components:

•a gene therapy product comprising a gene encoding a photoactivatable channelrhodopsin protein, ChrimsonR, delivered via a modified AAV2 known as AAV2 7m8; and

•an external wearable device in the form of biomimetic goggles that stimulate the engineered retinal cells. The images are projected by a light source that uses a specific wavelength onto the retina.

Development Program of GS030 for the Treatment of RP

We have conducted numerous preclinical studies including a local tolerance study in mice and a long-term toxicity and biodistribution study in monkeys. GS030 for the treatment of RP is currently in an ongoing Phase I/II trial. The first subject was treated in October 2018, and we are currently recruiting the extension cohort.

Preclinical Studies of GS030 in Non-Human Primates

GS030 was injected intravitreally in both eyes of monkeys. After two months, the retinas were dissected and connected to a multi-electrode array system to record the electrical activity of RGCs. At regular intervals the firing activity of the transduced RGCs was measured upon light activation at the appropriate wavelength and at varying intensities. The results demonstrate that two months post-injection, the RGCs of non-human primates are active, and have the ability to transmit visual information as normal RGCs would.

We conducted a confirmatory study in monkeys to assess the activity of GS030 at various doses and at six months post-injection.

GS030 proof-of-concept in non-human primates at six months post-injection

In healthy retinas, RGCs fire electric spikes to the visual cortex at frequencies that are proportional to light intensity, which is referred to as irradiance. In this experiment, monkeys are treated with GS030 and their retina is sampled after either 2 or 6 months. Retina are put on a multielectrode array and 590nm light is then shed onto the retina at increasing intensity. As irradiance increases, the electrodes are measuring the increase of the firing frequency of each transduced RGC. As shown in the chart above, the firing frequency of the RGCs increases almost proportionally to the light intensity, which is what one would expect in a normal eye.

These photographs above show microscopic views of monkey retinas after receiving treatment with GS030. (A) and (C) show that GS030 achieves efficient transfection of the central part of the retina (fovea and peri-fovea region). (B) shows a magnification of one RGC showing that the protein is in the cytoplasm and in the membrane of the cell, as confirmed in (D) with the view of the RGCs and their axons.

This study confirmed the initial data and supports the expression of ChrimsonR in the retina of monkeys.

Results of this study were published in Communications Biology in February 2021.

GLP Toxicity Studies to Assess Phototoxicity

This study assessed the phototoxicity of three levels of light intensities following GS030 injection of rd1 mice, a relevant model of RP. One dose level of GS030, which was the highest dose, was combined to a single two-hour exposure to 600nm light at three levels of intensity in order to cover the intended use in our Phase I/II clinical setting. The purpose of the study was to determine the local tolerability of light exposure on transduced RP retinas based on the following endpoints: histopathology of the retina, outer layer thickness, number of RGCs, cell viability and/or apoptosis.

GLP Toxicity Study to Evaluate Toxicity and Biodistribution

This study evaluated the toxicity, biodistribution and shedding of viral particles as well as immunogenicity of GS030 vector and ChrimsonR protein after IVT injection in non-human primates. Two dose levels of GS030 were injected bilaterally. The study allowed us to evaluate and confirm at three and six months the safety and local tolerability of the vector and protein, the biodistribution and shedding of the vector in tissues and fluids, as well as systemic and local ocular immunogenicity.

Proof-of-Concept Study Showing Restoration of Retinal Electrical Activity in a Mouse Model of RP

An rd1 mouse is affected by the degeneration of rods followed by the degeneration of cones, leading to the loss of vision five to six weeks after birth. When the retinas of such mice are dissected post-mortem and connected to a multi-electrode array, an electrical response to light is not detected. Using the same method with the retinas from rd1 mice that have received an IVT injection of GS030, an electrical response to light is produced and detected with the multi-electrode array and this response is a function of light intensity.

A New Generation of Channelrhodopsin-Based Gene Therapy

An Optimized Optogenetic Protein

We have conducted proof-of-concept studies with channelrhodopsin-2, or ChR2, which when introduced into RGCs, has proven to restore vision in a murine model of RP. However, activation of ChR2 requires high-intensity blue light at 470nm wavelength which has been shown to be toxic for the retina and is not practical for clinical use.

We have therefore developed a novel channelrhodopsin protein, known as ChrimsonR, which responds to light at near-red wavelength, where light scattering decreases and absorption by endogenous chromophores is reduced, meaning that long-term safety should be significantly improved compared to other channelrhodopsins.

A Powerful Gene Delivery Vector

Since RGCs are the cells closest to the vitreo-retinal surface, they are amenable to AAV infection with IVT injection, a major advantage from a surgical standpoint given the relative ease of administration. Our AAV is an AAV2 modified in its capsid with an inserted 7m8 sequence. Experiments have demonstrated that AAV2 7m8 has markedly improved expression in RGCs and other retinal cells compared to AAV2 in both rodents and non-human primates.

Optoelectronic External Wearable Medical Device: The Biomimetic Goggles

The natural range of light sensitivity of human photoreceptor cells is broader than that of channelrhodopsins. To achieve adequate stimulation of transduced RGCs, we combine our gene therapy-based treatment with an external wearable medical device, which allows the amplification of the image at specific optimal wavelength of the selected opsin.

We are developing an external wearable medical device composed of:

•a visual interface integrating an asynchronous time-based image sensor (also called a neuromorphic video camera), and a digital micromirror array, or DMD, driven by a microprocessor, that convey the visual information signal and light to the macula; and

•a pocket processor connected to an optoelectronic stimulation device that processes the visual information and controls a light source in order to encode and amplify corresponding light signals at a specific narrowband wavelength of 580-610nm.

Software is provided to medical centers that allows the tuning and definition of parameters to optimize the patient response.

The figure set forth below presents the components of the external wearable medical device:

External Wearable Medical Device Components

We determined the necessary specifications for the external wearable medical device to optimize the specific light wavelength for activation of the ChrimsonR proteins while considering the particular anatomy of the eye. Our team is developing the algorithms necessary to operate the device in close collaboration with the Laboratory of Mathematics Applied to Vision of the Université Pierre et Marie Curie, or UPMC, in Paris, France. We have designed a prototype that will be further developed in advance of Phase III clinical trials and commercialization.

Preclinical Development of GS030 for RP

We have also conducted several studies in order to support the clinical Phase I/II CTA submission.

Preliminary Toxicity Study Showing Safety of GS030 in Non-Human Primates

We conducted an exploratory ocular histopathology study in non-human primates to investigate potential ocular toxicity following single bilateral IVT administration of GS030. No ophthalmological signs of intolerance or toxicity, structural modifications or inflammation of the retina were observed up to six months post-injection. A slight and transient increase in the serum anti-AAV2 immunogenicity, or neutralizing antibodies, was observed. GS030 was thus locally and systemically well tolerated up to six months.

We submitted a request for a non-clinical scientific advice recommendation from the EMA in April 2016, as well as a request for a Type C meeting with the FDA in December 2016, to validate the non-clinical program and future requirements for the device. Both the EMA and the FDA have agreed with our strategy in principle to evaluate toxicity in a rodent disease model and in non-human primates, and we therefore initiated the studies during the fourth quarter of 2016.

Clinical Development Program of GS030 for RP

We have initiated a Phase I/II, open-label, multi-center trial to evaluate the safety and tolerability of GS030 and the external wearable medical device in RP subjects. Our CTA was authorized in the United Kingdom in December 2017, in France in May 2018 and our IND was released in August 2018 in the United States. The trial includes secondary endpoints that could serve to demonstrate proof-of-concept of the efficacy of our optogenetics approach in RP patients. Restoration of visual perception would serve as a proof-of-concept for the combination of GS030 treatment with the use of biomimetic goggles.

We plan to enroll up to 18 subjects across up to four cohorts. The first subject was treated in October 2018 at the Moorfields Eye Hospital in London, United Kingdom, and the recruitment of the third cohort was completed in Q3 2020. The initial three cohorts has undergone dose escalation to determine the maximum tolerated or feasible dose of GS030. In the fourth cohort, the maximum tolerated will be administered for safety analysis and proof-of-concept data collection based on the fourth DSMB recommendation in September 2021. We anticipate receiving interim data in H2 2022.

The trial is planned to include adult subjects with documented diagnosis of RP. The initial cohorts will enroll RP subjects with virtually no light perception or limited to light perception. Pending safety outcomes, RP subjects with higher levels of visual acuity may be considered for inclusion in the fourth cohort. As RP is a disease of photoreceptor degeneration, the restoration of vision sense will require some level of intactness of the downstream components of the visual apparatus, including the neuronal elements of the retina, RGCs, optic nerve and primary visual cortex. We believe that subjects with higher degree of visual acuity would derive greater benefit from treatment with our GS030 product candidate by virtue of their visual apparatus being better preserved.

The trial is planned to encompass the testing of traditional ophthalmic parameters, such as visual acuity tests and also functional vision tests, such as avoiding obstacles or moving in unfamiliar or changing environments. We plan to carry out subject evaluation prior to GS030 administration with and without the biomimetic goggles to establish baseline parameters. Subsequent to IVT injection of GS030, a visual rehabilitation program will ensue, comprising a training period for learning to use the biomimetic goggles in a controlled laboratory environment, including in fixed and mobile simulations and subsequently in common indoor and outdoor environmental conditions.

Baseline ophthalmological testing will be completed before and after IVT injection of GS030 with and without biomimetic goggles. Given the varied levels of disease state, it is not expected that all subjects will show improvement in all secondary outcome measures. Furthermore, use of the biomimetic goggles will require training and, therefore, we expect that the learning period will vary among subjects. As a result, the time point of demonstrating efficacy may vary among subjects. Improvement will be assessed by whether a subject can perform a visual task with “goggles on” when light-induced activation of the optogenetic protein is expected to occur compared to baseline and also compared to “goggles off” when no or insufficient photo-activation of the optogenetic protein should take place.

The Data Safety Monitoring Board (DSMB) completed its second planned safety review of the ongoing PIONEER Phase I/II clinical trial of GS030, GenSight’s novel product combining gene therapy and optogenetics for the treatment of Retinitis Pigmentosa (RP). The DSMB confirmed the absence of any safety issues for the second cohort of three subjects, who each received a single intravitreal injection of 1.5e11 vg (viral genomes) and used a wearable optronic visual stimulation device after the injection. The DSMB recommended moving forward as planned without any modification in the protocol and recruiting the third cohort of three subjects who are to receive the maximal dose of 5e11 vg.

The independent Data Safety Monitoring Board (DSMB) completed its third safety review of the ongoing PIONEER Phase I/II clinical trial of GS030 combining AAV2-based gene therapy with optogenetics for the treatment of Retinitis Pigmentosa (RP) in September 2021. The DSMB found no safety issue in the third cohort of patients, who received an intravitreal injection with the highest dose (5e11 vg) among the three cohorts studied to date, followed by the use of a wearable optronic visual stimulation device. Based on GS030’s safety profile, the DSMB recommended selecting this dose for the extension cohort and using the protocol without any modification. Recruitment of this cohort has begun.

On May 25, 2021 the Company announced that the top-notch scientific journal Nature Medicine published the first case report of the partial recovery of visual function in a blind subject with late stage RP. The subject had been diagnosed with RP 40 years prior to enrollment in the PIONEER phase I/II clinical trial. Prior to receiving GS030 the patients visual acuity was so low he could only perceive light. Four and a half months after injection of GS030, the subject was trained on the use of the GS030-MD device (proprietary light-stimulating goggles that project the right wavelength and intensity of light onto the treated retina). Seven months after the start of his training, the subject began to report signs of visual improvement. Visual function tests showed he acquired the ability to perceive, locate, count and touch objects when the treated eye was stimulated with theGS030-MD goggles. The subject could not perform the tasks without the goggles. Electroencephalographic (EEG) recordings were taken while the subject performed vision-oriented tasks and the corresponding signals demonstrated neurophysiological activity in the visual cortex.

A second patient case was reported by the Company on November 17, 2021 showing significant visual recovery after GS030 optogenetic treatment. Twelve months following injection of GS030 the subject could detect and correctly locate objects of different sizes and contrasts placed on a white table, with a 57% success rate when wearing the GS030-MD goggles compared to only 24% without the device. The optogenetic therapy has been well-tolerated up to 3 years after a single injection administered to 9 subjects treated. There have been no systemic issues related to the gene therapy and no adverse events leading to study discontinuation and no participants have withdrawn.

Regulatory Interaction for GS030

In April 2016, we requested the EMA’s Committee for Advanced Therapies, or CAT, to issue a recommendation on the classification of our GS030 product, which is constituted of the biological product, in the form of gene therapy, and an external wearable medical device, in the form of biomimetic goggles. Based on the above considerations, EMA/CAT considers that the Product GS030 falls within the definition of a Gene Therapy Medicinal Product of an Advanced Therapy Medicinal Product as provided in Article 2(1) of Regulation (EC) No 1394/2007. We sought the same advice at the FDA’s Office of Combination Products. GS030 has been classified as a combination product whose primary mode of action is provided by the gene therapy part of GS030-DP, and the Center for Biologics Evaluation and Research, or CBER, is the jurisdiction in charge of evaluation. The regulatory pathway is based on the following classification: an IND will be necessary for clinical trial initiation, and a BLA will be required at the time of marketing authorization. In order to validate the adequacy of our non-clinical toxicology and safety program designed to support the first-in-man study, we submitted a request for non-clinical scientific advice from the EMA in April 2016 and an early Type C meeting with the FDA. Both the EMA and FDA have agreed with our strategy in principle to evaluate toxicity in a rodent disease model and in non-human primates, and we completed these toxicology studies in 2017.

In order to obtain agreement on the adequacy of the data presented to support initiation of an IND in the United States, a formal Type B Pre-IND meeting was held with the FDA in December 2017. During this meeting, the FDA agreed in principle with our Phase I/II clinical trial design, as well as CMC and medical device aspects to support an IND.

The U.S. Food & Drug Administration (FDA) has granted Fast Track Designation to GS030 in October 2021.

Fast Track is a process intended to facilitate the development and expedite the review of drugs for the treatment of serious conditions where there is an unmet medical need. The purpose is to get important new drugs to the patient earlier. Drugs that receive Fast Track designation may be eligible for more frequent communications and meetings with FDA to discuss the drug's development plan, including the design of the proposed clinical trials, and ensure collection of appropriate data needed to support drug approval. Drugs with Fast Track designation may also qualify for Accelerated Approval, Priority Review or Rolling Review of New Drug Applications (NDA) or Biologic License Applications (BLA) if relevant criteria are met.

Market Opportunity for GS030 in Dry AMD and GA

AMD is a degenerative disorder characterized by loss of the photoreceptors and preservation of the RGCs, and is driven by genetic and environmental factors. Central vision, which is essential to read, perform precise tasks and recognize faces, is lost. Peripheral visual field is usually preserved. Macular degeneration typically occurs in patients over the age of 55. The early form of AMD is called dry AMD and can evolve over time to late AMD. Late AMD can take two forms, either wet AMD or GA. Dry AMD is six times more prevalent than wet AMD. Approximately 15 million people are affected with AMD in the United States, with a global prevalence of 170 million, and dry AMD accounts for approximately 80% of all cases of late-stage AMD. The prevalence of AMD increases significantly in those older than 75, reaching 22% in the population over 90.

The following image illustrates the deterioration of normal vision to blindness in AMD:

GS030: Our Planned Strategy for the Treatment of Dry AMD and GA

We believe that our optogenetics technology platform could be used for the treatment of dry AMD or GA. Because GS030 uses optogenetics and can address diseases of photoreceptor degeneration regardless of the type of mutation, we believe that GS030, if successful in the treatment of RP, would be entirely transferable to the dry form of AMD and would offer enormous benefit to a common disease currently unamenable to therapy. Although RP and GA have very different origins, both diseases are characterized by the degeneration of the photoreceptor cells in the patient’s retina. Upon evidence of clinical proof-of-concept in RP, we may initiate clinical trials of GS030 for the treatment of dry AMD and GA.

5.2.4 LEVERAGING OUR PLATFORMS TO ADDRESS CENTRAL NERVOUS SYSTEM DISORDERS.

We have established an integrated development platform to replace or restore the function of retinal cells that have degenerated in order to regain quality of sight for patients, thereby transforming their lives. We intend to pursue the application of our integrated development platform to other indications beyond ophthalmology, in particular, for degenerative diseases of the central nervous system.

5.2.5 PHARMACO-ECONOMICS OF BLINDNESS AND VISUAL IMPAIRMENT.

Blindness and visual impairment impact not only the individual but also the family, caregivers, and the community, leading to significant societal costs. The total annual cost of vision disorders and blindness in the United States was estimated to be $139 billion in 2013, and the total cost of blindness alone in the European Union was estimated at €32 billion, or up to €60,000 per patient per year. These figures include direct costs such as medical treatment, medical visual prostheses, adaptations and assistance devices, and special training and assistance programs, as well as indirect costs resulting from impaired vision, the loss of productivity and the need for supportive care, long-term care and the costs of social programs. These conditions also can have significant, multidimensional effects on patients’ quality of life, including their physical and emotional well-being.

5.3Important events in the development of the Company

April 2012 | Incorporation of the Company on the basis of a collaborative effort involving renowned academic institutions.
March 2013 | Series A private round raising €19.7 million through Novartis Venture Fund, Abingworth, Versant Ventures, Vitavest S.à r.l. and Bpifrance (FBIMR).
February 2014 | Initiation of a Phase I/II clinical trial to assess safety and tolerability of LUMEVOQ® in Leber’s Hereditary Optic Neuropathy, or LHON.
June 2015 | Positive interim safety report of the Phase I/II clinical trial confirming safety and tolerability of LUMEVOQ® in LHON.
July 2015 | Series B private round raising €32.1 million (or €30.8 million net proceeds) through our Series A investors joined by Fidelity Management & Research Company, Perceptive Advisors, Jennison Associates, HealthCap and Sphera Global HealthCare Fund.
December 2015 | Initiation of two Phase III clinical trials to demonstrate efficacy of LUMEVOQ® in LHON.
July 2016 | Listing of our shares on Euronext Paris which allowed the Company to raise approximately €45.2 million (or €41.4 million net proceeds).
January 2017 | U.S. Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to the Company’s product candidate GS030 for the treatment of Retinitis Pigmentosa.
April 2017 | Creation of the first subsidiary, GenSightBiologics Inc., registered and located in the Unites States of America.
June 2017 | Capital Increase which allowed to raise €22.5 million (or €20.7 million net proceeds), by means of a private placement reserved to a category of persons, U.S. and European institutional investors specialized in healthcare and biotechnology.
December 2017 | Positive long-term visual acuity gains and safety results from Phase I/II Study of LUMEVOQ® for the treatment of Leber Hereditary Optic Neuropathy.
December 2017 | GenSight Biologics received MHRA approval to initiate Phase I/II PIONEER clinical trial of GS030 gene therapy in Retinitis Pigmentosa.
April 2018 | Top-line data at 48 weeks of the REVERSE Phase III clinical trial with LUMEVOQ® in LHON.
October 2018 | Top-line data at 72 weeks of the REVERSE Phase III clinical trial with LUMEVOQ® in LHON.
October 2018 | Treatment of first subject in first-in-man PIONEER Phase I/II clinical trial of GS030 combining gene therapy and Optogenetics for the treatment of Retinitis Pigmentosa.
December 2018 | Additional data reporting sustained quality of life improvements at Week 72 of the REVERSE Phase III clinical trial with LUMEVOQ® in LHON.
February 2019 | Top-line data at 48 weeks of the RESCUE Phase III clinical trial with LUMEVOQ® in LHON.
February 2019 | Completion of an €8 million capital increase without discount subscribed entirely by Sofinnova.
April 2019 | Top-line data at 72 weeks of the RESCUE Phase III clinical trial with LUMEVOQ® in LHON.
May 2019 | Top-line data at 96 weeks of the REVERSE Phase III clinical trial with LUMEVOQ® in LHON.
July 2019 | GenSight Biologics completes enrollment of LUMEVOQ® REFLECT Phase III trial in the treatment of LHON ahead of schedule.
September 2019 | Top-line data at 96 weeks of the RESCUE Phase III clinical trial with LUMEVOQ® in LHON.
October 2019 | Reporting of evidence of LUMEVOQ® DNA transfer to contralateral eye of primates unilaterally injected with LUMEVOQ® Gene Therapy.
December 2019 | First Temporary Authorization for Use (ATU nominative) granted to the National Eye Hospital of the Quinze-Vingts in Paris by the French National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM).
December 2019 | Interim analysis of 15 patients in REALITY natural history study supporting REVERSE and RESCUE efficacy results.
December 2019 | GenSight Biologics obtains €15 million in financing through a bond issuance from Kreos Capital and a reserved capital increase from Sofinnova and 3SBio.
April 2020 | Positive Data Safety Monitoring Board Review of PIONEER Phase I/II Trial of GS030.
July 2020 | Sustained efficacy and safety among LHON patients 3 years after LUMEVOQ® treatment.
July 2020 | GenSight Biologics obtains €7million non-dilutive loan and renegotiate bond agreement with Kreos Capital.
July 2020 | Final REALITY natural history study supporting REVERSE and RESCUE efficacy results.
July 2020 | GenSight Biologics draws down €4 million through Tranche B from Kreos Capital.
September 2020 | GenSight Biologics submits EU Marketing Authorization Application for LUMEVOQ®.
September 2020 | GenSight Biologics reports new analysis demonstrating statistically significant and clinically meaningful difference between visual outcomes in LUMEVOQ®-treated patients and natural history of Leber Hereditary Optic Neuropathy (LHON).
October 2020 | GenSight Biologics successfully raises €25 million in an oversubscribed private placement with U.S. and European institutional investors.
November 2020 | GenSight Biologics reports validation of LUMEVOQ® Marketing Authorization Application (MAA) by European Medicines Agency.
December 2020 | GenSight Biologics Announces Publication of Results from LUMEVOQ® REVERSE Pivotal Phase III Trial and Non-Human Primate Study in Science Translational Medicine.
December 2020 | GenSight Biologics announces the partial conversion of convertible bonds and full exercise of share warrants by Kreos Capital.
January 2021 | GenSight Biologics Announces Publication of Results from LUMEVOQ® RESCUE Pivotal Phase III Trial in AAO journal Ophthalmology®.
February 2021 | GenSight Biologics Announces the Publication in Communications Biology of the Proof-of-Concept for GS030-Drug Product in Non-Human Primates.
February 2021 | GenSight Biologics Announces Publication of Results from LUMEVOQ® Phase I/IIa Clinical Trial REVEAL in BioDrugs.
March 2021 | GenSight Biologics successfully raises €30 million in an oversubscribed private placement with European and U.S. institutional investors.
May 2021 | GenSight Biologics Announces Publication of Results from the REALITY LHON Natural History Study in the Journal Eye.
May 2021 | GenSight Biologics Provides 2021 Operations Update in the Context of Covid-19.
May 2021 | GenSight Biologics Appoints Country Leads for France, Germany and the UK in Preparations for LUMEVOQ® Commercial Launch.
May 2021 | GenSight Biologics Announces Nature Medicine Case Report Showing Visual Recovery after GS030 Optogenetic Treatment.
June 2021 | GenSight Biologics Announces Publication of Indirect Comparison Showing Treatment Effect of LUMEVOQ® versus Natural History in Frontiers in Neurology.
June 2021 | GenSight Biologics Reports Topline Results from REFLECT Phase III Clinical Trial, Confirming LUMEVOQ® Efficacy Including Better Efficacy with Bilateral Treatment.
July 2021 | GenSight Biologics Announces Approval of the LUMEVOQ® Cohort Temporary Authorization for Use (ATUc) in France.
August 2021 | GenSight Biologics Announces Publication of RESTORE Study Data Demonstrating Sustained Efficacy 3 Years After Unilateral Injection of LUMEVOQ®.
September 2021 | Clinical Data on GenSight Biologics’ LUMEVOQ® and GS030 Gene Therapies to be Presented at 2021 ISGEDR and Several Investor and Industry Meetings in September.
September 2021 | UK MHRA grants GenSight Biologics’ LUMEVOQ® ophthalmic gene therapy Promising Innovative Medicine designation.
September 2021 | GenSight Biologics Announces Publication Analyzing Visual Parameters of ND4-LHON Subjects before LUMEVOQ® treatment in Phase III Trials.
September 2021 | GenSight Biologics Announces Positive Data Safety Monitoring Board Review of PIONEER Phase I/II Clinical Trial of GS030 as Optogenetic Treatment for Retinitis Pigmentosa.
October 2021 | GenSight Biologics Announces the Publication of a Review of Gene Therapy Trials for LHON in International Ophthalmology Clinics.
October 2021 | GenSight Biologics Announces FDA Grant of Fast Track Designation for Optogenetic Therapy GS030 as Treatment for Retinitis Pigmentosa.
November 2021 | GenSight Biologics Provides Update on Manufacturing Timeline Needed for LUMEVOQ® Regulatory Filing.
November 2021 | GenSight Biologics Announces Extension of Day 120 Clock Stop of LUMEVOQ® EMA Regulatory Filing.
November 2021 | GenSight Biologics Reports Second Patient Case Showing Significant Visual Recovery after GS030 Optogenetic Treatment.
December 2021 | GenSight Biologics Announces Publication of Non-Human Primate Study Reporting Presence of LUMEVOQ® Vector DNA in Contralateral Eyes After Unilateral Injection.
December 2021 | GenSight Biologics Confirms Sustained Efficacy and Safety of Bilateral LUMEVOQ® Injections at 2-Year Follow-Up of REFLECT Phase III Trial.
December 2021 | GenSight Biologics Company has incorporated a second subsidiary, GenSight Biologics France SAS registered and located in France.
January 2022 | GenSight Biologics reports clinically meaningful vision improvement is maintained 4 years after one-time treatment with LUMEVOQ® gene therapy.
April 2022 | GenSight Biologics provides update on LUMEVOQ® manufacturing timeline
April 2022 | GenSight Biologics Granted Six-Month Extension in LUMEVOQ® European Regulatory Review

5.4Strategy and objectives

Our goal is to transform the lives of patients suffering from severe degenerative diseases of the eye and central nervous system through the development and commercialization of novel therapies by combining gene therapy-based approaches with our proprietary MTS and optogenetics technology platforms. The key elements of our strategy are the following:

•Complete clinical development and obtain regulatory approval for our lead product candidate, LUMEVOQ®, for the treatment of LHON.

We reported top-line results of our two most advanced ongoing Phase III clinical trials of LUMEVOQ® for the treatment of LHON, RESCUE and REVERSE, in 2018 and 2019. We reported topline of our third Phase III clinical trial REFLECT in June and December 2021. We expect that the complete results at 96 weeks of our Phase III REVERSE and RESCUE trials will be sufficient to support filing for marketing authorization in the European Union. LUMEVOQ® has received orphan drug designation for the treatment of LHON in the United States and the European Union. We believe that LUMEVOQ® has the potential to be the first FDA-approved therapy for LHON.

•Advance clinical development of our second most advanced product candidate, GS030, using our optogenetics technology for the treatment of RP.

GS030 has demonstrated that it can restore light sensitivity in the retina in animal models. In late 2017, we received MHRA approval to conduct a Phase I/II clinical trial of GS030 in blind RP subjects. We treated the first subject in October 2018 and expect to complete recruitment of the extension cohort in the second half of 2022. We anticipate receiving interim data within one year after the last subject is treated. GS030 has received orphan drug designation for the treatment of RP in the United States and the European Union. The FDA has granted Fast Track Designation to GS030 in October 2021. We believe that due to its ability to introduce a gene encoding for light-sensitive protein into target cells, GS030 has the potential to be the first therapy that partially or fully restores sight to RP patients.

•Expand our pipeline by leveraging our proprietary MTS technology platform.

Mitochondrial defects are associated with several severe degenerative diseases of the optic nerve as well as diseases of the central nervous systems. We believe our discovery capabilities and clinical experience will allow us to pursue the preclinical and clinical development of treatments using our MTS technology platform to more broadly target degenerative diseases such as other forms of LHON or diseases of the central nervous system. For example, while our later stage Phase III LHON trials are designed to treat subjects with the mutation in the ND4 gene, we plan to initiate preclinical development for GS011 using our MTS technology to treat LHON due to mutation in the ND1 gene. In addition, our MTS technology platform has the potential to address neurodegenerative diseases of the central nervous system caused by mitochondrial defects, such as Kearns-Sayre syndrome, Alpers disease, Parkinson’s disease and ALS.

•Pursue preclinical development of other indications using our optogenetics technology platform.

The initial focus of our optogenetics technology platform using GS030 is for disorders of the photoreceptor cells, in particular RP. However, because GS030 can address diseases of photoreceptor degeneration regardless of the type of mutation, we believe that GS030 may be extended to address patients suffering from dry AMD and GA, both areas of significant unmet medical need. We plan to explore other indications outside of ophthalmology where we are able to use light to stimulate the neurons, such as congenital deafness, pain treatment and vagus nerve stimulation.

•Directly commercialize our lead product candidate, LUMEVOQ®, in key geographies and retain the option to commercialize GS030 by ourselves.

We hold worldwide commercialization rights to our platform technologies, product candidates and development programs. If approved, we intend to commercialize LUMEVOQ®, initially in the United States and the European Union, ourselves. Due to the orphan nature of LHON, we believe a targeted sales and marketing organization would be able to reach specialized ophthalmology centers and their patients. We have built, and continue to expand upon, key relationships with ophthalmic experts and patients of severe retinal neurodegenerative diseases around the globe, since we anticipate that a large majority of patients suffering from this disease will be referred to a limited number of large, well-equipped centers with neuro-ophthalmologists and retina specialists in each country. We have initiated early dialogue meetings with relevant payers and HTA bodies in the key markets to prepare for timely local reimbursement submissions. Due to the broad patient populations that GS030 may address, we may enter into strategic partnerships to maximize commercial value of our product candidate.

•Acquire or in-license complementary technologies and product candidates.

In addition to our current product candidates, we will evaluate acquisition or in-licensing opportunities with the potential to expand and diversify our pipeline in ophthalmology and other neurodegenerative disorders. We believe that our management team’s expertise in the gene therapy field and the broad applicability of our proprietary technology platforms provide us with a competitive advantage in evaluating product opportunities.

5.5Research and development, patents and licenses

5.5.1 OVERVIEW.

We engage in substantial research and development efforts to develop innovative product candidates. Research and development expenses consist primarily of:

•sub-contracting, collaboration and consultant expenses, that primarily include the cost of third-party contractors such as CROs, who conduct our non-clinical studies and clinical trials;

•personnel costs, including salaries, related benefits and share-based compensation, for our employees engaged in scientific research and development functions;

•licensing and intellectual property costs, including upfront payment for exclusive licensing;

•purchases, real-estate leasing costs and rental income received from sublease agreements, as well as conferences and travel costs; and

•depreciation and amortization.

Our research and development expenses in the periods presented, and for the current period to date, mainly relate to the following activities:

•LUMEVOQ®: Our Phase I/II dose-escalation safety study REVEAL for LUMEVOQ® was initiated in 2014, recruitment was completed in April 2015 and a follow-up study is currently ongoing. LUMEVOQ® entered into two parallel Phase III trials, RESCUE and REVERSE, in the fourth quarter of 2015, following the release of our IND application by the FDA. The trials are designed as a double-masked, sham-controlled, multi-center, multi-country clinical trial in Europe and the United States. We completed enrollment of all 37 patients for REVERSE in February 2017, and completed the enrollment of 39 patients for RESCUE in July 2017. A third Phase III trial was initiated in the fourth quarter of 2017, REFLECT. This trial is designed as a randomized, double masked, placebo-controlled, multi-center clinical trial. The recruitment of 98 patients was completed in July 2019. Topline data were issued during the second quarter of 2021.

•GS030: In 2015, we conducted preclinical, proof-of-concept studies with different molecules that led to the definition of GS030. We initiated GLP, toxicology studies on non-human primates. We obtained the approval to initiate Phase I/II PIONEER clinical trials from MHRA in December 2017. The first patient was treated in October 2018 in the United Kingdom. The recruitment of the third cohort was completed in Q3 2020.

Our direct research and development expenses consist principally of external costs, such as manufacturing expenses, non-clinical studies, startup fees paid to investigators, consultants, central laboratories and CROs in connection with our clinical studies, acquiring and manufacturing clinical study materials and costs related to collaborations, which we allocate to our specific research programs. In addition, we allocate personnel-related costs, depreciation and other indirect costs to specific programs.

Research and development activities are central to our business. Product candidates in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. We expect that our research and development expenses will continue to increase in the foreseeable future as we initiate clinical trials for certain product candidates and pursue later stages of clinical development of other product candidates.

A change in the outcome of any of these variables with respect to the development of LUMEVOQ®, GS030 or any other product candidate that we are developing could mean a significant change in the costs and timing associated with the development of such product candidates. For example, if the FDA, the EMA or other regulatory authority were to require us to conduct non-clinical and clinical studies beyond those which we currently anticipate will be required for the completion of clinical development, or if we experience significant delays in enrollment in any clinical trials, we could be required to spend significant additional financial resources and time on the completion of clinical development. For a discussion on the risks associated with completing the development projects on schedule, see Section 3.2, “Risks Related to the Discovery and Development of and Obtaining Regulatory Approval for Our Product Candidates” of this Universal Registration Document.

5.5.2 RESEARCH AND DEVELOPMENT EXPENDITURES.

From 2020 to 2021, the total amount spent by us for research and development activities slightly increased from €22.4 million to €22.9 million, respectively.

Our research and development expenses for the periods presented, and for the current period to date, mainly relate to LUMEVOQ® and GS030, see Section 7.3, “Results of Operations – Comparisons for the Twelve Months Ended December 31, 2020 and 2021 – Research and Development Expenditures” of this Universal Registration Document.

Our research and development expenses consist principally of external costs, such as manufacturing expenses, non-clinical studies, startup fees paid to investigators, consultants, central laboratories and CROs in connection with our clinical studies, costs related to acquiring and manufacturing clinical study materials and costs related to collaborations, which we allocate to our specific research programs. In addition, we allocate personnel-related costs and other indirect costs to specific programs.

The following table sets forth the cost for our research and development for the fiscal years ending December 31, 2020 and 2021:

In thousands of euros | As of December 31,
2020 | 2021
Personnel expenses (1) | 3,903 | 4,844
Sub-contracting, collaborations and consultants | 15,359 | 15,626
Licensing and intellectual property | 2,168 | 1,318
Office costs | 28 | 22
Travel and entertainment expenses | 245 | 323
Depreciation and amortization expenses | 397 | 366
Others | 286 | 421
Total research and development expenses | 22,386 | 22,920

(1) Includes €749 K and €1,404 K related to share-based compensation expense as of December 31, 2020 and 2021 respectively.

5.5.3 MEDICAL AND SCIENTIFIC COMMITTEE.

In addition to our own research and development teams, we have a Scientific Advisory Board comprised of seven renowned scientists from different countries who are opinion leaders in their Specialties and key assets to our business. The function of the Scientific Advisory Board is to identify new technological advances that may be of interest for our business.

Since our inception, our Scientific Advisory Board has been comprised of the following members:

•Dr. Botond Roska (Chairman of our Scientific Advisory Board) is Director of the Institute of Molecular and Clinical Ophthalmology Basel, Switzerland. He was educated at University of California Berkeley, Harvard University and Harvard Medical School as well as at Semmelweis Medical School. He studies the structure and function of the retina, thalamus and cortex. His group pioneered cell type specific optogenetic vision restoration.

•Professor José-Alain Sahel (Vice-Chairman of our Scientific Advisory Board) chairs the Institut de la Vision, a center of excellence in ophthalmology assembling scientific teams (UPMC, INSERM and CNRS) as well as the French National Eye Hospital, featuring access to cohorts of well-diagnosed patients and a state-of-the-art Clinical Investigation Center. He chaired the Institut de la Vision, a center of excellence in ophthalmology assembling scientific teams (UPMC, INSERM and CNRS) until 2021.

•Professor Jean Bennett (Vice-Chairman of our Scientific Advisory Board) is Professor of Ophthalmology and Cell and Developmental Biology and a Senior Investigator in the F. M. Kirby Center for Molecular Ophthalmology at the University Of Pennsylvania School Of Medicine. Professor Bennett also has an appointment as a Senior Investigator at the Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia.

•Luk H. Vandenberghe, Ph.D., is Assistant Professor at Harvard Medical School and runs an active research laboratory at the Massachusetts Eye and Ear Infirmary and the Schepens Eye Research Institute. He directs the Grousbeck Gene Therapy Center which is focused on the biology of somatic gene transfer, the development of enabling technologies in gene therapy and the translation of clinical programs with a particular emphasis on vision and hearing restoration.

•Professor Ernst Bamberg is Professor of Biophysical Chemistry at University of Frankfurt, and Director of the Department of Biophysical Chemistry of the Max Planck Institute für Biophysik in Frankfurt. Pr. Bamberg is the inventor of the optogenetics approach and has been at the fore front of this technology since its discovery.

•Professor Connie Cepko is Professor at Harvard Medical School. Professor Cepko works on the mechanisms that direct development of the central nervous system of vertebrates and, in particular, on the vertebrate retina. Professor Cepko has produced seminal works in the mechanisms that lead to the death of photoreceptors in the many inherited forms of human blindness.

•Dr. Serge Picaud, Ph.D., chairs the Institut de la Vision, a center of excellence in ophthalmology assembling scientific teams (UPMC, INSERM and CNRS). Over the last 15 years, Dr. Picaud has developed many cellular and animal models of different retinal diseases for assessing the efficacy of neuroprotection or other therapeutic strategies. Dr. Picaud thus developed the culture of post-mortem human retinal tissue, which provides the means to test AAV vectors efficacy on human retinal neurones.

To our knowledge, as of the date of this Universal Registration Document, there are no conflicts of interest between the position of Dr. Botond Roska and Professor José-Alain Sahel in the Company and their position in FMI and Institut de la Vision, respectively.

5.5.4 COLLABORATION, PARTNERSHIP AND RELATED AGREEMENTS.

To our knowledge, as of the date of this Universal Registration Document, there are no conflicts of interest between the duties of our directors and officers and their personal interests, as they have no interest of any kind in the companies that are parties to the collaboration, partnership and related agreements mentioned below.

Our main collaboration, partnership and related agreements include the following as of this Universal Registration Document:

Agreements Relating to LUMEVOQ®

Genethon

Partnership Agreement Relating to the Research, Development and Commercialization of LUMEVOQ®

•Object:

In February 2013, we entered into a partnership agreement with Genethon. Under the terms of this agreement, Genethon is free to exploit the data, know-how, materials and inventions, whether patentable or not, developed or generated in the course of performing a given research and development project that relate to the processes, materials and assays used to manufacture biological products for any purpose without further obligation or payment to us. We may exploit the data, know-how, materials and inventions, whether patentable or not, developed or generated in the course of performing a given research and development project that relate to a product being developed by the parties pursuant to a given research and development project for any purpose at our own discretion, subject to the payment to Genethon of any milestone payments and royalties negotiated and agreed in a product addendum.

•Obligations of GenSight:

Under the terms of the partnership agreement, we are primarily responsible for (i) the performance of all in vitro and in vivo preclinical studies and for all clinical activities and, as sponsor, for the initiation, conduct and management of all clinical trials to be conducted in the context of the research and development project, and (ii) all regulatory affairs matters related to the development of the product(s) (other than matters specific to product manufacturing) with support from Genethon.

•Obligations of Genethon:

Genethon is primarily responsible for (i) the development of the processes to manufacture product(s) and for the manufacture of product(s) required for preclinical and clinical studies; and (ii) all regulatory affairs matters related to the manufacture of the product(s), including the elements of clinical trial and marketing authorization submissions that relate to the manufacture of the product(s).

•Financial obligations:

Costs are shared between us and Genethon in accordance with certain principles set forth in the partnership agreement. Each party bears its own internal costs incurred in the performance of preclinical activities. We are responsible for all external costs incurred by the parties in the performance of preclinical activities. Genethon is responsible for all internal and external costs incurred to manufacture research quality grade batches of the products in the context of preclinical activities. Genethon also assumes the internal and external costs incurred to manufacture all batches, whether GMP or not, of products used for regulatory preclinical toxicology studies, and one GMP batch for the initial Phase I clinical studies. We are responsible for all internal and external costs incurred by the parties in the performance of clinical activities. In addition, we bear all internal and external costs for the manufacture of all GMP batches of products other than any GMP preclinical toxicology batches, and the initial GMP both for Phase I clinical studies, the costs of which are borne by Genethon. Genethon bears all internal costs associated with activities of regulatory support in connection with manufacturing a product, while all such external costs are borne by us.

•Proprietary rights:

Under the terms of the partnership agreement, Genethon is free to exploit the data, know-how, materials and inventions, whether patentable or not, developed or generated in the course of performing a given research and development project that relate to the processes, materials and assays used to manufacture biological products for any purpose without further obligation or payment to us. We may exploit the data, know-how, materials and inventions, whether patentable or not, developed or generated in the course of performing a given research and development project that relate to a product being developed by the parties pursuant to a given research and development project for any purpose at our own discretion, subject to the payment to Genethon of any milestone payments and royalties negotiated and agreed in a product addendum.

•Term and termination:

The partnership agreement will continue in full force and effect for the longer of (i) a period of 10 years; or (ii) until the expiration/termination of the last project addendum duly executed between us and Genethon, unless otherwise terminated under the terms of the partnership agreement.

Agreements Relating to GS030

Sight Again Program

Consortium Agreement Relating to the Research and Development of Complimentary Therapeutic Remedies for GS030

•Object:

In July 2014, we entered into a consortium agreement with Pixium Vision S.A., a company based in France that develops vision restoration systems and Fondation Voir et Entendre, or FVE, a scientific foundation that funds scientific programs in the field of ophthalmic diseases. This consortium agreement, known as “Sight Again,” or the Program, aims to further unlock technology hurdles in the development of new therapeutic approaches to restore sight to legally blind patients suffering from differing stages of RP. Sight Again is part of Programme d’Investissement d’Avenir, a major investment initiative launched and organized by the French Government. Under the agreement, we, in conjunction with Pixium Vision and FVE, are focusing on two complementary therapeutic remedies: an optogenetic gene therapy developed by us, GS030, and a vision restoration system comprising a sub-retinal implant developed by Pixium Vision, PRIMA, designed to deliver improved visual perception. Both therapeutic remedies require a visual stimulation device, comprising a visual interface, a mobile processor and software.

During the collaboration period, the Program is governed by a joint steering committee, or JSC, consisting of representatives of the parties to the collaboration agreement. The JSC is responsible for, among other things, monitoring and assessing the progress of collaboration activities, validating the results and information provided by working groups, modifying or suspending the program in whole or in part and approving amendments to the agreement.

•Obligations of GenSight:

Under the terms of this agreement we are responsible for conducting all research and development activities in relation to our product candidates, from proof of concept to request for marketing authorizations.

•Proprietary rights:

Under the terms of the agreement, results obtained become the property of the party responsible for carrying out the research. In the case of joint research, results become the property of the parties involved with the research on a prorata basis in accordance with their respective contributions. We may freely use our own and joint results, except for research benefiting third-parties. We may be granted an operating license should we need specific knowledge of results of another party, and a free use of rights of products developed by FVE under the Program as well as a right of first review on any of the results of FVE. We and Pixium Vision have been granted a joint-exclusive operating license, each in our respective fields, on joint results obtained within the program.

•Financial obligations:

In consideration for this joint exclusivity, we and Pixium Vision pay royalties to FVE, calculated as a percentage of net sales generated by the joint results and joint patents. Such royalties may not exceed 0.6 percent of revenues generated by the commercial use of the patent, and an annual threshold of €50 K per Company, and shall expire when the cumulated amount of royalties paid reaches a total of €500 K.

•Term and termination:

The term of the agreement is five years and six months, subject to prior termination.

Master Agreement Relating to the Sight Again Program

In December 2014, we entered into a master agreement relating to the Program with Bpifrance Financement, Pixium Vision and FVE setting forth the characteristics of the Program, to fix the amount and conditions for awarding funding granted by Bpifrance Financement as well as to clarify the principles and arrangements for monitoring the implementation of the Program by Bpifrance Financement.

Financial Aid Agreement Relating to the Sight Again Program

In December 2014, we entered into a financial aid agreement relating to the Program with Bpifrance Financement setting forth the amounts and conditions upon which Bpifrance Financement shall grant financial aid to the Program. We will benefit from approximately €6.8 million, of which €1.1 million is available as subsidies and approximately €5.7 million as repayable advances. The approximately €5.7 million repayable advances and any interest thereon will only be repayable if and when the product hits the market. Should we, within two years following the termination of this financial aid agreement, reach cumulated revenues of €80.0 million (excluding taxes) for a period of 15 years from the first year of repayment we shall be required to make an additional payment to Bpifrance Financement of a maximum aggregate amount of approximately €2.7 million. The financial aid from Bpifrance Financement is intended to cover both industrial research and experimental development.

On June 3, 2020, the PSPC Steering Committee made the following decisions:

For all the partners of the SIGHT AGAIN Project consortium: expenses will be taken into account until key step 4.

For GenSight Biologics,

•removal of the specific regulatory condition in key step 3,

•postponement of repayment deadlines by 2 years for Gensight Biologics,

•implementation of a minimum lump sum reimbursement of €819,185, i.e. 20% of the overall recoverable advance paid.

The terms of the financial aid agreement have been modified accordingly.

Amendments Relating to GS030

The terms of the consortium agreement, master agreement and financial aid agreement originally applied to the development of the optogenetics product candidate targeting RP known as GS020, a precursor to GS030. The parties have supplemented the agreements to include provisions relating to the development of GS030.

Agreements Relating to LUMEVOQ® and GS030

Specific Research Agreements Under the Framework Agreement Relating to Research and Development in Ophthalmic Diseases (LUMEVOQ® and GS030)

In October 2014, as a part of the framework agreement, we entered into a specific agreement with UPMC, Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique for the development and evaluation of the visual stimulation goggles, for a duration of 24 months. This agreement terminated on October 2016.

In November 2014, as a part of the framework agreement, we entered into a specific research agreement with UPMC, Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique for a program aiming to restore high acuity vision with optogenetic therapy, and defining the technical means required and the milestones to be achieved.

In June 2015, as a part of the framework agreement, we entered into a specific research agreement with UPMC, Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique for a program aiming to develop and approve clinical prototypes of glasses for the stimulation of an optogenetically transfected retina.

5.5.5 INTELLECTUAL PROPERTY.

To our knowledge, as of the date of this Universal Registration Document, there are no conflicts of interest between the duties of our directors and officers and their personal interests as they have no interest of any kind in the companies that are parties to the in-license agreements mentioned below.

We rely on licenses granted by third-parties to develop our product candidates. We have rights to use and exploit certain issued patents and pending patent applications under license from certain third-parties.

Our main in-license agreements include the following:

Agreements Relating to LUMEVOQ®

Inserm Transfert

License Agreement for Patents Relating to LUMEVOQ®

•Object:

On October 12, 2012, we entered into a license agreement with Inserm Transfert S.A. (acting as delegatee of Inserm). Under the license agreement, Inserm Transfert and Inserm granted us (i) an exclusive, royalty-bearing worldwide license under certain patent rights and biological material in the treatment of ocular diseases in humans (including mitochondrial diseases of the ocular area), (ii) a non-exclusive, royalty-bearing worldwide license under certain patent rights and biological material in the treatment of mitochondrial diseases in humans together with (iii) a non-exclusive, royalty-bearing worldwide license under certain know-how, to develop, make, have made, use, and sell or otherwise distribute certain products, in the treatment of mitochondrial diseases and ocular diseases in humans, with a limited right to grant sublicenses.

•Proprietary rights:

Inserm Transfert and Inserm reserved the right on their behalf and that of all other non-profit academic research institutions to practice and use the patent rights and biological material in the treatment of ocular diseases in humans (including mitochondrial diseases of the ocular area) (i) for any academic purposes as well as (ii) for the performance of research programs performed in the frame of industrial partnerships and (iii) with our prior written approval on the clinical protocol, for certain non-profit clinical research. Inserm Transfert reserved (a) the right to practice and use the know-how for any purposes and (b) the right to practice and use as the patent rights and biological material for any purposes outside the treatment of ocular diseases in humans. Under the agreement, we have the first right of negotiation for exploitation rights of any results that may issue from such non-profit clinical research in the treatment of ocular diseases in humans (including mitochondrial diseases of the ocular area) and under certain conditions.

•Obligations of GenSight:

We are required to use our best efforts to develop the products in compliance with a certain development plan and to use our reasonable efforts to introduce the product into the commercial market, in each case, as soon as practicable, consistent with reasonable business practices. Under the agreement, we manage the prosecution, defense and maintenance of the licensed patent rights, at our own cost and in consultation with Inserm Transfert.

•Financial obligations:

Upon entering into the license agreement we paid an upfront license fee and reimbursed Inserm Transfert for all expenses incurred by it prior to entry into the license agreement in connection with the filing, prosecution, defense and maintenance of the patent rights. We are responsible for the payment of all future fees and costs relating to the prosecution, defense and maintenance of the patent rights during the term of the license agreement. In addition, we are required to make certain milestone payments to Inserm Transfert upon the achievement of certain development, regulatory and commercial milestone events. Under the terms of the license agreement, we also are required to pay Inserm Transfert low-to mid-single-digit royalties on incremental annual worldwide net sales of the product.

•Term and termination:

The license agreement will continue in full force and effect until the later of (i) the expiration of the last to expire patent right covering the manufacture, use or sale of the licensed product in any country of the world and (ii) ten years after the first commercial sale of the licensed product in a country in which a royalty is paid, unless otherwise earlier terminated under the terms of the license agreement. Inserm Transfert may at its sole discretion convert the license in the treatment of ocular diseases in humans into a non-exclusive license or terminate the agreement if (a) we have not timely met any of the development milestones in the development plan and fail to cure within 60 days of written notice from Inserm; (b) we interrupt certain development activities in respect of any licensed product for more than nine months; (c) we interrupt commercialization of a licensed product for more than 12 months after a first commercialization of such product in a country; (d) there is no commercialization of a licensed product within two years following the obtaining of its commercialization approval in a country; (e) we have not put the licensed product into commercial use and are not keeping the products reasonably available to the public within ten years of the effective date of the agreement; or (f) if we cease business operations or become the subject of a petition in bankruptcy.

Association Française contre les Myopathies

License Agreement for Scientific Data Relating to LUMEVOQ®

•Object:

On December 2, 2013, we entered into a license agreement for use of scientific data with the Association Française contre les Myopathies, or AFM, the French Muscular Dystrophy Association, Genethon and Inserm Transfert, acting as a delegate of Inserm and on behalf of the UPMC, or UPMC collectively, the licensors. Under the agreement, the licensors granted us a worldwide, exclusive, royalty-bearing license, with a limited right to grant sublicenses, for the use of certain scientific data and information developed, owned or controlled by the licensors, to develop, make, have made, use, and sell or otherwise distribute certain products, including to obtain authorization to develop and commercialize products for the treatment of mitochondrial diseases and ocular diseases in humans as described in our license agreement with Inserm Transfert. The scientific data are defined as data needed to obtain agencies authorizations.

•Obligations of GenSight:

We are required to use all commercially reasonable efforts to develop the products in compliance with the development plan set forth in our license agreement with Inserm Transfert and to use our reasonable efforts to introduce the product into the commercial market, in each case, as soon as practical, consistent with our reasonable business practices.

Under the license agreement, we have committed to achieving certain milestones relating to the development, manufacture and commercialization of the licensed products, including certain regulatory, clinical and commercial objectives. Under certain circumstances, such as the imposition of government regulation restricting the implementation of the development program or requiring changes thereto, unforeseen results in preclinical experiments or clinical trials or technical constraints, we and Inserm Transfert may reasonably extend the development plan.

•Financial obligations:

We paid the licensors a one-time license fee of €10 K. We also are obliged to make milestone payments ranging from €13 K to €375 K upon the achievement of certain development, regulatory and commercial milestone events. Under the terms of the license agreement, we are required to pay to the licensors low single-digit royalty payments on annual worldwide net sales.

•Term and termination:

The license agreement will continue in full force and effect until the later of (i) the expiration of the patent rights licensed to us under our license agreement with Inserm Transfert and (ii) ten years after the first commercial sale of the product in a country in which a royalty is paid, unless otherwise earlier terminated under the terms of the license agreement. Inserm Transfert may at its sole discretion convert the exclusive license under the agreement into a non-exclusive license or terminate the agreement if (a) we have not timely met any of the development milestones in the development plan; (b) we interrupt certain development activities in respect of any product for more than nine months; (c) we have not put the product into commercial use and are not keeping the products reasonably available to the public within ten years of the effective date of the agreement; or (d) if we cease business operations to become the subject of a petition in bankruptcy.

President and Fellows of Harvard College

License Agreement for the use of Harvard Master Cell Bank relating to LUMEVOQ®

•Object:

On June 18, 2019, we entered into a license agreement with President and Fellows of Harvard College (“Harvard”). Under the license agreement, Harvard granted us a non-exclusive, worldwide, royalty-bearing license, non-transferable without its prior consent, with right to grant sublicenses, for the use of biological material (an Harvard proprietary Master Cell Bank) to develop, have developed, make, have made, market, offer for sale, sell, have sold, promote, have promoted, import and/or export any licensed products (including LUMEVOQ®), for the prevention and/or the treatment of ocular diseases.

•Obligations of Harvard:

Harvard is required to deliver us a reasonable supply of the biological material as soon as practicable and to the extent reasonably request by ourselves.

•Obligations of GenSight:

We are required to use commercially reasonable efforts to develop, market and commercialize the licensed products and we are subject to reporting obligations.

•Financial obligations:

We paid Harvard a non-refundable license issuance fee of $25 K. In addition, we agreed to pay an annual license maintenance fee as from the first commercial sale of a licensed product ranging from $25 K to $75 K (creditable against running royalties), a milestone payment of $25 K upon achievement of marketing authorization for the first licensed product in any country, and a running royalty of less than 1% on net sales for a period of 15 years from the date of the first commercial sale (on a licensed product by licensed product basis).

•Term and termination:

The license agreement will continue in full force and effect until the expiration of the payment obligations, unless earlier terminated. We also have the right to terminate the agreement at any time and for any reason upon 90 days’ prior written notice.

Upon termination, we will have a perpetual, fully paid-up, non-exclusive, worldwide, non-transferable license to use Harvard’s Master Cell Bank to make, have made, market, offer for sale, sell, have sold, import and/or export any licensed products, including LUMEVOQ® for the prevention and/or the treatment of ocular diseases.

Agreements Relating to GS030

Adverum Biotechnologies (formerly Avalanche Biotechnologies)

License Agreement for Patents Relating to GS030

•Object:

On February 23, 2014, we entered into a non-exclusive license agreement with Adverum. Under the license agreement, Adverum granted us a worldwide non-exclusive royalty-bearing sublicense, with a limited right to grant further sublicenses, under certain patents and patent applications to which Adverum has obtained certain rights from the Regents of the University of California, or the Regents, to use, make, have made, import, sell, and offer for sale products and services that comprise a recombinant adeno-associated virus serotype 2 7m8 vector, or AAV2 7m8, to deliver any of three genes (channelrhodopsin, halorhodospin or rod-derived cone viability factor) for the treatment of ocular diseases in humans.

•Obligations of GenSight:

Under our license agreement with Adverum, we are obliged to use commercially reasonable efforts to develop, manufacture and commercialize the licensed products at our own cost and expense in accordance with a specific development plan under the Adverum agreement and are obligated to achieve certain specified milestones, including regulatory approvals, by certain target dates. If we fail to achieve any of these milestones by its target date, we have the option to extend the target date by 12 months upon the payment of $50 K to Adverum for each such extension.

•Financial obligations:

We paid Adverum a one-time license fee of $30 K in addition to $145 K as reimbursement for past costs for preparing, filing, prosecuting and maintaining the licensed patent rights. Under the terms of the license agreement, we also are required to reimburse Adverum for all such present and future costs up to a maximum of $30 K per year, together with an annual license maintenance fee of $30 K (minus the patent expenses paid in the prior year). Further milestone payments on a product-by-product basis will be due, upon the achievement of certain milestone events.

Further, upon the sale of any products or services licensed under the Adverum agreement, we are required to pay to Adverum low-to mid-single-digit royalties on annual worldwide net sales of such licensed products and services. Our royalty payment obligations to Adverum endure on a country-by-country and product/service-by-product/service basis for so long as at least one valid claim of any patent sublicensed from Adverum covers the manufacture, use or sale of a given product/service in a given country.

•Obligations of Adverum:

Adverum is responsible for and retains sole control over the prosecution, filing, maintenance and enforcement of all patents licensed to us under the agreement.

•Term and termination:

The license agreement will continue in full force and effect on a country-by-country basis until there are no remaining royalty obligations in any country, at which time the agreement shall expire in such country, unless otherwise terminated by the parties in accordance with the terms of the license agreement. We may terminate the agreement at any time upon 90 days’ prior written notice to Adverum, and Adverum may terminate the agreement in part or its entirety upon written notice to us if we assign the agreement in violation of its terms or fail to timely meet any of our specified development or milestones achievement obligations.

Upon the termination of the license agreement between Adverum and Regents, our license agreement with Adverum will survive, provided that, among other things, we will be required to make any monetary payments that Adverum would have been required to make under its agreement with Regents had it not been terminated.

Massachusetts Institute of Technology

License Agreement for Patents Relating to GS030

•Object:

On January 6, 2016, we entered into a license agreement with the Massachusetts Institute of Technology, or M.I.T., upon exercising an option right granted under the patent option agreement between M.I.T. and us, dated January 9, 2015. Under this license agreement, M.I.T. granted to us a royalty-bearing, license to certain patent rights jointly owned by M.I.T. and the University of Alberta, for use of the ChrimsonR or photoactivatable halorhodopsin protein (known as Jaws) gene expression sequences, in the retina for the prevention and treatment of blindness in humans. The license is exclusive but subject to the rights of M.I.T., the University of Alberta and any other non-profit research institute to practice under the patent for research, teaching and educational purposes, the U.S. government’s royalty-free, non-exclusive, non-transferable license to practice the patent, and certain mandatory third-party sublicensing requirements.

•Financial obligations:

Under the terms of this license agreement, we agreed to pay a license issue fee of $45 K, license maintenance fees up to $100 K per year and variable payments up to $7.3 million depending on the achievement of milestone events. We also agreed to pay running mid-single-digit royalties on future net sales.

This license agreement has been amended in April 2017, under which we will provide the M.I.T. with a written research and development plan no later than July 1, 2018.

This license agreement has been amended a second time in May 2018, under which we will provide the M.I.T. with a written research and development plan no later than July 1, 2019.

This license agreement shall remain in effect until the expiration or abandonment of all issued patents and patent applications under this license agreement, unless earlier terminated. We have the right to terminate this license agreement, for any reason, upon at least six months prior written notice to M.I.T., and upon payment of all amounts due to M.I.T. under the agreement. M.I.T. has the right to terminate this license agreement (i) immediately upon written notice if we cease to carry on our business related to the agreement, or (ii) if we fail to pay any amounts due and payable within 30 days.

Sorbonne Université, CNRS, Inserm and SATT Lutech

License Agreements for Patents relating to GS030

•Object:

On May 6, 2019, we entered into a license agreement with Sorbonne Université, CNRS, Inserm and SATT Lutech. Under this license agreement, we are granted an exclusive, worldwide, royalty-bearing license, non-transferable without the licensors’ prior consent and with right to grant sublicenses, to certain patents to develop, have developed, manufacture, have manufactured, own, supply, use, register, have registered, promote, distribute, have distributed, import, have imported, export, have exported, market and have marketed the product, a light stimulating device of photosensitive cells, part of GS030, for the treatment of vision disorders by optogenetic therapy.

•Proprietary rights:

Sorbonne Université, CNRS and Inserm reserved the right (i) to use the patent rights for any academic purposes and research programs performed by themselves or in the frame of partnerships with third parties, including in the field of treatment of vision disorders by optogenetic therapy, (ii) to grant any rights in the patents to third parties for any purposes outside the treatment of vision disorders by optogenetic therapy.

•Obligations of GenSight:

We are required to use commercially reasonable efforts to develop, market, promote and commercialize the product in the field of the treatment of vision disorders by optogenetic therapy. If we fail, without cause, to use such efforts to obtain at least a marketing authorization (MA) or biological license application (BLA) for a product by certain target dates or to develop product sales thereafter, SATT Lutech, on behalf of Sorbonne Université, CNRS and Inserm, will have the right to convert the exclusive license into a non-exclusive license.

•Financial obligations:

We paid the licensors a one-time license upfront payment of €30 K. We are also obliged to pay milestone payments upon achievement of certain development and regulatory milestone events. After the grant of a MA or BLA for the product, we are required to pay a fixed royalty fee for each first use of a product on a patient who has received the associated gene therapy treatment. In addition, we are required to pay an annual license maintenance fee creditable against the total paid amount of fixed royalty fee due on the same year.

We are responsible for the payment of all future fees and costs relating to the prosecution, defense and maintenance of the patent rights during the term of the license agreement unless i) we expressly refused the generating step and industrial property costs associated during the consultation phase with the licensors, in which case the patent right in question will automatically be excluded from the patents covered by the license, ii) SATT Lutech has granted a license on the patents to one or more third party outside the field of the treatment of vision disorders by optogenetic therapy in which case the costs will be shared equally, iii) the license has been converted into a non-exclusive license, in which case we will pay at most 50% of the industrial property costs due after the conversion (weighted, if relevant, by application of ii)). If we decide to cease bearing the industrial property costs, in full or part, the corresponding patent(s) will automatically be excluded from the scope of the license and the licensors will have the right to license said patent rights to third parties including in the field of treatment of vision disorders by optogenetic therapy.

•Obligation of the Satt Lutech

Satt Lutech, on behalf of Sorbonne Université, CNRS and Inserm, is responsible for and retains sole control over the management of the licensed patents, in consultation with us and, if relevant, with the third party licensed outside the field of the treatment of vision disorders by optogenetic therapy.

•Term and termination:

The license agreement will remain in force until the expiration of the last valid claim of the patent rights, on a country-by-country and product-by-product basis. We also have the right to terminate the agreement at any time and for any reason upon six months’ prior written notice.

5.5.5.1Our Intellectual Property Estate Patents

We strive to protect and enhance the proprietary technology, inventions and improvements that are commercially important to the development of our business, including seeking, maintaining and defending certain patent rights licensed from third-parties. We also rely on trade secrets and know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen and maintain our proprietary position in the fields of allogeneic transfer, optogenetics, gene therapy and specific optics and algorithms that may be important for the development of our business. We additionally may rely on regulatory protection afforded through data exclusivity, market exclusivity and patent term extensions where available. See Section 9, “Regulatory environment” of this Universal Registration Document.

Our future commercial success may depend, in part, on our ability to obtain and maintain patent and other proprietary protection for commercially important technologies, inventions and know-how related to our business; defend and enforce our in-licensed patents and any patents that we may own in the future; preserve the confidentiality of our trade secrets and proprietary know-how; and operate without infringing the patents and proprietary rights of third-parties. Our ability to stop third-parties from making, using, selling, offering to sell or importing our products may depend on the extent to which we have rights, either owned or in-licensed, under valid and enforceable patents, trade secrets or other know-how that cover these activities. In some cases, these rights may need to be enforced by third-party licensors.

Our rights to intellectual property, whether in-licensed, owned or co-owned are generally directed to methods of treatment or prevention of clinical indications important for our development programs, allotopic expression, mitochondrial trafficking, optogenetics, AAV vectors, transferring genetic material into cells, processes to manufacture and purify our product candidates, optics and other proprietary technologies and processes related to our product candidates. We also possess significant know-how and trade secrets relating to our product candidates.

In-licensed Patent Rights

As of the date of this Document, we in-licensed at least 3 U.S. and foreign patent applications and at least 39 U.S. and foreign patents, that have been filed by or on behalf of our licensors.

Product candidate | Owner | Title | Patent Term | Countries | Current status
LHON (LUMEVOQ®) | Inserm | Expression of mitochondrial protein by an enhanced allotopic approach | 2026 | United States European Union | European Union: granted, no opposition filed United States: two divisional pending
RP (GS030) | University of California (Adverum) | Adeno-associated virus virions with variant capsid and methods of use thereof | 2032 | Australia, Canada Singapore, Israel, China (3x), European Union (2x), Korea, Japan, United States (4x), Russia, Mexico, South Africa | Granted in US, EP, JP, CN, MX, RU, ZA and AU
RP (GS030) | M.I.T. | Channelrhodopsins for optical control of cells | 2032 | Korea, United States, European Union, Hong Kong | United States: three patents granted and one application pending Granted in Europe and Korea
RP (GS030) | Sorbonne Univ. CNRS INSERM | Method and device for controlling a device for aiding vision | 2032 | Australia, Canada, Hong Kong, China, European Union, Korea, Japan, United States | Granted in US, EP, JP, CN, KR, AU, HK, CA
RP (GS030) | Sorbonne Univ. CNRS INSERM | Display control precedent and device for implementing the method |  | European Union, United States | Granted in EP and US
RP (GS030) | Sorbonne Univ. CNRS INSERM | Method for downsampling a signal outputted by anasynchronous sensor |  | European Union, United States | Granted in Europe and US

With regard to the LUMEVOQ® product candidate, as discussed above, we have in-licensed a patent family from Inserm Transfert that relates to an expression vector for the delivery of a protein into the mitochondrion of a mammalian cell and the uses thereof. This patent family contains two pending U.S. application and one granted European patent. The granted European patent and the pending U.S. applications, if issued, are expected to expire in 2026, subject to possible patent term extensions.

With regard to the GS030 product candidate, as discussed above, we have exclusively in-licensed from M.I.T. patent applications pending in the United States, Hong Kong and South Korea and a granted European patent directed to ChrimsonR. The granted European patent and pending applications, if issued, are expected to expire in 2032, subject to possible patent term extensions. In addition, as discussed above, we have non-exclusively in-licensed from Adverum a patent family that relates to the AAV2 7m8 vector, with patents granted in the U.S., Europe, China, Australia, Mexico, Russia, South Africa and Japan, and patent applications pending in China, United States, Europe, Canada, Israel, South Korea, Singapore and Brazil, where the granted patents and pending applications, if issued, are expected to expire in 2032, subject to possible patent term extensions.

Product candidate | Owner | Title | Patent Application Number | Filing date | Countries | Currents status
RP (GS030) | GenSight Biologics UPMC CNRS INSERM | Optogenetic visual restoration using ChrimsonR | US62/329692 | 29/04/2016 | United States, European Union, China, Japan, Korea, Canada, Australia, Hong Kong | Granted in Japan and pending elsewhere
RP (GS030) | GenSight Biologics UPMC CNRS INSERM | Device for illuminating an object with a controlled light intensity and associated method | EP16305741.7 | 17/06/2016 | United States, European Union, China, Japan, Korea, Canada, Australia | Pending
RP (GS030) | GenSight Biologics UPMC CNRS INSERM | Medical device intended to be worn in front of the eyes | EP16306005.6 | 02/08/2016 | United States, European Union | Granted in the U.S. and Europe
RP (GS030) | GenSight Biologics UPMC CNRS INSERM | Objective, camera and system adapted for optogenetics | EP17305805.8 | 28/06/2017 | United States, European Union, China, Japan, Korea, Canada, Australia | Granted in China and pending elsewhere
RP (GS030) | GenSight Biologics | Method and device for processing asynchronous signals generated by an event-based light sensor | EP 18305020.2 | 11/01/2018 | United States, European Union, China, Japan, Korea | Pending
LHON (LUMEVOQ®) | GenSight Biologics | Recombinant AAV2 vectors and methods of using the same | US62/683,501 | 11/06/2018 | United States, European Union, China, Japan, Korea, Canada, Australia | Pending
RP (GS030) | GenSight Biologics | Method for controlling an optogenetic device using a command law for the radiant power of a light source and associated devices | EP19305135.6 | 05/02/2019 | United States, European Union, China, Japan, Korea, Canada, Australia | Pending
RP (GS030) | GenSight Biologics | Method for controlling an optogenetic device using filtering and associated devices | EP19305136.4 | 05/02/2019 | United States, European Union, China, Japan, Korea, Canada, Australia | Pending
RP (GS030) | GenSight Biologics | Viewing apparatus and method for projecting a light signal | EP19305561.3 | 03/05/2019 | United States, European Union, China, Japan, Korea, Canada, Australia | Pending

Trademarks

GenSight is a registered Community Trademark covering 26 member States of the European Union (including UK).

The brand name chosen for GS010, as approved by the EMA for use in the MAA, is LUMEVOQ® (lenadogene nolparvovec). LUMEVOQ® is a registered Community Trademark (including UK), and is also registered in the U.S, Australia, Israel, New Zealand, Singapore, and Taiwan. Upon regulatory approval, GenSight intends to commercialize GS010 under LUMEVOQ® trademark.

The brand name chosen for GS030 is LUMOVI®. LUMOVI® is a registered Community Trademark (including UK), and is also registered in the U.S. Upon regulatory approval, GenSight intends to commercialize GS030 under LUMOVI® trademark.

We may, in the future, file additional applications to register GenSight, LUMEVOQ® and/or LUMOVI® in other territories and/or file applications for new trademarks covering current or future products and/or services in certain markets of interest. See Section 3.5, “Legal Risks and Risks Related to our Intellectual Property — Our trademarks and trade names may not be adequately protected and we may not be able to build name recognition in our markets of interest” and Section 18.6, “Legal and Arbitration Proceedings” of this Universal Registration Document.

5.6Competition

The biopharmaceutical industry, including the gene therapy field, is characterized by rapid scientific technological changes and significant competition. Any product candidates that we successfully develop and commercialize will have to compete with therapies that may become available in the future. We face competition from pharmaceutical and biotechnology companies, as well as from academic institutions, governmental agencies and public and private research institutions.

We are aware of a number of companies focused on developing gene therapies in various indications, including Adverum Biotechnologies, Inc., Ultragenyx Pharmaceutical, Inc., Applied Genetic Technologies Corporation, Asklepios BioPharmaceutical, Inc., Audentes Therapeutics, Inc., bluebird bio, Inc., GlaxoSmithKline, Biogen, Inc., Spark Therapeutics, Inc., uniQure N.V. and Voyager Therapeutics, Inc., as well as several companies addressing other methods for modifying genes and regulating gene expression. Any advances in gene therapy technology made by a competitor may be used to develop therapies that could compete against any of our product candidates.

For our specific retinal gene therapy products, the main competitors include:

LUMEVOQ® for the Treatment of LHON: The Huazhong University in China, which completed Phase I/II studies in 2013 using gene therapy, recently published data with nine months follow-up and the evaluation of both safety and some visual acuity outcomes. The purpose of these studies is exclusively academic. We are aware of a Chinese company, Neurophth, whose gene therapy NR082, which uses recombinant adeno-associated viral serotype 2 vector (rAAV2) containing a codon-optimized of NADH-dehydrogenase subunit 4 (ND4) gene, that was granted an orphan designation in the U.S. in September 2020 and received IND clearance in January 2022 to proceed to clinical trials in the U.S.. The data on safety and efficacy were generated from three investigator-initiated trials. Their gene therapy was also granted orphan designation by the EMA in January 2022. We are aware of other companies and institutions focused on developing therapies in the LHON space that do not involve gene therapy, including: Santhera Pharmaceuticals Holding AG using a chemical entity, Idebenone, approved under exceptional circumstances in Europe; and Mitotech, whose mitochondria-targeting cardiopolin peroxidation inhibitor Visomitin had been originally developed for the treatment of Dry Eye.

GS030 for the Treatment of RP: To our knowledge, we are the only Company in the Clinic with a technology that utilizes light at near-red wavelength with goggles. RetroSense Therapeutics, LLC, or RetroSense, is developing a ChR2-based optogenetic product that is in Phase I studies that will have to utilize blue light to stimulate the ChR2 without goggles. Retrosense was acquired by Allergan plc in September 2016. Applied Genetic Technologies Corporation, or AGTC, is partnering with Bionic Sight to develop an optogenetic therapy combining a ChR-based gene therapy and a neuro-prosthetic device using an algorithm for retinal coding. This program is still in preclinical development. In addition, the only approved non-therapeutic treatment for RP is retinal implants. Nanoscope Therapeutics is developing optogenetic gene therapies using Multi-Characteristic Opsin (MCO) to re-sensitize the retina to detect low light levels. Their lead product, MCO-010, is in clinical development for retinitis pigmentosa (RP) and Stargardt disease.

GS030 for the Treatment of GA: No approved therapy currently exists for GA. Most major clinical-stage therapeutic treatments for GA are in the field of cell therapy, including lampalizumab, an anti-Factor D, the development of which F. Hoffmann-La Roche Ltd. terminated post unsuccessful Phase III data. GlaxoSmithKline plc’s anti-amyloid beta monoclonal for patients with GA is in Phase II clinical trials. Novartis’ LFG-316 C5 monoclonal antibody for patients with GA is in Phase II clinical trials. Apellis Pharmaceuticals, Inc. is currently developing a C3 inhibitor, which has completed Phase II and initiated Phase III clinical trials. Gyroscope Therapeutics, Ltd, started in 2019 a Phase I/II FOCUS study of a gene therapy (GT005) coding for an inhibitor of the Complement System, in patients with geographic atrophy due to dry AMD.

GS030 for the Treatment of Dry AMD: No approved therapy currently exists for dry AMD. Ophthotech Corporation’s Zimura, a complement C5 inhibitor, is currently in a Phase IIb clinical trial. Johnson and Johnson are developing Palucorcel, which utilizes human embryonic stem cells that recently completed a Phase I/II trial. Similarly, Astellas Pharma Inc. is developing a stem cell treatment currently in Phase II. BioTime, Inc. is developing OpRegen, a dry AMD-targeted therapy that replaces missing retinal pigment epithelium cells with OpRegen cells and is currently in a Phase I/IIa dose escalation study. Regenerative Patch Technologies requires a subretinal implant of stem cells and is in a Phase I/II trial.

Many of our potential competitors, alone or with their strategic partners, have substantially greater financial, technical and other resources than we do, such as larger research and development, clinical, marketing and manufacturing organizations. Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated among a smaller number of competitors. Our commercial opportunity could be reduced or eliminated if competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop. Competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. Additionally, technologies developed by our competitors may render our potential product candidates uneconomical or obsolete, and we may not be successful in marketing our product candidates against competitors.

5.7Investments

5.7.1 HISTORICAL INVESTMENTS.

Our historical investments since 2015 involve mainly the acquisition of property, plant and equipment, and intangible assets. The following table sets forth our net cash used in investing activities as of December 31, 2020 and 2021:

In thousands of euros | As of December 31,
2020 | 2021
Cash flows from investment activities |  |
Acquisitions of property, plant and equipment | (6) | (32)
Acquisitions of intangible assets | — | —
Acquisitions / reimbursement of non-current financial assets | (370) | —
Acquisitions / reimbursement of current financial assets | — | 16
Net cash flows from investment activities | (376) | (16)

5.7.2 FUTURE PLANNED INVESTMENTS.

As of the date of this Universal Registration Document, we do not have any material commitments to make investments in the future.

5.7.3 JOINT VENTURE.

N/A

5.7.4 ENVIRONMENTAL ISSUES.

•The Company has not identified any significant environmental risks related to its business that could require it to set a provision for such risks or to provide specific training for its employees. To date, the Company has not identified any opportunity to join an initiative to protection of biodiversity and adaptation to the consequences of climate change. The actions of the fight against food waste are not an issue given the activity of the Company.

•The Company regularly raises awareness among its employees on ways to reduce its environmental impact.

Despite an environmental impact deemed low, the Company and its employees are involved in sustainable development initiatives. The Company applies environmentally responsible paper management practices such as the use of an electronic document management system, setting all printers to default to double-sided printing, and purchasing only reams of paper of “ecological quality” (EU Ecolabel or PEFC). All of these practices thus constitute a virtuous cycle that makes it possible to avoid cutting down trees as much as possible.

5.8Manufacturing

We have chosen to outsource manufacturing to specialized contract manufacturing organizations, or CMOs. As part of this strategy, we have hired experienced chemistry, manufacturing and controls, or CMC, and quality assurance personnel in order to (i) assess potential CMO partners, (ii) conduct the necessary audits and due diligence in connection with partner CMOs, (iii) oversee, review and audit the CMC process to be used for all regulatory submissions and (iv) oversee, review and control all the methods and protocols used to ensure that the final product meets our quality specifications.

We partner with leading CMOs in gene therapy manufacturing, including Brammer Bio and Catalent to produce non-clinical and clinical drug products for clinical development and future commercialization. We have made significant efforts to scale up and optimize the manufacturing process with a view to the delivery of commercial batches.

Our AAV-based gene therapy products are produced using transient triple transfection process for LUMEVOQ® and the baculovirus process for GS030. Production is carried out in compliance with current good manufacturing practices, or cGMP, by CMOs that have been certified by national regulatory authorities.

Manufacturing Process Using Transient Triple Transfection for LUMEVOQ®

The transient triple transfection-based production process uses adherent HEK293 cells amplified in multi-tray cell-culture systems. Cells are co-transfected with three independent plasmids. Transfected cells are harvested and cell lysate is then clarified in order to eliminate cellular debris.

Purification of the AAV vector is then achieved by immunoaffinity and filtration in the final formulation buffer, leading to drug substance.

The concentration of the drug substance is adjusted to a defined concentration, before being sterile filtered and filled into individual vials, to eventually become the drug product. Drug product is stored at <-60°C.

Batches for the Phase III trials were produced at the Henogen S.A., which was acquired by Groupe Novasep, facility in Belgium in compliance with cGMPs. In anticipation of our commercial needs and process validation, we implemented the transfer of the manufacturing process to the Brammer Bio facility in Cambridge, Massachusetts in October 2017, to ensure commercial supply for the European Union and the United States. The batches used for the ongoing Temporary Authorization for Use have been produced at Brammer Bio facility. For each batch production, a series of quality control tests are performed during the process and at release to assess product strength, quality, purity and safety under controlled and validated standard operating procedures in accordance with cGMP.

In November 2021, the Company announced that its planned PPQ campaign at Brammer Bio had failed due to an equipment issue in the filtration steps. A new campaign was initiated in December 2021 generating drug substance whose viral genome titer fell below the acceptance threshold. Resulting investigations led by external experts have traced the outcome to operational difficulties in specific stages of the downstream process. To prevent the repeat of these issues, the Company is working with its manufacturing partner to implement targeted corrections around enhanced process control and more rigorous supervision inside the manufacturing suites. In addition, the Company has decided to manufacture engineering lots to confirm the robustness of the corrective actions. GenSight Biologics has appointed Scott Jeffers in April 2022 as Chief Technical Officer, based in the Boston area in the US where Brammer Bio is located, to lead all pharmaceutical development and manufacturing activities. The Company now targets the restart of the PPQ campaign in Q3 2022.

Manufacturing Process Using Baculovirus Production for GS030

The AAV is produced in SF9 insect cells using two recombinant baculovirus vectors. One vector carries the viral genome, and the other carries elements for the expression of functions required for replication of the AAV genome and assembly of the viral capsids.

The SF9 cells are cultivated in suspension in a serum-free medium in single-use bioreactors. Production of AAV by the SF9 insect cells/baculovirus method has proven to be an efficient and scalable means of recombinant AAV production.

During the manufacturing process, the AAV vector is isolated from lysed, harvested cells by affinity chromatography. The vector is further purified by ion-exchange chromatography to create the bulk drug substance, or BDS. To produce the drug product, the BDS is adjusted to a defined concentration with formulation buffer, then sterile filtered before being filled into individual vials. Drug product is stored at <-60°C.

Manufacturing Process for the GS030 Medical Device

The goggles will be manufactured and tested at an established ISO13485-certified site in France, under the control of our Quality Assurance team. The devices will be certified to initially meet European and U.S. requirements, and will be extended to other countries via the international MDSAP program.

5.9Sales and marketing

We hold worldwide commercialization rights to our platform technologies, product candidates and development programs. If approved, we intend to commercialize LUMEVOQ®, initially in the European Union and the United States, ourselves. We will be opportunistic in pursuing partnerships that can broaden the geographic footprint of LUMEVOQ® outside our initial focus markets, once the core regulatory files are finalized. Because LHON is a rare disease, we believe a targeted sales and marketing organization would be able to reach specialized ophthalmology centers and their patients while effectively engaging with reimbursement authorities to secure access for these patients. We have built, and continue to expand upon, key relationships with ophthalmic experts and patients of severe retinal neurodegenerative diseases around the globe, since we anticipate that a large majority of patients suffering from this disease will be referred to a limited number of large, well-equipped centers with top neuro-ophthalmologists and retina specialists in each country. Due to the broad patient populations that GS030 may address, we may enter into strategic partnerships to maximize commercial value of our product candidate.

The Company has appointed Sissel Rodhal in February 2022 as Senior Vice President of Commercial Operations to build a strong and adaptable commercial organization to secure the successful launch of LUMEVOQ® in Europe in Q4 2023.

6

ORGANIZATIONAL STRUCTURE