fdmt-10k_20201231.htm

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2020

Commission File Number 001-39782

4D Molecular Therapeutics, Inc.

(Exact name of Registrant as specified in its Charter)

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (510) 505-2680

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

Title of each class Trading Symbol(s) Name of each exchange on which registered

Common Stock, par value $0.0001 per share FDMT The Nasdaq Global Select Market

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes☐No☒

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes☐No☒

Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes☒No☐

Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was required to submit such files). Yes☒No☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐

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

The registrant was not a public company as of June 30, 2020, the last business day of its most recently completed second fiscal quarter, and therefore, cannot calculate the aggregate market value of its voting and non-voting common equity held by non-affiliates as of such date. The registrant’s Common Stock began trading on the Nasdaq Global Select Market on December 11, 2020.

The number of shares of Registrant’s Common Stock outstanding as of March 15, 2021 was 26,692,879.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the registrant’s definitive Proxy Statement relating to the 2021 Annual Meeting of Stockholders are incorporated herein by reference in Part III of this Annual Report on Form 10-K to the extent stated herein. The proxy statement will be filed with the Securities and Exchange Commission within 120 days of the registrant’s fiscal year ended December 31, 2020.

Table of Contents

Page

PART I

Item 1. Business 1

Item 1A. Risk Factors 72

Item 1B. Unresolved Staff Comments 136

Item 2. Properties 137

Item 3. Legal Proceedings 137

Item 4. Mine Safety Disclosures 137

PART II

Item 6. Selected Financial Data 139

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 152

Item 8. Financial Statements and Supplementary Data 153

Item 9A. Controls and Procedures 153

Item 9B. Other Information 153

PART III

Item 10. Directors, Executive Officers and Corporate Governance 154

Item 11. Executive Compensation 154

Item 14. Principal Accounting Fees and Services 154

PART IV

Item 15. Exhibits, Financial Statement Schedules 155

SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K contains forward-looking statements concerning our business, operations and financial performance and condition, as well as our plans, objectives and expectations for our business operations and financial performance and condition. Any statements contained herein that are not statements of historical facts may be deemed to be forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “predict,” “potential,” “positioned,” “seek,” “should,” “target,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. These forward-looking statements include, but are not limited to, statements about:

• the timing or likelihood of regulatory filings and approvals;

• the rate and degree of market acceptance of our product candidates;

• the pricing and reimbursement of our product candidates, if approved;

• our financial performance; and

These forward-looking statements are based on management’s current expectations, estimates, forecasts and projections about our business and the industry in which we operate and management’s beliefs and assumptions and are not guarantees of future performance or development and involve known and unknown risks, uncertainties and other factors that are in some cases beyond our control. As a result, any or all of our forward-looking statements in this Annual Report on Form 10-K may turn out to be inaccurate. Factors that may cause actual results to differ materially from current expectations include, among other things, those listed under the section titled “Risk Factors” and elsewhere in this Annual Report on Form 10-K. Potential investors are urged to consider these factors carefully in evaluating the forward-looking statements. These forward-looking statements speak only as of the date of this Annual Report on Form 10-K. Except as required by law, we assume no obligation to update or revise these forward-looking statements for any reason, even if new information becomes available in the future. You should, however, review the factors and risks we describe in the reports we will file from time to time with the SEC after the date of this Annual Report on Form 10-K.

iii

PART I

Item 1. Business.

Overview

We are a clinical-stage gene therapy company pioneering the development of product candidates using our targeted and evolved AAV vectors. We seek to unlock the full potential of gene therapy using our platform, Therapeutic Vector Evolution, which combines the power of directed evolution with our approximately one billion synthetic capsid sequences to invent evolved vectors for use in targeted gene therapy products. Our targeted and evolved vectors are invented with the goals of being delivered through clinically routine, well-tolerated and minimally invasive routes of administration, of transducing diseased cells in target tissues efficiently, of having reduced immunogenicity and, where relevant, of having resistance to pre-existing antibodies. We believe these key features will help us to potentially create targeted gene therapy product candidates with improved therapeutic profiles, and to address a broad range of diseases from rare to large patient populations, including those that other gene therapies are unable to address. Each of our product candidates is created with one of our targeted and evolved AAV vectors. Our platform is designed to be modular, in that an evolved vector invented for a given set of diseases can be equipped with different transgene payloads to treat other diseases affecting the same tissue types. We believe this modularity will help inform the clinical development of subsequent product candidates using the same vector.

We have built a deep portfolio of gene therapy product candidates initially focused in three therapeutic areas: ophthalmology (intravitreal vector), cardiology (intravenous vector) and pulmonology (aerosol vector). We have three product candidates that are in clinical trials: 4D-125 for the treatment of X-linked retinitis pigmentosa (“XLRP”) in a Phase 1/2 clinical trial, 4D-110 for the treatment of choroideremia in a Phase 1 clinical trial, and 4D-310 for the treatment of Fabry disease in a Phase 1/2 clinical trial. Our two IND candidates are 4D-150 for the treatment of wet age-related macular degeneration (“wet AMD”), and 4D-710 for the treatment of cystic fibrosis lung disease. We expect to file the INDs and to initiate clinical trials for both of these programs in the second half of 2021.

We believe our competitive advantages, combined with our highly experienced team, help to position our company to create, develop, manufacture and, if approved, effectively commercialize targeted gene therapies that could transform the lives of patients suffering from debilitating diseases.

Our Approach: Therapeutic Vector Evolution Platform

Gene therapy holds tremendous promise as a transformative therapeutic class. However, the majority of gene therapies have encountered limitations such as inflammation and toxicity, high dose requirements, limited efficacy and neutralization by pre-existing antibodies, due in part to their utilization of conventional AAV vectors that are naturally occurring and non-targeted. Through our Therapeutic Vector Evolution platform we apply the principles of directed evolution to invent targeted and evolved vectors for the delivery of genes to specific tissue types for diseases involving the same target tissue(s). Our product candidates are designed and engineered to utilize our targeted and evolved vectors to potentially address the limitations encountered with gene therapies utilizing conventional AAV vectors.

Leveraging a wide range of molecular biology techniques, we have developed a collection of 40 distinct libraries that are comprised of approximately one billion synthetic capsid sequences. We next define a Target Vector Profile that identifies the optimal vector features for the specific tissue type(s) and related set of diseases we seek to target, with the goal of overcoming limitations encountered by conventional AAVs. We then deploy Therapeutic Vector Evolution with our capsid libraries in NHPs and use competitive selection to identify targeted and evolved vectors from our libraries that demonstrate the strongest match to the Target Vector Profile. Our three lead vectors have unique structural changes as compared to the conventional naturally occurring AAV capsid as shown below.

Our three lead targeted and evolved vectors comprise numerous diverse and biologically important differences from the conventional AAV capsid, as illustrated in the computer generated representations of the three-dimensional capsid structures depicted below. The colorized areas illustrate these differences.

Based on preclinical data reported to date from our NHP and human cell models, including preclinical head-to-head comparisons with relevant conventional AAV vectors, we observed that our targeted and evolved vectors were well-tolerated and achieved enhanced delivery, increased transgene expression, reduced immunogenicity and/or improved antibody resistance when compared to conventional AAV vectors. We have not compared our targeted and evolved vectors to conventional AAV vectors in patients in clinical studies.

As we advance through clinical trials, we plan to evaluate the following potential design features of our targeted and evolved vectors and product candidates:

Our Product Candidate Pipeline

We are developing a diverse pipeline of product candidates for both rare and large market diseases, including patient populations that other gene therapies are unable to address. Our initial product candidates are focused on the following therapeutic areas: ophthalmology, cardiology and pulmonology. Each of our product candidates leverages a targeted and evolved vector we invented through our Therapeutic Vector Evolution platform. Below is a summary of our product candidate pipeline and our next anticipated milestones:

‡ Reporting in coordination with our partner Roche.

§ The Research stage involves (1) defining the Target Vector Profile then deploying Therapeutic Vector Evolution with our capsid libraries in non-human primates (NHPs) and using competitive selection to identify targeted and evolved vectors from our libraries that demonstrate the strongest match to the Target Vector Profile; then (2) optimizing our product candidates using the lead vector by conducting in vivo and in vitro evaluation of various transgene and promoter construct candidates in cell and animal models, and the selection of at least one product candidate to move forward into IND-enabling studies.

Ophthalmology Pipeline: Intravitreal Product Candidates

We are developing product candidates to treat tissues throughout the retina. Our targeted and evolved AAV vector, R100, was invented for routine intravitreal injection, leading to transgene expression across the entire surface area of the retina, and in the major cell layers of the retina.

We currently have four ophthalmology product candidates that utilize our proprietary intravitreal R100 vector:

Cardiology Pipeline: Intravenous Product Candidates

With our cardiology product candidates, all of which are wholly owned, we plan to treat patient populations in both primary cardiomyopathies, that involve the heart only, as well as cardiomyopathies that are secondary to systemic diseases, such as lysosomal storage diseases. Our cardiology product candidates utilize our targeted and evolved AAV vector, C102, which was invented for routine low dose intravenous administration and delivery to the heart, leading to transgene expression in heart muscle cells throughout the organ. For lysosomal storage diseases involving the heart and other organs, including Fabry disease, our product candidates are designed for transgene expression both within the heart and in other targeted tissues.

Our initial cardiology product candidate 4D-310 is in an ongoing Phase 1/2 clinical trial in adult patients with classic (severe) Fabry disease. 4D-310 is designed to address all critically affected organs, including the heart, kidney, and blood vessels through direct intracellular transgene expression. To our knowledge, 4D-310 is the only Fabry disease product candidate specifically designed to treat cardiomyocytes. We expect to report initial clinical data from this trial in the second half of 2021.

Pulmonology Pipeline: Aerosol Delivery Product Candidates

With our pulmonology product candidates, all of which are wholly owned, we plan to treat diseases that affect the lungs. Our pulmonology product candidates utilize our targeted and evolved vector, A101, which was invented for aerosol delivery to all major regions within the lung, including airways and alveoli, and successful penetration of the mucus barrier for transduction of lung airway cells, overcoming potential barriers such as pre-existing AAV antibodies and other inhibitory proteins within the mucus barrier. Our products utilizing A101 are designed for delivery as an aerosol to the lung epithelial cell surface resulting in efficient airway and alveolar cell transduction and transgene expression.

Our initial pulmonology product candidate 4D-710 is in IND-enabling preclinical development for cystic fibrosis lung disease. We expect to file an IND and to initiate a Phase 1/2 clinical trial for 4D-710 in the second half of 2021.

Our Team

Our experienced team consists of biotherapeutics developers, entrepreneurs, innovative gene therapy scientists and clinicians to execute our platform, product design and development and commercialization strategies. Collectively, our team has more than 100 years of combined experience in the field of viral vector gene therapy, including leadership of over 30 clinical trials from Phase 1 through Phase 3 and product approval. We are led by our Chief Executive Officer and co-founder, David Kirn, M.D., who has over 25 years of experience creating and growing therapeutic platform companies, including viral vector gene therapy and oncolytic virus technologies, and advising on the design, preclinical translation and clinical development of viral vector gene therapeutics for leading life science companies, such as Onyx Pharmaceuticals, Novartis International AG, Pfizer Inc., Bayer AG and Biogen Inc. Our Executive Chairman, John Milligan, Ph.D., is the former CEO and President of Gilead Sciences, where he spent over 29 years scaling the company and commercializing numerous transformative therapies across multiple disease areas. Our Chief Scientific Advisor and co-founder, David Schaffer, Ph.D., pioneered the application of directed evolution to the capsid of AAV vectors 20 years ago. Our Chief Operating Officer and Chief Technical Officer, Fred Kamal, Ph.D., has over 25 years of industry experience in product manufacturing and quality, including most recently with AveXis, Inc. where he was a key contributor to the development and biologics license application (“BLA”) for the AAV product Zolgensma (onasemnogene abeparvovec). Our Chief Medical Officer, Robert S. Fishman, M.D., brings over 20 years of clinical trial execution and product development expertise. Our board of directors also brings significant experience in biopharmaceutical commercial execution and strategic initiatives.

Our Strategy

Our vision is to unlock the full potential of gene therapy to address as many patient populations as possible in both rare and large market diseases. We have developed the following strategies and guiding principles to achieve our goals:

Invent targeted and evolved AAV vectors using the power of directed evolution to unlock the full potential of gene therapy with transformative gene therapy products

Our Therapeutic Vector Evolution platform allows us to move beyond conventional AAV vectors and has enabled us to develop proprietary targeted and evolved vectors based on a Target Vector Profile for any set of diseases we strive to treat. This platform empowers us to select the best (or “fittest”) targeted and evolved vector, matching the Target Vector Profile for any set of related diseases, out of our 40 distinct libraries comprising approximately one billion synthetic capsid sequences. Our goal is to unlock the full potential of gene therapy by creating targeted gene therapies based on these vectors. As compared to gene therapy products utilizing conventional AAV vectors, we believe our targeted gene therapies, if approved, will enable treatment of broader patient populations within specific diseases, diseases currently not addressed by gene therapy and large market diseases.

Apply our modular product design and engineering to help inform the clinical development of subsequent product candidates using the same vectors used for prior product candidates

Our targeted gene therapy product candidates are modular, in that a single targeted and evolved vector can be equipped with different transgene payloads to enable treatment of multiple different diseases affecting the same tissue type(s). Our preclinical and clinical development will provide us with insights and clinical proof-of-concept for a given vector equipped with one transgene. Development of subsequent product candidates could also be more efficient, as manufacturing, preclinical, clinical and regulatory activities will be guided by experience with preceding product candidates using the same vector.

Develop and commercialize a diverse portfolio of transformative gene therapy products in a broad range of therapeutic areas with significant unmet needs, including rare and large patient populations

We are building a diverse portfolio of product candidates. We believe this diversity increases our likelihood of success in contrast to relying on a single vector or disease area as evidenced by our: (1) multiple proprietary vectors delivered by different routine, well-tolerated and minimally invasive routes of administration specific to the disease, (2) therapeutic area diversity including ophthalmology, cardiology and pulmonology; and (3) opportunity to address both rare and large patient populations not currently addressed with conventional AAV vectors. We seek to develop our wholly owned product candidates through market approval and to retain product marketing rights for key products, regions and strategic therapeutic areas.

Build a fully integrated biopharmaceutical company by advancing our capabilities in product development and commercialization, and expanding our manufacturing facilities and internal proprietary Good Manufacturing Practice (“GMP”) capabilities

To become a fully integrated biopharmaceutical company, we are building robust internal capabilities including translational and clinical research and development, regulatory affairs, manufacturing and quality which can mitigate operational risks, reduce costs, and increase product development control and speed. In the future we intend to build commercialization capabilities, including sales and marketing.

We believe robust internal manufacturing capabilities are of particular importance in gene therapy due to the high complexity of producing these therapies. Our current in-house manufacturing capabilities include GMP manufacturing, production capabilities for IND-enabling GLP toxicology studies and

research candidate production (upstream, downstream and fill/finish). We intend to further maximize the robustness and internal control of our manufacturing processes from discovery and process development through to clinical-grade cGMP manufacturing and to scale these capabilities to support later stage clinical programs and indications where clinical trials require more patients and/or higher intravenous doses. In the future we intend to build manufacturing capacity sufficient to support commercialization of any product candidates that are approved.

Selectively execute strategic collaborations to maximize the potential value of our Therapeutic Vector Evolution platform

We intend to enter into patient advocacy foundation alliances and academic collaborations, and to evaluate potential strategic corporate partnerships. We believe that alliances with patient advocacy organizations, such as the Cystic Fibrosis Foundation, can be beneficial for funding, patient enrollment, regulatory strategy, product design and clinical development. In addition, we intend to further expand our enabling technologies and our intellectual property portfolio by pursuing new opportunities through our sponsored research agreements with our Chief Scientific Advisor Dr. Schaffer and U.C. Berkeley. We will continue to evaluate new opportunities to partner with biopharmaceutical companies that we believe enhance our ability to deliver value for stockholders and clinical benefits for patients.

Our Therapeutic Vector Evolution Platform

Gene Therapy Successes and Limitations of Current Conventional Non-Targeted AAV Vectors

Gene Therapy Overview

Gene therapy aims to address diseases caused by gene mutations and gene dysregulation. Gene therapies hold the promise of delivering transformative and durable benefit to the patient by addressing the underlying molecular root cause of genetic diseases, in many cases, by introducing a functional version of the patient’s defective gene into their own cells. Gene therapy has shown the potential to halt the progression of rare diseases, as well as to enable or restore critical human functions. Gene therapies may be delivered to their target cells either in vivo or ex vivo and can be paired with other therapeutic approaches including cell therapy and gene editing.

The transformative potential of gene therapy has been demonstrated across multiple rare disease areas. There has been significant progress over the last decade in the field of gene and cell therapies, including with AAV based gene therapy. Further, the number of companies developing gene and cell therapy products has increased significantly over the last five years. There are currently a number of approved viral vector gene therapy products, including Zynteglo, Zolgensma, Luxturna, Imlygic and Strimvelis.

The physical construct of gene therapies are comprised of two essential components:

Generalized components of an AAV gene therapy include the vector and a therapeutic payload consisting of DNA encoding a promoter, transgene, polyadenylated (“pA”) tail for stability, and inverted terminal repeats (“ITR”) to support packaging and other functionality within the target cell.

Key Challenges with Conventional AAV Vectors

The fundamental gene therapy components used in current gene therapy candidates originated largely from academia, some as early as the 1960s, with limited improvements since their discovery. The majority of AAV gene therapy companies use conventional AAV vectors that are comprised of naturally occurring AAV capsids (protein shells) of a few specific subtypes, including AAV1, AAV2, AAV5, AAV8, AAV9, AAVhu68, AAVrh10, and AAVrh74. In some cases, minor changes have been made to these naturally occurring, non-targeted capsids in an attempt to enhance non-specific transduction. While gene therapy holds tremendous promise as a transformative therapeutic class, the demonstrated hurdles with conventional AAV vectors may limit the diseases and patient populations that can be effectively addressed.

We believe that there arefour fundamental challengesthat hinder gene therapies that utilize conventional AAV vectors which may adversely impact their product safety, efficacy and commercial potential:

Our Solution: Evolved Vectors for Targeted Gene Therapy

We are pioneering the development of targeted gene therapies based on our targeted and evolved vectors. Using our Therapeutic Vector Evolution platform, we invent targeted and evolved vectors that are designed to address specific diseases and their associated tissue(s). We believe our proprietary vectors will allow us to overcome known limitations of conventional AAV vectors, and to potentially address a broad range of both rare and large patient populations that cannot be addressed with conventional vectors. Based on our Target Vector Profile for a set of diseases, we select vectors in NHPs from our 40 distinct libraries made up of approximately one billion synthetic capsid sequences. Subsequently, we characterize and evaluate a lead targeted and evolved vector for delivery and transgene expression through extensive studies in NHP and human cell and organotypic tissue assays.

The first step in directed evolution is to generate massive genetic diversity. Starting with the genomes of multiple naturally occurring AAV variants, and their ancestral predecessors, we employ numerous molecular biology techniques to create our 40 distinct libraries comprising approximately one billion synthetic capsid sequences.

Starting with our 40 distinct libraries comprising approximately one billion synthetic capsid sequences, we conduct Therapeutic Vector Evolution, including competitive selection, to identify targeted and evolved vectors that fit a Target Vector Profile. The illustration below highlights the Target Vector Profile design and subsequent selection process whereby competitive pressure is applied over a varying number of selection rounds for each program. Capsids with the best fitness for the Target Vector Profile are enriched at each round and are designated lead vectors.

Key Design Features of Our Targeted and Evolved Vectors

Through our proprietary Therapeutic Vector Evolution platform, we invent targeted and evolved vectors that we believe have the potential to display superiority to conventional AAV vectors with respect to four key design features:

• Improved transduction of target cell types and tissues

• Lower toxicity with reduced inflammation

• Ability to resist neutralization by pre-existing antibodies in humans

As shown below, we have generated animal proof-of-concept data in both NHP and knock-out mouse disease models in vivo, and in human cells in vitro, that we believe provide evidence regarding the potential for our targeted and evolved vectors to show superiority over conventional AAV vectors. Our goal is to develop products that are safer, more efficacious, administered at lower doses, more efficiently manufactured, and, if approved, more effectively commercialized.

Targeted Delivery to, and Transduction of, Specific Tissues by Routine Clinical Routes of Administration

We select targeted and evolved vectors that are administered through what we believe to be the optimal method of delivery for a particular disease, with the goal of circumventing physical barriers en route to specific tissues or cell types in the body.

In our first example of targeted delivery in NHPs in vivo, our targeted and evolved vector for the retina, R100, was invented for intravitreal administration. We believe intravitreal injection is the optimal

route of gene therapy administration for the retina, as evidenced by widespread use of approved intravitreally administered biologics, that generate over $9.7 billion in annual global sales for the treatment of wet AMD, diabetic retinopathy and related diseases. The R100 vector is leveraged in modular fashion for use in all four of our current ophthalmology product candidates: 4D-110, 4D-125, 4D-135 and 4D-150. Conventional AAV capsid vectors such as AAV2 are not able to reach retinal cells effectively following intravitreal injection due to barriers such as the inner-limiting membrane barrier between the vitreous and target retinal cells. As a result, gene therapies utilizing conventional vectors have relied on delivery by subretinal surgery. This is a complex procedure that requires highlyspecialized retinal surgeons to perform surgery in an operating room setting, and results in a bleb of fluid within a detached area of retina that comprises less than 1% of the total retina surface, based on published data. Potential complications include retinal tears and retinal detachments.

In contrast, in preclinical studies intravitreal R100 transduced the entire retinal surface area and a high percentage of cells in all layers of the retina, including photoreceptors and retinal pigment epithelial (“RPE”) cells in NHP. Of note, the ocular anatomy and physiology in NHPs closely mirrors that of humans. We therefore believe our products designed and engineered with R100 have potential tolerability, biologic activity and commercial advantages compared with product candidates that require subretinal surgical injection.

Structure-function studies suggested that the potential of R100 to penetrate through the inner-limiting membrane barrier may be associated with reduced binding to heparan sulfate, which is a major component of the barrier. R100 subsequently binds and transduces target retinal cells at higher efficiency than the conventional AAV2 vector. The improved transduction was associated with enhanced binding to sialic acid on the target cells.

Target Vector Profile for R100 intravitreal delivery to the retina:

Following intravitreal injection, conventional AAV vectors (top panel) such as AAV2 are not able to reach retinal cells effectively due to barriers such as the inner-limiting membrane barrier between the vitreous and target retinal cells. R100 administered by intravitreal injection (bottom panel) was able to penetrate through these barriers to transduce the entire retinal surface area when administered to NHP. A high percentage of cells was subsequently transduced in all layers of the retina, including photoreceptors and retinal pigment epithelial (“RPE”) cells. Structure-function studies suggest that the potential of R100 to penetrate through barriers such as the inner-limiting membrane barrier was associated with reduced binding to heparan sulfate. R100 subsequently bound and transduced target retinal cells at higher efficiency than the conventional AAV2 capsid. This improved transduction was associated with enhanced binding to sialic acid on the target cells.

The subretinal surgical injection route of administration with conventional AAV vectors resulted in delivery to a limited bleb area of the retina (top panel, dotted line), leaving the vast majority of the retina untreated; according to published data bleb coverage was <1% of the retina with subretinal injection. Within this bleb, viable retinal cells were transduced (top panel, colorized area). The intravitreal route of administration with conventional vector AAV2 resulted in a small area of transduction around the fovea due to interference across the retina by the inner limiting membrane (“ILM”) (center panel, colorized ring). By contrast, intravitreal injection route of administration with our targeted and evolved vector, R100, resulted in transduction across the entire surface area of the retina, including the major cell layers of the retina (bottom panel, colorized area) in NHP.

Intravitreal injection route of administration with our targeted and evolved vector, R100, resulted in transduction across the entire surface area of the retina, including the major cell layers of the retina in NHP.

R100 has been well-tolerated in both NHP and in patients. In our on-going clinical trials, we have administered two product candidates utilizing our R100 vector to patients via intravitreal injection. Treatment has been generally well-tolerated with no dose-limiting toxicities. In addition, we have administered these product candidates in 91 NHP eyes injected in three different GLP toxicology studies with no adverse findings reported.

To date, our two clinical stage ophthalmology product candidates 4D-125 and 4D-110, both of which utilize the R100 vector, have exhibited favorable toxicity and tolerability profiles in GLP toxicology studies as summarized below.

In our second example of targeted delivery in NHPs in vivo, our targeted and evolved vector, C102, was invented for improved delivery to and transduction of cardiac muscle tissues (cardiomyocytes), when administered by IV at low doses, with minimal inflammation. Barriers to IV delivery to heart muscle may include organs such as the liver and blood components including complement, immune cells and antibodies.

Target Vector Profile for C102 intravenous delivery to the heart:

Conventional AAV capsid vectors (top panel) such as AAV8 do not effectively deliver to heart muscle tissue following low dose IV administration. Potential barriers include clearance by organs such as the liver, and blood components including complement, immune cells and antibodies. Conversely, IV administered C102 (bottom panel) has exhibited robust delivery and broad transduction of cardiac tissues, including cardiomyocytes.

In NHPs, we observed that intravenous delivery of C102 at relatively low doses for delivery to muscles (1E13 – 5E13 vg/kg) resulted in genome delivery to 100% of the 30 heart tissue samples evaluated through all regions of the heart in NHP. Transgene protein expression was detected in 29 of the 30 samples, providing evidence of intracellular protein production in cardiomyocytes.

C102 delivery to, and transduction of, NHP cardiomyocytes:

The figure below illustrates the broad distribution of samples collected in our C102 biodistribution study. Samples were collected from 10 locations across the four regions of the heart in 3 NHPs. Intravenous delivery of C102 at relatively low doses (1E13 vg/kg) resulted in genome delivery to 100%, and protein expression in 97%, of the 30 heart tissues evaluated.

Immunohistochemistry for marker transgene protein expression showed widespread gene expression in cardiomyocytes in a preclinical study. In addition, in a preclinical study we observed that C102 was more efficiently delivered to cardiac tissues than conventional vectors such as AAV8 (shown below) and AAV9. C102 targeted the heart muscle tissue more efficiently than AAV8, and showed a 12-fold improvement in genome delivery to the heart muscle tissue. We have not compared C102 to AAV8 or AAV9 in patients in clinical studies.

C102 delivered genetic payloads to cardiac tissue more efficiently than conventional AAV vectors in NHP:

In vector characterization studies in NHP, C102 delivered 12-fold more EGFP marker gene to cardiac tissue on average than did AAV8

Cardiac muscle tissue transduction and protein expression in NHP heart:

NHP cardiomyocyte transduction and marker transgene expression (“EGFP”) was detected by immunofluorescence 8 weeks after intravenous injection of C102 (right panel), whereas conventional vector AAV8 transduced cardiomyocytes to a lesser extent than did C102 (center panel). Non-transduced control NHP heart did not exhibit visible EGFP staining (left panel) (L, left; R, right, V, ventricle; A, atrium)

In our third example of targeted delivery in NHPs in vivo, our targeted and evolved AAV vector for lung tissues, A101, was invented for aerosol delivery to lung airway and alveolar cells. This vector was selected for penetration through the mucus and other potential barriers, and for resistance to pre-existing antibodies in humans. A101 is used as the targeted and evolved vector in 4D-710, our product candidate for patients with cystic fibrosis lung disease.

Target Vector Profile for A101 aerosol delivery to lung airway and alveoli:

Conventional AAV capsid vectors such as AAV2 (top panel) are not able to reach lung tissue effectively following aerosol administration, due to mucus and other potential barriers including antibodies and components of innate immunity. Conversely, aerosol administered A101 (bottom panel) is designed for robust and broad transduction of lung cells, including trachea, bronchi and alveoli.

In NHPs, we observed that aerosol delivery of A101 via a standard nebulization device, approved for use in humans, resulted in genome delivery to, and GFP marker gene expression and transduction of, 100% of the 48 lung sites evaluated. We evaluated proximal and medial airways and alveoli in the lung. In addition to efficient lung tissue transduction, we also observed distribution to organs outside the lung was minimal. Genomes in tissues outside the lung were either undetectable or in extremely low concentrations (less than 0.1% of the average genomes per microgram of DNA in the lung tissues) as shown below. This data confirms the efficient protein production throughout all major regions of the lung with minimal biodistribution to the rest of the body.

The figure below illustrates the broad distribution of samples in NHPs collected in our A101 biodistribution study. Samples were collected from 16 locations in the three regions of the lung in 3 NHPs. Aerosol delivery of A101 at a dose of 1E13 vg resulted in genome delivery to, and protein expression in, 100% of the 48 lung tissues evaluated.

Aerosol delivery of A101 carrying the EGFP transgene in NHPs was associated with EGFP protein detection (red) by immunofluorescence in proximal (trachea) and medial (bronchi) airway and alveoli.

Aerosol delivery of A101 in NHPs resulted in high levels of genome localization as exhibited in the chart below. A101 genome localization was limited in liver and heart, and not present in other tissues outside the lung. EGFP marker protein expression was also detected in all lung samples.

Potential for Improved Transduction and Transgene Expression in Target Human Cell Types and Tissues

We invent targeted and evolved vectors for a specific set of diseases to fit a defined Target Vector Profile, in an effort to generate higher levels of transgene expression than conventional AAV vectors.

In our first example of improved target tissue transduction leading to higher levels of expression and more cells transduced, we observed superior transduction with R100, our intravitreally administered targeted and evolved vector. R100 was significantly more efficient than AAV2 at transducing human retina cells in vitro, such as RPE cells below. These in vitro studies comparing R100 to AAV2 helped to inform our decision to move the vector forward and to develop R100-based product candidates. We have not conducted any clinical studies in patients comparing AAV2 to R100. AAV2 is the conventional vector most commonly used for retina treatment in humans. R100 is leveraged in modular fashion for use in all of our ophthalmology product candidates, including 4D-110, 4D-125, 4D-135 and 4D-150.

R100 exhibited significantly higher transduction of stem cell derived human retinal pigment epithelial cells in vitro compared to conventional AAV2 across a broad range of concentrations. R100 transduced a higher percentage of cells than AAV2, and marker transgene expression was superior to AAV2

PMEL17 = premelanosome protein, a marker of retinal pigmented epithelial cell identity %EGFP+/PMEL17+ Cells = the percentage of EGFP-expressing cells within the PMEL17-expressing retinal pigmented epithelia population, a quantification of the transduction efficiency of the capsid for the target cell type MOI = multiplicity of infection, a description of dose (vg per cell) for in vitro experiments

In our second example of improved transduction versus conventional AAV vectors, our targeted and evolved vector C102 was invented to efficiently target human heart muscle cells (cardiomyocytes); C102 is used in 4D-310 for Fabry disease. Conventional AAV vectors AAV1, AAV8 and AAV9 have been used by competitors to target heart muscle cells; however, we believe limited transduction with these conventional AAV vectors may limit efficacy and lead to high dose requirements that may present safety challenges. In preclinical studies, C102 exhibited significantly improved transduction of human cardiomyocytes (ventricular phenotype) compared to conventional AAV vectors across a wide range of concentrations, as shown below. These in vitro studies comparing C102 to AAV1, AAV8 and AAV9 helped to inform our decision to move the vector forward and to develop C102-based product candidates. We have not conducted any clinical studies in patients comparing conventional vectors to C102.

C102 exhibited significantly higher transduction in vitro relative to conventional AAV1, AAV8 and AAV9, in human cardiomyocytes of ventricular phenotype. C102 transduced a higher percentage of cells than conventional AAV, and marker transgene expression was superior to conventional AAV

cTnT = cardiac troponin T, a marker of cardiomyocyte cell identity

DAPI = a marker of cell nuclei

MOI = multiplicity of infection, a description of dose (vg per cell) for in vitro experiments

%EGFP+/cTnT+ Cells = the percentage of EGFP-expressing cells within the cTnT-expressing cardiomyocyte population, a quantification of the transduction efficiency of the capsid for the target cell type

Potential for Low Toxicity with Reduced Inflammation Profile

We believe that targeted and evolved vectors invented via Therapeutic Vector Evolution have the potential to cause less inflammation, require lower doses and lead to a lower overall toxicity profile versus conventional AAV vectors such as AAV8 and AAV9. As others have reported, high IV doses with AAV9-based gene therapies in humans and NHPs have been associated with toxicity and inflammation in heart, kidney, liver and neural tissues. Others have also reported that high dose IV treatments with a product candidate incorporating AAV8 have, tragically, resulted in three patient deaths in a clinical trial for X-linked myotubular myopathy.

As illustrated below, in contrast to AAV9, our targeted and evolved vector C102 (used in 4D-310 for Fabry disease) was not associated with significant inflammation or toxicities in NHP heart tissues after IV administration. AAV9 was associated with inflammation and damage in heart tissue as shown on histology and blood tests shown below. These in vivo studies comparing C102 to AAV9 helped to inform our decision to move the vector forward and to develop C102-based product candidates. We have not conducted any clinical studies in patients comparing AAV9 to C102.

After dosing of NHPs with IV C102, no meaningful heart inflammation or toxicity was observed, in contrast to meaningful heart inflammation and necrosis observed in NHPs receiving AAV9, as illustrated in the H&E staining below. Immune cell infiltrate (dark purple) and cardiomyocyte death (rounded formation of cardiomyocytes in pink) associated with AAV9 are highlighted in the left image below. Lack of similar infiltrate associated with C102 is highlighted in the right image below (no dark purple, elongated cardiomyocytes in pink with magenta cell nuclei). Quantification of the full histological analysis provided by an independent veterinary pathologist is included below these images. Of note, the two vectors carried the same CAG promoter and EGFP transgene payload, were packaged and purified using the same process, were quantified using the same assay, and administered in identical fashion at the same contract research organization (“CRO”).

After dosing of NHPs with IV C102, no meaningful cardiac troponin release into the blood was observed, in contrast to meaningful elevations in cardiac troponin observed in NHPs receiving AAV9. Of note, the two vectors carried the same CAG promoter and EGFP transgene payload, were packaged and purified using the same process, were quantified using the same assay, and administered in identical fashion at the same CRO.

Overall, our three lead targeted and evolved vectors, R100, C102 and A101, have exhibited favorable tolerability results in NHPs and mice in toxicology studies across our lead product candidate development programs, as summarized below.

Potential to Resist Inhibition by Pre-Existing Neutralizing Antibodies from Humans: Potential for Re-Dosing and Treating Larger Patient Populations

We have invented targeted and evolved vectors for resistance to inhibition by pre-existing neutralizing antibodies in the human population. We believe that vectors invented in this fashion may broaden our potential addressable patient population compared to conventional AAV vectors. We believe that enhanced resistance to antibodies may result in less neutralization, and therefore potentially better efficacy, after patient treatment. Finally, we believe we have the potential to re-dose patients after receiving other AAV gene therapies, and when desirable by developing product candidates with different targeted and evolved vectors that target the same tissues. This approach would utilize a vector whose antibodies do not cross-react with the vector used in the preceding AAV gene therapy treatment.

For example, the Target Vector Profile for our targeted and evolved vector A101 included aerosol delivery and resistance to antibodies in humans; A101 is used in 4D-710 for cystic fibrosis. As shown below, we observed that A101 had significantly greater antibody resistance than conventional AAV1, AAV2, AAV5, AAV8 and AAV9. These in vitro studies comparing A101 to conventional vectors helped to inform our decision to move the vector forward and to develop A101-based product candidates. We have not performed any clinical studies in patients comparing conventional vectors to A101.

A101 exhibited superior resistance to human antibodies (present in human IVIG) in vitro compared to conventional AAV vectors AAV1, AAV2, AAV5, AAV8 and AAV9 as measured by transduction percentage.

Our Proprietary Therapeutic Vector Evolution Platform

Our proprietary Therapeutic Vector Evolution platform is based on the principles of directed evolution. Directed evolution is a high-throughput platform approach that harnesses the power of evolution in order to create biologics with new and desirable characteristics.

The first step of directed evolution involves the generation of massively diverse libraries of biological variants. In the second step, a target profile is designed with desired biological characteristics. In the final step, selective pressures are applied to these libraries forcing competition to select for improved variants with the desired biological characteristics. This method has been successfully utilized by other researchers to generate protein therapeutics with enhanced biological activities, antibodies with enhanced binding affinity and enzymes with new specificities. The importance of this biotechnology was demonstrated when the Nobel Prize for Chemistry was awarded in 2018 for work on directed evolution of proteins, antibodies and enzymes performed by academic investigators including Dr. Frances H. Arnold at Caltech; these investigators have no relationship to 4DMT.

Our co-founder and Chief Scientific Advisor, Dr. David Schaffer, pioneered the use of directed evolution to create improved AAV capsids for use as gene therapy vectors at U.C. Berkeley over 20 years ago. Over the past seven years, we have developed and industrialized our Therapeutic Vector Evolution platform to invent targeted and evolved vectors for use in human therapeutic products. Since in-licensing several libraries from the U.C. Berkeley and creating over 30 newer libraries at our company, we have a total of 40 diverse libraries comprising approximately one billion proprietary synthetic capsid sequences. In addition, we have developed significant experience in performing Therapeutic Vector Evolution programs in NHPs, with 14 capsid selections completed to date. We believe this will help us to develop product candidates to address a broad swath of diseases in rare and large patient populations, including those other gene therapies cannot.

Diverse Libraries of Synthetic Capsid Sequences

Each library results from the application of a different genetic diversification methodology, such as variable loop mutagenesis, random peptide insertion, random point mutagenesis, DNA shuffling and ancestral reconstruction, and is also defined by its starting material (AAV capsid gene sequences). Furthermore, we apply bioinformatics, emerging technologies, and experience and know-how resulting from previous discovery programs to continually improve and expand our libraries and improve our ability to select customized targeted and evolved vectors.

We believe the size and diversity of our proprietary synthetic capsid libraries represent a differentiating competitive advantage for us in the field of gene therapy.

Our 40 distinct libraries comprise approximately one billion synthetic capsid sequences. Each library results from the application of a different genetic diversification methodology, such as variable loop mutagenesis, random peptide insertion, random point mutagenesis, DNA shuffling and ancestral reconstruction, and is also defined by its starting material (AAV capsid gene sequences). We have estimated the number of capsid sequences for 37 of these libraries as illustrated below.

The Target Vector Profile Followed by Competitive Vector Selection

We employ a rigorous approach to inventing targeted and evolved vectors based on what we consider an optimal vector and product profile, which we term the Target Vector Profile. For any set of target diseases that affect the same tissue(s), this profile includes any combination of the following: the optimal route of administration for targeting the specific tissue(s) in humans, the optimal dose range, the desired distribution of vector transduction within the target organs, overall biodistribution and/or antibody resistance.

We use our Therapeutic Vector Evolution platform to select the “fittest” targeted and evolved capsid that best matches our Target Vector Profile. We achieve this through serial rounds of “selection”, or discovery, with each round of selection filtering down to fewer and fewer synthetic capsids from the original library. This funneling process is achieved by applying selective pressures—forcing competition—among all synthetic capsid variants in the library to achieve delivery to the target cells as defined in the Target Vector Profile. Each round is performed in a primate in vivo, sometimes in the presence of human antibodies.

By the end of a typical Therapeutic Vector Evolution process, we will have identified approximately two to four targeted and evolved vectors, or hits, based on their frequency in the final pool of synthetic capsid sequences, in addition to numerous sequences present at lower frequencies. We then file patent applications disclosing select identified gene sequences from the discovery program. We believe this deliberate approach to selection in vivo in NHPs and in human tissues should lead to identification of targeted and evolved vectors with a higher likelihood of therapeutic benefit in humans.

Vector Invention Results to Date

We have completed 14 unique vector selection programs or “selection processes” for specific proprietary synthetic capsids with specific Target Vector Profiles. Across our clinical development and discovery portfolio, we have utilized four different routes of administration, including intravenous, intravitreal, aerosol, and intrathecal administrations. We have completed discovery programs targeting a diverse array of tissue types including various retinal cell types, heart and skeletal muscle tissues, different lung cell types, liver, brain, dorsal root ganglia, and synovial joints. We have identified and filed patent applications on over 300 unique targeted and evolved vectors.

Characterization of Novel Vector Variant “Hits” and “Leads”

Vector hits are typically characterized by three major criteria: manufacturing, human cell and human organotypic model transduction, and delivery to tissues in NHPs by the designated route of administration. Vector hits may also be evaluated for transduction in the presence of human antibodies. In order to perform characterization studies, vectors are armed with marker gene payloads such as enhanced green fluorescent protein (“EGFP”). After these hits have been evaluated, a lead vector is selected.

Directed Evolution-Based Promoter and Transgene Discovery Platforms

To complement our Therapeutic Vector Evolution platform and modular development approach, we are generating next-generation optimized promoter elements and transgenes using a combination of directed evolution and proprietary algorithms.

Currently available promoters may lack sufficient strength of expression and selectivity for clinical benefit of AAV gene therapies. In addition, for some AAV gene therapy products a smaller promoter region may be essential for the gene payload to fit in the AAV. Therefore, we believe there is a need for better promoters for many AAV products to enable or enhance their therapeutic benefit. We generate Target Promoter Profiles for any given product and disease target. This promoter profile includes target

cell specificity and strength in order to maximize tolerability and/or biologic activity, as well as any necessary size constraints. Under one of our sponsored research agreements with U.C. Berkeley, we are working with our co-founder Dr. Schaffer to create customized and proprietary promoters for use in our pipeline products. Our libraries of novel and diverse synthetic promoters have been engineered and currently comprise approximately ten million unique sequences. Our discovery platform identifies the best promoters within the libraries for a specific Target Promoter Profile.

In addition to our synthetic promoters, we are developing next-generation optimized transgene discovery platform. Our discovery platform uses a high-throughput approach, harnessing both directed evolution and rational design algorithms, to identify novel transgenes that express therapeutics proteins. For example, we have developed transgenes to express RNAi in target cells of interest for treatment of disease. These transgene-expressed RNAi molecules, or ddRNAi, are anchored by a microRNA backbone that not only enhances stability and limits off-target effects, but also facilitates high expression within target cells and thereby increases efficacy. Our technology allows us to powerfully knock down disease-causing transcripts, combining a design for a high degree of selectivity with the goal of long-term expression afforded by AAV-based gene therapy.

Product Pipeline

Overview

Our platform enables a broad and diverse pipeline of transformative targeted gene therapies that we are advancing through clinical trials. We currently have a product pipeline that includes targeted gene therapies in three therapeutic areas: ophthalmology, cardiology (primary or secondary to systemic diseases) and pulmonology.

For each of these therapeutic areas, we invented a targeted and evolved lead vector employing Therapeutic Vector Evolution. These lead vectors were designed for delivery by optimal and routine clinical routes to the target tissue(s). As illustrated below, our platform is designed to be modular in that an evolved vector invented for a given therapeutic area can be equipped with different transgene payloads to produce unique product candidates to treat other diseases affecting the same tissue type(s). We believe this modularity will help inform the clinical development of subsequent product candidates using the same vector.

Lead vectors that have been invented through Therapeutic Vector Evolution are used to design and engineer product candidates for specific diseases. These product candidates are tested in NHP and in human cell & disease models prior to IND filing and entry into clinical trials. While a first product candidate utilizing one of our targeted and evolved vectors is advancing through development, we build additional product candidates to follow closely and rapidly by using the same lead vector in modular fashion.

Our pipeline includes product candidates for both rare disease and large patient populations and is represented in the chart below.

‡ Reporting in coordination with our partner Roche.

Ophthalmology Therapeutic Area

Introduction

We are developing product candidates to treat severe ophthalmology diseases. Our targeted and evolved vector, R100, is used in all four of our ophthalmology product candidates and was invented for routine intravitreal injection, leading to transgene expression across the entire surface area of the retina, and in the major cell layers of the retina. We believe this modularity will help inform the clinical development of subsequent product candidates using the same vector.

Our product candidate 4D-125 is enrolling patients in an ongoing Phase 1/2 clinical trial in patients with XLRP related to mutations in the RPGR gene. The primary objectives of this trial are to evaluate the safety and maximum-tolerated dose of 4D-125. Secondary endpoints include assessments of biologic activity, including both visual field function and anatomical endpoints. Enrollment has been completed in the dose escalation phase of this study, with six patients treated. The dose expansion phase of this study will enroll patients at the highest Phase 1 dose of 1E12 vg/eye. 4D-125 has been well tolerated without any dose-limiting toxicities. We expect to report initial clinical data in the second half of 2021. 4DMT currently holds the worldwide commercialization rights for 4D-125 and Roche holds an exclusive option to in-license the product prior to pivotal trial initiation.

Our product candidate, 4D-110, is enrolling patients in an ongoing Phase 1 clinical trial in patients with choroideremia related to mutations in the CHM gene. The primary objectives of this trial are to evaluate the safety and maximum-tolerated dose of 4D-110. Secondary endpoints include assessments of biologic activity, including visual acuity, visual field function and anatomical endpoints. Enrolled patients have been followed previously inour natural history study, in which we have enrolled 55 patients, and have followed 47 of these patients for at least two years. Enrollment has been completed in the dose escalation phase of this study, with six patients treated. The dose expansion phase of this study will enroll patients at the highest Phase 1 dose of 1E12 vg/eye. 4D-110 has been well tolerated without any dose-limiting toxicities. In coordination with our partner Roche, we expect to report initial clinical data in 2022.

We also have two wholly owned preclinical product candidates. We are developing 4D-150 for the treatment of wet AMD and diabetic retinopathy, including DME, and we expect to initiate a wet AMD clinical trial for 4D-150 in the second half of 2021. We are also developing 4D-135 for the treatment of adRP. We expect to initiate IND enabling studies for 4D-135 in 2021.

4D-125 for X-Linked Retinitis Pigmentosa (“XLRP”)

Disease Background, Unmet Medical Need and Target Patient Population XLRP is a rare inherited X-linked recessive genetic disorder that causes progressive vision loss and blindness in boys and young men. There are currently no approved therapies for XLRP. Seventy percent of cases are caused by mutations in the retinitis pigmentosa GTPase regulator (“RPGR”) gene. The estimated worldwide prevalence of XLRP due to RPGR variants is approximately one in 25,600 people, which represents approximately 24,000 patients in the United States, and France, Germany, Italy, Spain and the United Kingdom (together, EU-5). It is characterized by dysfunction and degeneration of photoreceptors in the retina. Loss of RPGR function in retinal cells causes the progressive loss of rod and cone photoreceptors, leading to the progressive loss of vision. Symptoms of XLRP are initially characterized by night blindness, followed by loss of peripheral visual field, decreasing visual acuity and eventually blindness. While males are usually the most affected, approximately 25% of heterozygous females experience loss of vision.

Our Solution

We are developing 4D-125 for the treatment of patients with XLRP with RPGR mutations. 4D-125 is designed to benefit patients at all stages of XLRP, including early stage patients whose entire viable retinas are not adequately treated by subretinal surgery. This product candidate is comprised of R100 and carries a codon-optimized RPGR transgene engineered for expression within human photoreceptors. In NHP models, we have observed widespread transduction and transgene expression across the entire retinal surface. We believe that 4D-125 has the potential to successfully treat XLRP patients at the earliest stages of their disease progression and ideally, slow or prevent progression and retain vision.

Competition and Differentiation: AAV Gene Therapy for XLRP

Several companies are developing subretinal AAV gene therapies for patients with XLRP. Subretinal administration results in transduction and direct treatment of only a small fraction of the retina. On Phase 1 and 2 trials, investigators have reported improvements in visual field function within the localized retina area receiving the treatment bleb in a subset of patients. These AAV gene therapies require invasive subretinal surgery, which has been associated with subretinal surgery-related adverse events. In addition, subretinal surgery results in transduction of only a small fraction of the retina and is therefore limited to patients with more advanced disease with a small remaining area of viable retinal cells.

We believe 4D-125 has the potential to be differentiated from other AAV gene therapies in clinical development, to our knowledge, on the basis of four design features:

Preclinical Animal Model Pharmacology and Toxicology Studies

We completed a single dose IND-enabling toxicology and biodistribution study in 30 NHPs with 4D-125. 4D-125 was administered at doses of 1E11 vg/eye or 1E12 vg/eye by intravitreal injection. Animals were sacrificed at three weeks, three months or six months. No meaningful toxicities were reported anywhere in the body, including specifically within the retina. Mild, transient uveitis was observed, but no chronic inflammation was reported; all animals were under systemic immunosuppression during the study. We detected vector genomes and XLRP transgene RNA expression in all treated retinas at both dose levels; the genome and RNA levels were higher in the high dose animals.

In an in vitro model of the disease, XLRP patient photoreceptors were derived from XLRP-diseased white blood cells that had been reprogrammed into induced pluripotent stem cells. Diseased photoreceptors were transduced with 4D-125 and protein lysates were harvested 30 days post-transduction. 4D-125 transduced cells expressed significantly more transgene product (hRPGRorf15) than control cells. Moreover, this expressed protein was shown to be active as measured by glutamylation (GT335).

Clinical Development: Phase 1/2 Clinical Trial

We are currently enrolling patients on a Phase 1/2 clinical trial. This is a dose-escalation and dose-expansion trial of intravitreal injection with 4D-125 in patients with clinically significant XLRP due to RPGR gene mutation. The primary objectives of this trial are to evaluate the safety and maximum tolerated dose of 4D-125. Secondary endpoints include assessments of biologic activity, including both visual field function and anatomical endpoints. Enrollment has been completed in the dose escalation phase of this study, with six patients treated. The dose expansion phase of this study will enroll patients at the highest Phase 1 dose of 1E12 vg/eye. 4D-125 has been well-tolerated and has not resulted in dose-limiting toxicities. No serious adverse events related to the agent have been reported. We expect to report initial clinical data from this trial in the second half of 2021.

4D-110 for Choroideremia

Disease Background, Unmet Medical Need and Target Patient Population

Choroideremia is a monogenic blinding disease, affecting approximately 13,000 patients in the United States and EU-5. No products are approved currently for the treatment of this disease in the United States or European Union. This X-linked, progressive degenerative disease of the retina and choroid is caused exclusively by mutations in the CHM gene that encodes for the REP1 protein. While

choroideremia primarily affects men, some heterozygous females also suffer variable visual loss from the condition.

Choroideremia initially manifests as night-blindness and peripheral visual field defects, usually starting in the first two decades of life. As the disease progresses, the visual field begins to constrict relatively early in the disease’s progression, which hinders patients’ ability to conduct daily activities, such as driving. Many patients become blind by 30 years of age. A patient with advanced disease will be legally blind by virtue of poor visual acuity and minimal preserved visual field. Almost all mutations in the CHM gene result in production of a non-functional REP1 protein. REP1 is essential for the activation (prenylation) of Ras-associated binding (“Rab”) proteins involved in intracellular vesicle trafficking.

Our Solution

We are developing 4D-110 for the treatment of choroideremia. 4D-110 is designed for a single intravitreal injection and to benefit patients at all stages of disease, including early stage patients whose entire viable retinas are not adequately treated by subretinal injection. 4D-110 is comprised of R100 and is engineered to deliver the CHM transgene, the dysfunctional gene in choroideremia, to human RPE cells safely. We believe that 4D-110 has the potential, if approved, to successfully treat choroideremia patients at the earliest stages of their disease progression and ideally, slow or prevent progression and retain vision.

Competition and Differentiation: AAV Gene Therapy for Choroideremia

Conventional subretinal AAV gene therapy approaches are being developed to treat choroideremia. Subretinal administration results in transduction and direct treatment of only a small fraction of the retina. Biogen is developing a subretinally administered product candidate for choroideremia called NSR-REP1. In 2018, data was reported from a Phase 1/2 clinical trial in patients with end-stage choroideremia, who have only a small remaining area of viable retinal cells in the central field of vision and reduced visual acuity. In this trial, investigators concluded that best corrected visual acuity improved in a subset of patients. A pivotal randomized Phase 3 clinical trial was initiated in 2018. This AAV gene therapy approach requires invasive subretinal surgery, which has been associated with subretinal surgery-related adverse events. In addition, subretinal surgery results in transduction of only a small fraction of the retina and is therefore limited to patients with more advanced disease who have a small remaining area of viable retinal cells.

We believe 4D-110 has the potential to be differentiated from AAV gene therapies in development on the basis of four design features:

Preclinical Animal Model Pharmacology and Toxicology Studies

A total of 44 NHPs have been treated with 4D-110 on two GLP toxicology and biodistribution studies. No significant adverse effects or toxicities were reported.

We completed a single dose IND-enabling toxicology and biodistribution study in 27 NHPs dosed with 4D-110. 4D-110 was administered at doses of 1E11 vg/eye or 1E12 vg/eye by intravitreal injection. Animals were sacrificed at three weeks, three months or six months. No meaningful toxicities were reported anywhere in the body, including specifically within the retina. Mild, transient cortico-steroid responsive anterior uveitis was reported in a minority of treated NHP. No chronic inflammation was reported; all animals were under systemic immunosuppression during the study. We detected vector genomes and CHM/REP1 transgene RNA expression in all treated retinas at both dose levels; the genome and RNA levels were higher in the high dose animals.

We subsequently completed a bilateral intravitreal 4D-110 GLP toxicology and biodistribution study in 17 NHPs dosed with 4D-110. 4D-110 was administered at doses of 3E11 vg/eye or 1E12 vg/eye by intravitreal injection. Animals were sacrificed at three weeks, 13 weeks and 26 weeks. No meaningful toxicities were reported anywhere in the body, including specifically within the retina.

Transient cortico-steroid responsive uveitis was reported. No chronic inflammation was reported; all animals were under systemic immunosuppression during the study. We detected vector genomes and CHM/REP1 transgene RNA expression in treated retinas at both dose levels.

In preclinical pharmacology studies involving human choroideremia patient-derived RPE cells, 4D-110 led to functional REP1 protein expression that corrected RAB27A trafficking from the cytoplasm to the cell membrane. In similar fashion to normal RPE cells, 4D-110-treated diseased RPE cells derived from choroideremia patients had RAB27A protein associated with their cell membranes; this finding confirmed the functionality of the REP1 protein expressed from 4D-110. In contrast, in untreated diseased cells, RAB27A was demonstrated diffusely throughout the cytoplasm.

Clinical Development: Phase 1 Clinical Trial and Natural History Study

We have fully enrolled a natural history study of over 50 patients with choroideremia to document rate of visual and anatomical decline, and to identify candidates who are most likely to benefit from participation in our current Phase 1/2 clinical trial. Fifty-five patients were enrolled and 47 of these patients have been followed for at least two years. Statistically significant declines in fundus autofluorescence area were reported by investigators over the two-year span after enrollment, with progression evident within 12 months. We expect that many of these subjects will enroll in our current Phase 1 clinical trial, or in future trials we may conduct.

We are currently enrolling patients on a Phase 1 clinical trial. This is a dose-escalation and dose-expansion trial of intravitreal injection with 4D-110 in patients with choroideremia due to CHM gene mutation. The primary objectives of this trial are to evaluate the safety and maximum-tolerated dose of 4D-110. Secondary endpoints include assessments of biologic activity, including visual acuity, visual field function and anatomical endpoints. Endpoint changes in each individual treated patient over time, before treatment while on the Natural History Study, will be compared to endpoint changes after 4D-110 treatment in the same patient whenever possible. Patients may therefore serve as their own control for assessments of these endpoints. Enrollment has been completed in the dose escalation phase of this study, with six patients treated. The dose expansion phase of this study will enroll patients at the highest Phase 1 dose of 1E12 vg/eye. 4D-110 has been well-tolerated and has not resulted in dose-limiting toxicities. In coordination with our partner Roche, we expect to report initial clinical data from this trial in 2022. We licensed exclusive worldwide rights to 4D-110 to Roche.

We licensed exclusive worldwide rights of 4D-110 to Roche in 2017. We are primarily responsible for initial development, including preclinical development, manufacturing, filing and maintaining the IND and conducting the Phase 1 clinical trial. Upon completion of initial development, Roche will be

responsible for development including conducting any pivotal clinical trials and commercialization, if approved. We are entitled to development costs reimbursement, development milestones and royalties and sales milestones on this product candidate.

4D-150 for Wet AMD and Diabetic Retinopathy

Disease Background, Unmet Medical Need and Target Patient Population

Wet AMD is a type of macular degeneration where abnormal blood vessels (choroidal neovascularization or CNV) grow into the macula, the central area of the retina. As a consequence, CNV causes retina swelling and edema, and bleeding can occur and cause visual distortion and reduced acuity. The proliferation of abnormal blood vessels in the retina is stimulated by VEGF. This process distorts and can potentially destroy central vision and may progress to blindness without treatment. There are on average 200,000 new incidences of wet AMD per year in the United States alone. Wet AMD accounts for approximately 10% of all diagnosed cases of AMD, but it results in an estimated 90% of the legal blindness caused by all types of AMD. High expression levels of VEGF appear to play a causal role in the symptoms of wet AMD.

Diabetes mellitus affects approximately 400 million adults worldwide and the prevalence is expected to increase by approximately 45% in the next decade. Diabetic eye disease, primarily diabetic retinopathy (“DR”), is a leading cause of vision loss and blindness in working-age adults and occurs due to the development of diabetic macular edema (“DME”; swelling, edema and hemorrhage in the central vision) and complications arising from proliferative diabetic retinopathy (PDR; retinal neovascularization causing bleeding and retinal detachment). The prevalence of diabetic retinopathy is high, affecting almost one-third of adults over 40 years of age with diabetes. In the United States approximately 4.2 million adults have DR and 655,000 have vision-threatening DR.

The current treatment paradigm for wet AMD and diabetic retinopathy, including DME, is intravitreal injection of patients with anti-VEGF proteins that inhibit the proliferation of new blood vessels, reducing edema and bleeding and allowing some visual acuity to be recovered. Most anti-VEGF therapies require repeated intravitreal injections in office every few weeks to every few months to obtain full efficacy. When patients miss doses, they may experience accelerated vision decline. Based on current clinical experience, after several years of treatment, the early vision gains are frequently lost, and acuity declines are observed for reasons that may include variable treatment regimens and poor patient compliance.

We believe these major retinal diseases are ideal candidate applications for gene therapy. There are multiple products on the market that validate the anti-VEGF therapeutic approach, and emerging randomized clinical trial data suggests that inhibiting additional molecular targets can extend the efficacy and durability of anti-VEGF alone. Delivering intravitreal therapies to the eye is routine, and there is an advantage for a single dose gene therapy that can provide long-term efficacy in patients for whom compliance, or treatment resistance, is a problem.

Our Solution

We are developing 4D-150, a wholly owned intravitreal AAV gene therapy candidate for wet AMD and diabetic retinopathy, including DME. These angiogenic diseases of the retina, including wet AMD and diabetic retinopathy, represent therapeutic markets of over $9.7 billion in annual global sales. We retain all worldwide rights to 4D-150.

This product candidate is engineered for three distinct mechanisms-of-action. 4D-150 is engineered to inhibit VEGF and PlGF (placental growth factor) via aflibercept expression and secretion, and to inhibit a third angiogenic factor via an additional transgene insert. We believe that targeting three different angiogenic factors has the potential for greater efficacy versus a single anti-VEGF mechanism-of-action in patients with these retinal diseases, including patients with resistance to anti-VEGF therapy alone. Intravitreal delivery of biologics to the eye is routine, and there would be an advantage for a single

dose therapy that could provide long-term efficacy in patients for whom compliance, or treatment resistance, is a problem.

Competition and Differentiation: AAV Gene Therapy for wet AMD and Diabetic Retinopathy

AAV gene therapy approaches are being developed by several companies to treat wet AMD by delivering a functional copy of an anti-angiogenic transgene by either subretinal injection with a conventional AAV vector, or intravitreal administration with a mouse-evolved vector. It remains to be demonstrated whether conventional AAVs or mouse-evolved vectors can deliver significant retinal coverage while limiting off-target effects. In comparison, our targeted and evolved vectors are designed and tested in NHPs which more closely resembles the anatomy of the human eye. We believe this provides comprehensive retinal coverage through less invasive and more commonly used intravitreal injections while delivering an improved tolerability profile with limited inflammation. To our knowledge, 4D-150 would be the only AAV gene therapy asset in wet AMD and DR to utilize an intravitreal vector (R100) discovered through directed evolution in NHP. In addition, in vitro studies of R100 versus AAV2 have shown superior transduction by R100 on human retinal cells. We have not compared R100 to AAV2 in patients in clinical studies. R100 has been associated with a low inflammation profile and lack of adverse findings in 91 NHP eyes injected on GLP toxicology studies.

In addition, to our knowledge, 4D-150 is the first gene therapy product candidate for the eye designed to implement three mechanisms of action by directly inhibiting three different angiogenic growth factor targets, including VEGF and PlGF. We therefore believe there is significant differentiation between our gene therapy product candidate and other AAV gene therapeutics in development in this therapeutic area.

We believe 4D-150 has the potential to be differentiated from approved agents, and those in clinical development to our knowledge, on the basis of five design features:

Preclinical Animal Model Pharmacology and Toxicology Studies

We carried out a proof-of-concept efficacy study in NHPs with a research construct using the R100 vector to deliver an anti-VEGF transgene (R100.anti-VEGF). In this study using the retinal laser-induced CNV model, we treated animals with intravitreal R100.anti-VEGF at doses of both 1E11 and 1E12 vg per eye. Animals received steroid treatment for 28 days following IVT administration of R100.anti-VEGF and

remained off steroids for the remainder of the study. No adverse findings were reported in-life through 12 months of follow up. We demonstrated sustained transgene expression through detection of anti-VEGF activity in serial aqueous humor samples. Control animals had the most severe (grade 4) angiogenic and leaky retina lesions in approximately 26% (19 of 72) of laser-targeted sites at two weeks and four weeks. Conversely, none of the sites in treated animals at either dose level at either timepoint had grade 4 lesions (p<0.0001).

Our 4D-150 prototype comprising R100 expressing an anti-VEGF protein prevented development of Grade IV lesions at 2 and 4 weeks after administration in 100% of lasered locations in the NHP retina (at both low and high doses) with evidence of sustained transgene expression through detection of anti-VEGF activity in serial aqueous humor samples.

† In the 1E12 vg treatment group, three NHP eyes (18 lesions) and two NHP eyes (12 lesions) were not assessable at the 2 week and 4 week timepoints, respectively.

A study of 4D-150 is ongoing in the retinal laser-induced CNV model in NHPs to assess efficacy, toxicology and biodistribution.

Development Plan

We expect to initiate a clinical trial in the second half of 2021.

4D-135 for Autosomal Dominant Retinitis Pigmentosa (“adRP”)

Disease Background, Unmet Medical Need and Target Patient Population

adRP is a rare inherited autosomal dominant genetic disorder that occurs in both sexes and causes progressive vision loss and blindness. There are currently no approved therapies for adRP. adRP is characterized by dysfunction and degeneration of photoreceptors in the retina. Approximately 35% of adRP cases are caused by mutations in the rhodopsin (“RHO”) gene. The estimated worldwide prevalence of adRP due to RHO variants is approximately one in 52,000 people, which represents approximately 11,600 patients in the United States and EU-5. Loss of RHO function in retinal cells causes the progressive loss of rod photoreceptors, leading to the loss of vision experienced by patients. Symptoms of adRP are initially characterized by night blindness, followed by loss of peripheral visual field, decreasing visual acuity and eventually blindness.

Our Solution

We are developing 4D-135, a wholly owned intravitreal AAV gene therapy product candidate for the treatment of patients with adRP caused by mutations of the RHO gene. 4D-135 is designed to benefit patients at all stages of adRP, including early stage patients whose entire viable retina are not adequately treated by subretinal surgery. This product candidate is comprised of R100, an intravitreally administered targeted and evolved vector. 4D-135 is engineered to carry an RNAi targeting mutation-independent

adRP and aRHO transgene resistant to the RNAi in a broad suppress and replace approach. We retain all worldwide rights to 4D-135.

Competition and Differentiation: AAV Gene Therapy for adRP

A few companies are developing therapies for patients with adRP, including a subretinal AAV gene therapy product candidate. We believe 4D-135 has the potential to be differentiated from other AAV gene therapies in development to our knowledge, on the basis of five design features:

Preclinical Animal Model Pharmacology and Toxicology Studies

We plan to complete a single dose IND-enabling toxicology and biodistribution study in NHP. We are also developing an in vitro model of diseased photoreceptors derived from adRP patients. These diseased photoreceptors will be treated with 4D-135.

Development Plan

We expect to initiate IND-enabling studies for 4D-135 in 2021.

Cardiology Therapeutic Area

Introduction

We are developing product candidates to treat cardiomyopathies. These target indications may include both primary cardiomyopathies that involve the heart exclusively, as with hypertrophic cardiomyopathies, or secondary cardiomyopathies that occur in the context of a systemic disease syndrome, as with lysosomal storage diseases. In the context of secondary cardiomyopathies, such as Fabry disease, we design and engineer the product to treat all diseased organs including the high unmet medical need in the heart. Our targeted and evolved vector C102, used in all of our cardiology product candidates, was invented for low dose intravenous infusion, leading to transgene expression throughout the myocardium in all regions of the heart. We believe that this modular product approach, utilizing C102 for all of our cardiology product candidates, and by switching the therapeutic transgene inserts, will help inform the clinical development of subsequent product candidates using the same vector.

Our lead product candidate, 4D-310, is currently in an ongoing Phase 1/2 clinical trial in adult patients with Fabry disease. The primary objectives of this trial are to evaluate the safety and maximum-tolerated dose of 4D-310. Secondary endpoints include biomarker assessments of plasma AGA activity and markers of biologic activity in the heart, including cardiac MRI. We expect to treat early onset classic Fabry disease patientsas well as severely affected late-onset patients, including those with cardiomyopathy. We expect to report initial clinical data in the second half of 2021. 4D-310 received Fast Track Designation from the FDA in the third quarter of 2020 for the treatment of Fabry disease to improve pain, disability and organ dysfunction.

4D-310 for Fabry Disease

Disease Background, Unmet Medical Need and Target Patient Population

Fabry disease is a monogenic disease caused by mutations in the GLA gene which encodes for the alpha-galactosidase A (“AGA”) enzyme that results in the body’s inability to produce sufficient AGA enzyme activity, causing the accumulation of toxic levels of sphingolipids, such as the substrate globotriaosylceramide-3 (“Gb3”), in critical organs, including the heart, kidney and blood vessels. The cardiomyopathy in Fabry disease is the leading cause of death, accounting for 54% of deaths, and is secondary to the systemic lysosomal storage disease syndrome. Such substrate accumulation in the heart can lead to life-threatening heart failure, arrhythmias, vascular blockages. Fabry disease is progressive and fatal, with an average life expectancy of approximately 50 years. Progression of the disease causes significant reduction in the quality of life and significant economic burden associated with greater patient needs for supportive care.

Annual worldwide sales of Fabry medicines were approximately $1.5 billion in 2019. We estimate the potential initial addressable male Fabry patient population in the United States and EU-5 to be up to 19,000 individuals, 57% of which suffer from Classic Fabry disease. Of note, we estimate the prevalence of individuals with Fabry disease-associated GLA mutations in the United States and EU-5 falls between 50,000 and 70,000 in the United States and the EU-5 based on recent newborn screening. Pre-treatment antibody titers to gene therapy, including 4D-310, may result in a reduction in the addressable patient population, if antibody titers at baseline are shown to be predictive of treatment response and/or tolerability.

The current treatment paradigm for Fabry disease is an infusion of replacement AGA enzyme every two weeks, a class of therapies broadly referred to as enzyme replacement therapies (“ERT”). For example, Fabrazyme received accelerated regulatory approval in the United States based on improvements in kidney interstitial capillary substrate biopsy endpoint, but it failed the primary endpoint in registrational trials and lacks full approval in the United States.

In addition to high burdens of therapy, due to the short-half life in the blood, patients on ERTs lack therapeutic concentrations of AGA in their blood for the majority of time between infusions, potentially limiting clinical benefit. Furthermore, since AGA is normally produced within target cells themselves, ERTs reportedly lack efficient uptake by parenchymal cells including cardiomyocytes; hence, patients remain at risk of cardiac complications including death. Finally, antibodies develop to AGA in the majority of classic Fabry disease patients after ERT and can further worsen clinical outcomes.

Therefore, we believe cardiac-targeted treatment of Fabry disease is still an unmet medical need.

Our Solution

We are developing 4D-310 for the comprehensive systemic treatment of Fabry disease. 4D-310 is designed for an efficient, single low dose IV administration to benefit classic and late onset patients, including those who have previously received ERT. 4D-310 is comprised of C102 and is engineered with a codon-optimized GLA transgene under control of a ubiquitous promoter. 4D-310 is designed to generate both high, stable plasma AGA activity, potentially resulting in cross correction of a broad range of critical organs, and to generate AGA activity via intracellular production within disease cells including cardiomyocytes.

We believe 4D-310 has the potential for “mutation independent” treatment of both “classic” (early onset, severe) as well as late onset Fabry disease, both of which are often associated with cardiomyopathy. We believe reducing substrate in cardiomyocytes would represent a strategic advantage and significant opportunity in the treatment of Fabry-associated cardiomyopathy, which we believe remains a significant unmet medical need and leading cause of death in Fabry disease patients.

In addition, AGA produced by 4D-310 within target cells themselves will not be exposed to serum antibodies against AGA. These antibodies develop following ERT in approximately 80% of classic Fabry disease patients. We therefore have the potential to treat this patient population via intracellular production of AGA, in contrast to approaches that rely exclusively on delivery of AGA through the bloodstream.

Finally, single dose gene therapy treatment with 4D-310 may obviate the need for biweekly ERT infusions in these patients, and/or for every other day small molecule medicines for patients amenable to AGA chaperone therapy.

Competition and Differentiation: AAV and Lentivirus-Engineered Stem Cell Gene Therapy for Fabry Disease

Several companies are developing liver-expressing AAV gene therapy for Fabry disease through the use of non-targeted AAV designed for expression from the liver only using liver-specific promoters to restrict transgene expression to the liver. These product candidates are designed to produce and secrete AGA enzyme for activity in the blood, as with ERT, but with more stable blood levels than achieved with intermittent ERT infusions. When administered as ERT in patients, the AGA protein has not been shown definitively to enter cardiomyocytes or other affected parenchymal cells. It is therefore unclear whether gene therapy production of AGA from the liver or stem cells alone, with secretion into the bloodstream, would result in effective correction in cardiac muscle cells or other affected parenchymal cells such as in the kidney.

We believe 4D-310 is the only gene therapy candidate designed specifically to express the AGA enzyme in cardiac tissues, as well as in other affected tissues in these patients, potentially addressing a major unmet medical need.

We believe 4D-310 has the potential to be differentiated from approved agents, and those in clinical development to our knowledge, on the basis of four design features:

The target product profile for 4D-310 is compared to competing technologies below. Many aspects of this profile have been supported by data generated to date with either the C102 vector or with 4D-310 itself.

Preclinical Animal Model Pharmacology and Toxicology Studies

We completed an IND-enabling GLP toxicology and biodistribution study of 4D-310 in normal mice. No meaningful toxicity was reported at doses up to 1.5E14 vg/kg, based both on in-life and histopathology assessments. This dose is 300% of the highest planned dose in our Phase 1/2 clinical trial. 4D-310-mediated AGA expression and/or AGA enzyme activity was observed in all target tissues tested, including heart, kidney, blood vessels, small intestine and blood.

Pharmacology studies have been completed in Fabry disease knock-out mice. We observed that a single IV treatment with 4D-310 resulted in high stable blood concentrations and durable AGA production in target tissues, including the heart and kidney, and that toxic Gb3 metabolites were reduced significantly in all evaluated target tissues versus vehicle control. Efficacy was demonstrated with doses as low as 1E12 vg/kg. No adverse findings were observed in these knock-out animals at doses as high as 5E13 vg/kg.

Plasma AGA activity in Fabry mice after treatment with 4D-310 was measured to be approximately 1,200-fold higher than in control vehicle-treated Fabry mice at all measured timepoints after treatment with 4D-310 at 5E13 vg/kg.

WT = wild type

KO = Fabry knock out mouse model

Dose-dependent decrease in plasma lyso-Gb3 was measured at Week 8 in Fabry mice after treatment with 4D-310. 1E13 and 5E13 dose levels achieved reduction of plasma lyso-Gb3 by greater than 95%.

WT = wild type

KO = Fabry knock out mouse model

Dose-dependent decrease in tissue Gb3 was measured at Week 8 in Fabry mice after treatment with 4D-310). Tissue Gb3 levels in Fabry mice approached that of normal mice in both heart and liver at 1E13 vg/kg and 5E13 vg/kg dose levels. Kidney Gb3 levels were reduced by approximately 75% in the 1E13 vg/kg group and levels approached normal in the 5E13 vg/kg dose group.

In studies with 4D-310 in vitro in human Fabry patient-derived cardiomyocytes, we observed dose-related AGA expression and function. Data in Fabry patient-derived cardiomyocytes demonstrated that treatment with 4D-310 results in efficient transduction and functional AGA protein production; AGA activity was observed both within Fabry cardiomyocytes and secreted into the media.

Cardiomyocytes that were differentiated from Fabry patient-derived fibroblasts expressed functional secreted AGA enzyme after treatment with 4D-310.

MOI = multiplicity of infection

n.s. = not significant

NT = not treated

We performed a dose-ranging toxicity and biodistribution study in NHPs. Doses of 3E12, 1E13 and 5E13 vg/kg were well-tolerated and resulted in AGA activity concentrations in blood equal to 1.9-fold, 3.4-fold and 70-fold higher than pretreatment blood levels, respectively, within 14 days after treatment. NHPs used in this study were healthy and had normal baseline levels of AGA activity. No meaningful toxicity was noted clinically or with blood testing. Histopathology assessments were normal. Tissue analyses demonstrated dose-related 4D-310 genome delivery, RNA expression and AGA activity throughout the heart, especially within the left ventricle which is the key target tissue; AGA expression and enzymatic activity were also demonstrated within the kidney.

Delivery (genomes) and transduction (mRNA) were consistently measured throughout organs important to the management of Fabry disease in all NHPs treated with 4D-310. The number of positive tissue samples within NHPs across all three dose levels are indicated below.

Median plasma AGA activity in NHPs after treatment with 4D-310 was measured to be approximately 70-fold, 3.4-fold and 1.9-fold higher than baseline at 8 weeks after treatment with 4D-310 at 5E13, 1E13 and 3E12 vg/kg doses, respectively. Average plasma AGA activity levels for these time points are presented below.

Tissue AGA activity was measured in key organs in healthy NHPs, with normal baseline AGA activity levels, after treatment with 4D-310 at low, medium and high doses. Below are data for tissues which are most important to the management of Fabry disease.

IV delivery of 4D-310 in NHPs was associated with AGA enzyme detection (brown) by immunohistochemistry in the heart, kidneys and liver at low and high dose. Illustrative images below highlight transduction of cardiomyocytes at 5E13 vg/kg dose.

Clinical Development: Phase 1/2 Clinical Trial

We are currently enrolling patients on a Phase 1/2 clinical trial. The first patient dosed in the first quarter of 2021. This is a dose-escalation and dose-expansion trial expected to enroll early onset classic Fabry disease patients and severely affected late-onset patients with cardiomyopathy. The primary objectives of this trial are to evaluate the safety and maximum-tolerated dose of 4D-310. Secondary objectives include biomarker assessments of plasma AGA activity and markers of biologic activity in the heart, including cardiac MRI. We expect to report initial clinical data from this trial in the second half of 2021.

Pulmonology Therapeutic Area

Introduction

We are developing product candidates to treat lung diseases. Our targeted and evolved vector, A101, is used in all of our pulmonology disease product candidates and was invented for aerosol delivery, leading to transgene expression throughout all regions of the lung airways and alveoli, as well as resistance to pre-existing antibodies in the human population. We believe that this modular product approach, utilizing A101 for multiple product candidates by switching the therapeutic transgene insert, will help inform the clinical development of subsequent product candidates using the same vector.

Our first pulmonology product candidate is 4D-710 for cystic fibrosis lung disease. This IND candidate has completed a non-GLP dose-ranging toxicology and biodistribution testing study in NHPs by aerosol delivery. No notable adverse effects were reported, and widespread biodistribution and transgene expression were observed throughout all lung segments tested in all NHPs. We have initiated an IND-enabling GLP toxicology and biodistribution study in NHPs. We expect to initiate a Phase 1/2 clinical trial for 4D-710 in the second half of 2021.

4D-710 for Cystic Fibrosis Lung Disease

Disease Background, Unmet Medical Need and Target Patient Population

Cystic fibrosis is the most common fatal inherited disease in the United States and results from mutations in the cystic fibrosis transmembrane conductance regulator (“CFTR”) gene. Cystic fibrosis causes impaired lung function, inflammation and bronchiectasis and is commonly associated with repeat and persistent lung infections due to the inability to clear thickened mucus from the lung, often resulting in frequent exacerbations and hospitalizations and eventual end-stage respiratory failure. There is no cure for cystic fibrosis, and the median age of death for patients is approximately 40 years in developed

countries. Cystic fibrosis is considered a rare, or orphan, disease by both the FDA and the EMA. According to the Cystic Fibrosis Foundation, more than 30,000 people in the United States and more than 70,000 people worldwide are living with cystic fibrosis, and approximately 1,000 new cases of cystic fibrosis are diagnosed in the United States each year. Patients with cystic fibrosis require lifelong treatment with multiple daily medications, frequent hospitalizations and, ultimately, lung transplants in some end-stage patients. The quality of life for cystic fibrosis patients is compromised as a result of spending significant time on self-care every day and frequent outpatient doctor visits and hospitalizations.

Until recently, approved therapies to treat cystic fibrosis patients were only designed to treat the symptoms of cystic fibrosis, for example by preventing and controlling infections that occur in the lungs, rather than addressing the underlying cause of the disease. Accordingly, antibiotics are frequently used along with mucus-thinning drugs.

More recently, a new class of drugs called correctors and modulators target CFTR for patients with certain gene mutations. Several therapies from Vertex Pharmaceuticals Inc. have been approved for marketing in the United States and the European Union based on their ability to improve lung function in genetically defined subsets of cystic fibrosis patients. In 2019, the FDA approved triple drug therapy with Trikafta (elexacaftor/ivacaftor/tezacaftor), which Vertex believes would be applicable for up to 90% of cystic fibrosis patients, leaving at least 10% with no CFTR-targeted options. While these therapies improve lung function, they fall short of restoring it to the normal range in most patients, and these chronic therapies require daily dosing for the patient’s lifetime. In addition, the existing cystic fibrosis drugs have been associated with tolerability issues, thus limiting their use.

We believe there is a clinical need and market opportunity for a durable aerosolized therapy, delivered by breath-actuated nebulizer, that can restore normal CFTR function across all cystic fibrosis patient subgroups, including patients who are receiving combination CFTR-modulator therapies and/or do not have appreciable CFTR protein expression and are therefore not amenable to CFTR modulators. We expect to explore single agent therapy with 4D-710 initially in patients who are not amenable to CFTR modulators (estimated to include approximately 10% of all cystic fibrosis patients), and to explore single agent or combination therapy with CFTR modulators for the remaining approximately 90% of cystic fibrosis patients.

Our Solution

We are developing 4D-710 for the treatment of a broad range of cystic fibrosis patients independent of their specific CFTR mutation. 4D-710 is designed for efficient single dose aerosol delivery to the proximal and medial airways and alveoli, subsequent mucus barrier penetration, lung epithelial cell transduction, and resistance to pre-existing antibodies in humans. The intended result is to achieve CFTR expression within lung airway epithelial cells for correction of cystic fibrosis lung disease. 4D-710 is comprised of our targeted and evolved vector, A101, and a codon-optimized version of a synthetic truncated CFTR transgene deltaR-CFTR, which we refer to as microCFTR. microCFTR is a construct that retains the most critical functional components of the full-size CFTR gene and is small enough to fit within AAV vector packaging constraints.

We believe 4D-710 has the potential to treat a broad range of cystic fibrosis patients independent of their specific CFTR mutation. Initially we plan to focus on the approximately 10% of all patients who are not amenable to existing medicines targeting the CFTR protein as we believe these patients have the highest unmet medical need. In patients with CFTR mutations that are amenable to modulator medicines, while therapies demonstrate improvements in lung function, these modulators do not restore normal lung function in most patients. Further, these chronic therapies require daily dosing for the patient’s lifetime. We therefore expect to eventually develop 4D-710 in this patient population, as a single agent and/or in combination with these CFTR modulator small molecule medicines.

We have funding and an on-going research and development collaboration with the Cystic Fibrosis Foundation for the development of 4D-710.

Competition and Differentiation: AAV Gene Therapy for Target Disease

A number of biotechnology companies have pursued gene therapy solutions to treat cystic fibrosis. We believe these prior attempts to deliver AAV gene therapy to the lungs of cystic fibrosis patients have failed due to an inability of conventional AAV vectors to penetrate through the lung mucus barrier and transduce lung cells efficiently. Further, we believe antibody neutralization of AAV likely also played a role in the lack of significant efficacy, as the mucosal immune system actively transports large quantities of antibodies into all mucus secretions, including the lung mucosa.

While a number of companies are currently pursuing other gene therapy solutions utilizing liposomes, lentivirus or conventional AAV vectors, these product candidates are in early stages of development. Moreover, they are not, to our knowledge, comprised of AAV vectors evolved in NHPs for aerosol delivery diffusely throughout the lung airways and alveoli. In addition, we believe these products were not designed for resistance to pre-existing antibodies to conventional AAVs, which is potentially a key requirement for successful delivery in the lung. As a result, to our knowledge, 4D-710 is the only AAV gene therapy product candidate in development designed specifically with a vector selected for aerosol delivery in NHPs, including humans, and with resistance to antibodies in the human population.

We believe 4D-710 has the potential to be differentiated from approved agents, and those in clinical development to our knowledge, on the basis of four design features:

Preclinical Proof-of-Concept Study with Evolved AAV for Aerosol Delivery in the Cystic Fibrosis Pig Model

Our co-founder Dr. Schaffer and his academic colleagues conducted preclinical proof-of-concept studies for utilizing directed evolution to discover vectors for delivering a corrective CFTR gene construct to cystic fibrosis lung tissue in a large animal model of cystic fibrosis, and in a human cystic fibrosis patient lung tissue model. Building on these previous proof-of-concept studies, our product candidate 4D-710 will utilize a vector, A101, that was evolved and selected in NHPs, which we believe is more relevant for human use. The product was designed to package the same microCFTR transgene payload in this vector that was customized for use in humans.

Dr. Schaffer and his colleagues first demonstrated the potential to treat cystic fibrosis via aerosolized delivery of a targeted and evolved AAV vector (AAV2H22) in a pig model of cystic fibrosis. AAV2H22 was selected for highly efficient transduction of lung epithelial cells in pigs by conducting multiple rounds of directed evolution using aerosolized dosing in pigs. Aerosol delivery of microCFTR using the AAV2H22vector resulted in CFTR expression in diseased pig lungs with expression patterns that resembled those observed in normal lungs from both pigs and humans. In addition to CFTR protein expression, AAV2H22-CFTR gene therapy also resulted in a significant increase in chloride ion transport compared to untreated controls as well as a reduction in bacterial colonies within the lungs of treated animals. Therefore, selection of an aerosol AAV vector in vivo in normal pigs led to the discovery of an AAV vector that was subsequently able to penetrate the thickened mucus barrier in the severe pig cystic fibrosis model.

Illustrative images in the top panels below exhibit the pattern of microCFTR expression observed by Steines et al. in normal pigs, untreated cystic fibrosis pigs and cystic fibrosis pigs treated with AAV2H22 carrying the microCFTR transgene payload (also referred to as CFTR-deltaR; same transgene utilized in 4D-710, but different AAV vector). The study involved six healthy pigs, six untreated cystic fibrosis pigs and three AAV2H22.microCFTR-treated cystic fibrosis pigs. These animals are represented by the dots in each of the graphs in the bottom panels which illustrate the range of responses between animals, and the significant difference between treated and untreated cystic fibrosis pigs.

CFTRDR = MicroCFTR, Cystic Fibrosis transmembrane conductance regulator with removal of the R domain, a truncated version of the CFTR transgene engineered to fit within the payload size limitations of AAV

Cl-= chloride ion

Isc = short circuit current, a measurement of Cl- movement through cell membranes

μA = microAmp

cm2 = square centimeter.

In addition, Dr. Schaffer and colleagues used directed evolution in an in vitro human organotypic air-liquid interface model of lung epithelium to select AAV2.5T, which we in-licensed with exclusive worldwide rights. In preclinical studies, AAV2.5T carrying microCFTR transduced human lung epithelial tissue and resulted in expression of functional protein as suggested by increased chloride ion transport as compared to untreated control.

We believe that these results demonstrate that a targeted and evolved vector can penetrate the mucus layer of diseased cystic fibrosis lungs and deliver functional CFTR protein in a well-validated large animal model of the disease, as well as in human cystic fibrosis patient-derived organotypic lung models.

Preclinical Animal Model Pharmacology and Toxicology Studies

In our NHP study of a single aerosol delivered dose of 4D-710 at two different dose levels, treatment resulted in widespread distribution, CFTR transgene expression throughout both proximal and medial airways and alveoli. No meaningful inflammation or adverse findings were reported on in-life examinations, hematology or clinical chemistry analyses, or lung histology analyses. Ex vivo studies demonstrated highly significant resistance to neutralization by human pooled antibody preparations, with human IVIG pooled from over 1,000 individuals.

Delivery (genomes) and transduction (mRNA) were consistently measured throughout lung segments and samples in NHPs treated with 3E13 vg of aerosolized 4D-710. Number of positive tissue samples across three NHPs are indicated below.

Aerosol delivery of 4D-710 in NHPs was associated with microCFTR protein detection by IHC (brown) in the proximal (trachea) and medial (bronchi) airway and in alveoli at low and high dose. Illustrative images below highlight transduction of the NHP lung at the 3E13 dose.

We plan to perform pharmacology studies in human cystic fibrosis lung tissues ex vivo in order to evaluate the function of the microCFTR transgene product; this protein has previously been shown to have relatively normal functional activity in a similar model ex vivo.

Development Plan

We have initiated an IND-enabling GLP toxicology and biodistribution study of 4D-710 in NHP. We expect to initiate a Phase 1/2 clinical trial for 4D-710 in the second half of 2021.

Competition

We are aware of several companies focused on developing gene therapies in various indications as well as companies addressing methods for modifying genes and regulating gene expression. We may also face competition from large and specialty pharmaceutical and biotechnology companies, academic research institutions, government agencies and public and private research institutions with genetic medicine and other therapeutic approaches.

With respect to 4D-125 for the treatment of XLRP, we consider our most direct AAV gene therapy competitors to be as follows: Biogen Inc. (candidate administered by subretinal surgery in a Phase 2 clinical trial), Applied Genetic Technologies Corporation (candidate administered by subretinal surgery in a Phase 1/2 clinical trial), Janssen Pharmaceuticals Inc. / MeiraGTx Holdings Plc (candidate administered by subretinal surgery in a Phase 1/2 clinical trial).

With respect to 4D-110 for the treatment of choroideremia, we consider our most direct competitors to be as follows: Biogen Inc. (candidate administered by subretinal surgery in a Phase 3 clinical trial) and Spark Therapeutics, Inc., a wholly owned subsidiary of Roche Holdings AG (candidate administered by subretinal surgery in a Phase 1/2 clinical trial).

We consider our most direct competitors with respect to 4D-150 for the treatment of diabetic retinopathy and wet AMD to be Eylea (aflibercept) from Regeneron Pharmaceuticals Inc., which is the

current wet AMD standard of care, and a combination of antibody-based programs including Lucentis and faricimab from Roche, KSI-301 from Kodiak Sciences Inc., and OPT-302 from Opthea Limited, and gene-therapy based programs including ADVM-022 from Adverum Biotechnologies and RGX-314 from RegenxBio Inc., which are both AAV-based programs in Phase 1 studies. In addition, Roche is developing the Port Delivery System with Lucentis for use in patients with wet AMD.

We consider our most direct competitors with respect to 4D-310 for the treatment of Fabry disease to be Amicus Therapeutics, which has Galafold (migalastat) approved as a small molecule chaperone for specific mutations, and several gene therapy companies including AvroBio Inc., which is in Phase 3 development of an ex-vivo lenti-AGA based program, Freeline Therapeutics Holdings Plc, which is in Phase 1 development of AAVS2-based FLT-190, and Sangamo, which is in Phase 1 development of AAV2/6-based ST-920. Other competitors include Sanofi Genzyme, Takeda Pharmaceutical Company Limited and Protalix BioTherapeutics, all of which either commercialize or develop enzyme replacement therapy for the treatment of Fabry disease.

We consider our most direct competitors with respect to 4D-710 for the treatment of cystic fibrosis to be Vertex, which has several approved CFTR modulators, as well as other gene therapy companies in preclinical development of cystic fibrosis programs, including Krystal Biotech Inc., Abeona Therapeutics Inc., Spirovant Sciences Inc. and Editas Medicine Inc.

Manufacturing

CMC Strategy

In order to fulfill our strategy to maximize the robustness and internal control of our manufacturing processes from discovery and process development through to clinical-grade cGMP manufacturing, we have designed and are continually developing and scaling a robust in-house manufacturing platform for both GMP and non-GMP manufacturing. While many companies in the AAV gene therapy field in-license clinical trial material or manufacturing technologies from other companies or academic manufacturing centers, in contrast, our manufacturing processes were developed internally using internal technology transfers from our own process development labs. Our current in-house manufacturing capabilities include GMP manufacturing (upstream, downstream and fill/finish), production capabilities for IND-enabling GLP toxicology studies and research candidate production. We intend to further scale these capabilities to support later stage clinical programs and indications requiring more patients and/or higher intravenous doses. In addition to our internal activities, we also collaborate with CMOs (Contract Manufacturing Organizations) such as Catalent.

Current Good Manufacturing Practices (“cGMP”) Capabilities

Our team has extensive experience with the manufacturing and analytical testing of numerous unique AAV capsids. Our team has internally manufactured approximately 90 unique AAV vectors, including both proprietary evolved 4DMT capsid variants and naturally occurring capsids. Our team has manufactured over 160 total lots of AAV vectors for research or clinical use. We have in-house cGMP manufacturing capabilities for clinical trial material production. Our manufacturing team has completed and released multiple lots of clinical trial material for our three product candidates in clinical development. This total also includes 13 lots of product candidate material for GLP toxicology and biodistribution studies. Leveraging internal testing capabilities in addition to qualified contract testing laboratories, we fully test and release our GLP and GMP lots for use in toxicology and clinical trials, respectively. We have developed and qualified assays for characterization, in-process testing and release and stability testing of our internally and externally manufactured proprietary AAV vectors.

Process Development Capabilities

We use robust, scalable and transferable manufacturing unit operations throughout both the vector characterization process and product development, which are both platform-specific and product-specific. The upstream manufacturing step involves triple plasmid transfections in an adherent HEK293 mammalian production cell line. Downstream manufacturing steps for purification and concentration

include multiple orthogonal column chromatography steps and tangential flow filtration. The downstream purification columns used in our process are from stable sources including General Electric. Using internally developed manufacturing processes and testing, we characterize our novel capsids and payloads. In addition, leveraging internal expertise and capabilities, we package and test our novel vectors with payloads using internally developed manufacturing processes.

Manufacturing Facilities

Our manufacturing facilities are on site at company headquarters in Emeryville, California and include process development labs, an analytical development lab, and a cGMP manufacturing facility. These manufacturing facilities are also designed for production of material for GLP toxicology and biodistribution studies. Our manufacturing facility is approximately 3,200 square feet, of which approximately 1,500 square feet is dedicated to product manufacturing. For larger scale production for Phase 1 to Phase 3 clinical trials as well as potentially commercial launch materials, we intend to build a second cGMP facility. In this new facility, we expect to utilize large-scale bioreactors that are designed to enable higher titer clinical trial material lots as well as commercial launch materials. These manufacturing facilities are also designed for production of material for GLP toxicology and biodistribution studies.

Manufacturing Team

Our team of approximately 30 highly trained individuals is led by our Chief Technical Officer and Chief Operating Officer, Dr. Kamal, and includes eight Ph.D. scientists. Collectively, they have significant experience in viral vector manufacturing, chemistry-manufacturing-controls (“CMC”), regulatory affairs, analytical and process development, and quality assurance and controls. Our team also has experience prior to 4DMT with manufacturing multiple viral vectors from preclinical studies through to multiple Phase 3 trials. For example, Dr. Kamal helped to write and compile the AAV gene therapy BLA for Zolgensma (Novartis), the first AAV gene therapy approved for intravenous administration in infants and babies.

Intellectual Property

Our commercial success depends in part on our ability to obtain and maintain proprietary protection for our product candidates, manufacturing and process discoveries, and other know-how, to operate without infringing the proprietary rights of others and to prevent others from infringing our proprietary rights. Our policy is to seek to protect our proprietary position by, among other methods, filing U.S. and foreign patent applications related to our proprietary technology, inventions and improvements that are important to the development and implementation of our business. We also rely on trade secrets, know-how, continuing technological innovation and potential in-licensing opportunities to develop and maintain our proprietary position.

Our product and lead optimization candidates were discovered by us utilizing our proprietary technology. We have filed several non-provisional and provisional patent applications, all owned by us, relating to our product and lead optimization candidates in the United States, certain foreign countries, and the World Intellectual Property Organization that are directed to compositions-of-matter, dosage unit forms, methods-of-treatment and medical use. We have also licensed several non-provisional patent applications, granted patents and international patent applications relating to our product and lead optimization candidates from U.C. Berkeley.

As of March 15, 2021, our solely owned patent portfolio includes seven pending U.S. non-provisional applications, seventy-one pending foreign applications, ten allowed foreign applications and six granted foreign patents. We expect that United States and European patents and the patent applications, if issued, would expire between May 2037 and November 2038, excluding any additional term from patent term adjustment or patent term extension if appropriate maintenance and other governmental fees are paid. Additional patent term for the presently issued or later issued U.S. patents may be awarded as a result of the patent term extension provision of the Hatch-Waxman Amendments of 1984. In the European Union member countries, a supplementary protection certificate, if obtained, provides a maximum five years of market exclusivity. Our solely owned patent portfolio also includes five pending U.S. provisional patent applications.

In other jurisdictions (currently, Australia, Bahrain, Brazil, Canada, Chile, China, Colombia, Costa Rica, Egypt, India, Indonesia, Iran, Israel, Japan, Korea, Kuwait, Malaysia, Mexico, New Zealand, Oman, Peru, Philippines, Qatar, Russia, Saudi Arabia, Singapore, South Africa, Thailand, United Arab Emirates, Ukraine and Vietnam), granted patents, and any patents issued on pending applications, where applicable, relating to our product and lead optimization candidates, including composition of matter, dosage unit form, method-of-treatment and medical use, are expected to expire between May 2037 and November 2038, if the appropriate maintenance, renewal, annuity, and other government fees are paid. These patents and patent applications (if applicable), depending on the national laws, may benefit from extension of patent term in individual countries if regulatory approval of any of our product or lead optimization candidates is obtained in those countries. For example, in Japan, the term of a patent may be extended by a maximum of five years in certain circumstances.

As of March 15, 2021, our in-licensed patent portfolio includes five granted U.S. patents and nine granted foreign patents or allowed foreign applications; each of these patents is expected to expire between June 2024 and June 2029. Our in-licensed patent portfolio also includes seven pending U.S. non-provisional patent applications and thirty-eight pending foreign patent applications. We expect that United States and European patents, if issued from applications in our in-licensed portfolio would expire between June 2024 and June 2038.

In other jurisdictions (currently, Australia, Brazil, Canada, China, France, Germany, Great Britain, Hong Kong, India, Italy, Japan, Korea and Mexico), granted patents issued on pending applications, where applicable, relating to our product and lead optimization candidates, including composition of matter and various other patents, including dosage unit form, method-of-treatment and medical use patents are expected to expire between June 2024 and June 2038, if the appropriate maintenance, renewal, annuity, and other government fees are paid. These patents and patent applications (if applicable), depending on the national laws, may benefit from extension of patent term in individual countries if regulatory approval of any of our product or lead optimization candidates is obtained in those countries. For example, in Japan, the term of a patent may be extended by a maximum of five years in certain circumstances.

Individual patents extend for varying periods depending on the date of filing of the patent application or the date of patent issuance and the legal term of patents in the countries in which they are obtained. Generally, patents issued for regularly filed applications in the United States are effective for 20 years from the earliest effective non-provisional filing date. In addition, in certain instances, a patent term can be extended to recapture a portion of the U.S. Patent and Trademark Office (“USPTO”) delay in issuing the patent as well as a portion of the term effectively lost as a result of the FDA regulatory review period. However, as to the FDA component, the restoration period cannot be longer than five years and the total patent term including the restoration period must not exceed 14 years following FDA approval. The duration of foreign patents varies in accordance with provisions of applicable local law, but typically is also 20 years from the earliest effective filing date. The actual protection afforded by a patent varies on a product by product basis, from country to country and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country and the validity and enforceability of the patent.

We also protect our proprietary technology and processes, in part, by confidentiality and invention assignment agreements with our employees, consultants, scientific advisors and other contractors. These agreements may be breached, and we may not have adequate remedies for any breach. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our employees, consultants, scientific advisors or other contractors use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.

Our commercial success will also depend in part on not infringing the proprietary rights of third parties. It is uncertain whether the issuance of any third-party patent would require us to alter our development or commercial strategies, alter our drugs or processes, obtain licenses or cease certain

activities. Our breach of any license agreements or failure to obtain a license to proprietary rights that we may require to develop or commercialize our future drugs may have a material adverse impact on us.

Strategic Collaborations

Collaboration and License Agreement with F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc.

In November 2017, we entered into a Collaboration and License Agreement (the “Roche Agreement”), with F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc., collectively referred to as Roche. Under the Roche Agreement, we granted Roche an exclusive, sublicensable, worldwide license under certain intellectual property rights to research, develop, make, use, import, export, and sell products and constructs using our proprietary AAV vectors to treat ophthalmological diseases and disorders, excluding treatment and prevention of cancer and central nervous system conditions (but not retinal nerves) and delivery of DNA-directed RNA interference (the “Roche Field”).

Under the terms of the Roche Agreement, we and Roche will engage in collaboration programs to develop one or more products, and choroideremia has been designated as the first collaboration program. We are primarily responsible for the initial development of such collaboration programs and Roche agreed to reimburse us for our development costs and expenses in accordance with the terms of the agreement. Upon completion of such initial development, we will transfer data, know-how and regulatory filings to the applicable collaboration program to Roche and Roche will be responsible for the development and commercialization of such program at its own cost and expense.

Subject to the terms of the Roche Agreement, either party may also develop one or more programs in the Roche Field independent of the other party at such party’s own cost and expense. Roche has an option to elect one or more of the programs that we may independently develop under the agreement, including XLRP, which we have designated as our initial independent program. If Roche exercises its option, and subject to its payment of the applicable option exercise fee, we will transfer our data, know-how and regulatory filings related to such programs. If Roche does not exercise its option within the applicable option period, we will have the sole right to commercialization of such product. Each party agreed to various diligence obligations under the agreement.

Pursuant to the Roche Agreement, we received an upfront payment from Roche of $21.0 million. In addition, we are entitled to contingent payments including (i) $1.0 million for each Roche nominated product beyond the first three, (ii) up to $30.0 million upon exercise of the option to convert a product we nominated and developed prior to pivotal clinical studies, (iii) up to $223.0 million in specified development milestones in connection with the licensed products, $86.0 million of which relate to choroideremia; and (iv) sales-based milestones of up to $123.0 million based on worldwide calendar year net sales in connection with licensed products. On a product-by-product basis, Roche will also be required to pay us tiered royalties for worldwide calendar year net sales of products at percentages ranging from the mid-to high-single digit to mid-teens, in each case subject to reductions in accordance with the terms of the agreement. The royalties are payable on a product-by-product and country-by-country basis until the later of ten years after the date of first commercial sale of such product in such country and the expiration of the last-to-expire licensed patent right covering such product, which will expire on May 12, 2037.

The Roche Agreement will expire on the later of expiration of all payment obligations and the date when no products are actively developed by either party or both parties in accordance with the terms of the agreement. Either party may terminate the agreement in its entirety or on a country-by-country basis if the other party fails to cure its material breach within 90 days of receiving notice. Roche may terminate the agreement in its entirety, on a product-by-product basis or on a country-by-country basis upon 90 days’ prior written notice. If we terminate the agreement for Roche’s material breach or if Roche terminates the agreement without cause, the rights to the products generally revert back to us. If we commercialize reverted products after such termination, we may be required to pay Roche tiered royalties for worldwide calendar year net sales of such products at percentages ranging from zero to the low-teens,

in each case subject to reductions in accordance with the terms of the agreement. If Roche terminates the agreement for our material breach, Roche may retain its rights under the license that we grant to Roche under our intellectual property rights and Roche’s payment obligations will survive.

Collaboration and License Agreements with uniQure biopharma B.V.

In August 2019, we entered into an Amended and Restated Collaboration and License Agreement (the “Amended and Restated uniQure Agreement”) with uniQure biopharma B.V., now uniQure N.V. (“uniQure”), which amended and restated the Collaboration and License Agreement that we entered into with uniQure in January 2014.

Under the Amended and Restated uniQure Agreement, we granted uniQure an exclusive, sublicensable, worldwide license under certain of our intellectual property rights, and other rights, to research, develop, make, use, and commercialize pre-selected AAV capsid variants (“Selected Variants”), and compounds and products containing such Selected Variants, using our proprietary AAV technology for delivery of gene therapy constructs to cells in the central nervous system and the liver (the “uniQure Field”). uniQure is solely responsible, at its cost and expense, to develop and commercialize the compounds and products containing the Selected Variants in accordance with the terms of the Amended and Restated uniQure Agreement. We retain all rights to all other AAV capsid variants, and compounds and products containing such AAV capsid variants, in the uniQure Field.

Also in August 2019, we entered into a separate Collaboration and License Agreement with uniQure (“Second uniQure Agreement”). Under the Second uniQure Agreement, the parties agreed to research and develop new AAV capsid variants that are not Selected Variants (New Variants) using our proprietary AAV technology for delivery of transgene constructs that affect certain targets (“uniQure Targets”) in the uniQure Field. We are responsible for the research of the New Variants, and uniQure is responsible for the development and commercialization of a certain number of compounds and products containing New Variants, that affect the uniQure Targets (“Licensed Products”). We granted uniQure an exclusive, sublicensable, worldwide license under certain of our intellectual property rights, and other rights, to research, develop, make, use, and commercialize the Licensed Products. We retain all rights to New Variants in the uniQure Field that affect targets other than the uniQure Targets. We also retain all rights to any new AAV capsid variants developed under the agreements that are not New Variants, and compounds and products containing such variants.

Under both the Amended and Restated uniQure Agreement and the Second uniQure Agreement, uniQure will be required to pay us royalties on worldwide annual net sales of licensed products at a mid-single digit percentage rate, subject to certain specified reductions. These royalties are payable on a product-by-product and country-by-country basis until the latest of ten years after the date of the first commercial sale of such product in such country, the expiration of the last-to-expire licensed patent right covering such product in such country (of which there are none), and the expiration of any applicable exclusivity granted by a regulatory authority in such country for such product (the “uniQure Royalty Term”). uniQure will also be required to pay us a portion of the amounts it receives for licensing or sublicensing to third parties our intellectual property rights licensed or other rights otherwise granted under the Amended and Restated uniQure Agreement, and a portion of the amounts it receives for licensing to third parties our intellectual property rights granted under the Second uniQure Agreement, each at a rate between mid-single digit to mid-twenties percentages, depending on the stage of development at which such third-party grant occurs.

Under both the Amended and Restated uniQure Agreement and the Second uniQure Agreement, under certain circumstances, we may propose to uniQure, and uniQure may grant to us, a non-exclusive right for us to develop and commercialize certain licensed products based on Selected Variants in the uniQure Field, or the New Variants in the uniQure Field to deliver transgene constructs that affect the uniQure Targets (“4DMT Proposed Products”). Pursuant to the Second uniQure Agreement, under certain circumstances, uniQure may propose to us, and we may grant to uniQure a non-exclusive right for uniQure to develop and commercialize certain licensed products using any new AAV capsid variants developed under the agreement that are not New Variants in the uniQure Field to deliver transgene

constructs that affect targets other than the uniQure Targets (“uniQure Proposed Products”). If either party obtains the rights to develop and commercialize a 4DMT Proposed Product or a uniQure Proposed Product, as applicable, such party will be required to pay the other party royalties on worldwide annual net sales of such products at a mid-single digit percentage rate, subject to specified reductions. These royalties will be payable on a product-by-product basis during the uniQure Royalty Term for such products. The party receiving such license will also be required to pay the other party a portion of the amounts that it may receive for licensing or sublicensing to third parties rights for such 4DMT Proposed Products or uniQure Proposed Products, as applicable, at a rate between mid-single digit to mid-twenties percentages depending on the stage of development at which the sublicense is granted.

Each of the Amended and Restated uniQure Agreement and the Second uniQure Agreement will expire on the expiration of all payment obligations of the parties under such agreement. Each party may terminate either agreement for the other party’s insolvency or bankruptcy. Each party may also terminate either agreement in its entirety in some circumstances or on an indication-by-indication basis if the other party fails to cure its material breach under the applicable agreement within 90 days of receiving notice, subject to an additional cure period in accordance with the terms of such agreement. uniQure may terminate either agreement upon 90 days’ prior written notice. In addition, uniQure may terminate the Second uniQure Agreement at any point prior to the first anniversary of the effective date if the joint research committee determines that it would be futile to continue the research program under the agreement, including if such committee determines that certain agreed-upon development success criteria will not be able to be met, or if we are not making bona fide efforts to achieve the mutually agreed timelines set forth in the research plan. If we terminate either agreement for uniQure’s material breach, insolvency or bankruptcy or if uniQure terminates either agreement for convenience or due to its determination of futility, the rights to the Selected Variants, and compounds and products containing such Selected Variants, or the uniQure New Variants, and compounds and products containing such uniQure New Variants, as applicable, generally revert back to us. If uniQure terminates either agreement for our material breach under the applicable agreement, insolvency or bankruptcy, uniQure may retain its rights to the intellectual property license grant under such agreement and uniQure’s payment obligations will survive.

Exclusive License and Bailment Agreements with The Regents of the University of California

In December 2013, we entered into two Exclusive License and Bailment Agreements (the “UC Agreements”) with The Regents of the University of California (the “UC Regents”) with one of the agreements covering AAV2 capsid mutants with novel properties for enhanced performance in gene therapy and the other covering AAV for enhanced gene delivery in the presence of neutralizing antibodies. Under both UC Agreements, the UC Regents granted us an exclusive, sublicensable license under certain patent rights to make, use, sell, offer to sell, and import products and services, and to practice methods in the United States and foreign countries where the licensed patent rights exist. The license grant under one UC Agreement is in all fields of use and the license grant under the other UC Agreement is in all fields of use, with the exception of the ophthalmic field. We agreed to certain general and specific diligence obligations under both UC Agreements in connection with the development, manufacture and sales of the licensed products, services and methods, in accordance with the terms of the UC Agreements.

Under each UC Agreement, we paid the UC Regents an upfront payment of $5,000. Further, at the closing of our Series A financing that was a qualified financing pursuant to the UC Agreements, we issued 311,812 shares of our common stock in aggregate under both agreements. Under each UC Agreement, we agreed to pay the UC Regents a specified annual license maintenance fee in each year in which we do not owe royalties to the UC Regents. We also agreed to pay the UC Regents a mid-teens to mid-twenties percentage range of any consideration, including royalties (“Sublicense Consideration”), we receive for the grant of a sublicense under the licensed patent rights under each UC Agreement, with the consideration payable to the UC Regents to not exceed such percentage range in the aggregate under both UC Agreements for the same sublicense grant. We may reduce any Sublicense Consideration if we sublicense any of our own or third-party patent rights under the sublicense grant based on the relative value of the sublicensed patents. Upon the achievement of specified development and regulatory

milestones by the first licensed product or method, we will be required to pay the UC Regents up to $3.1 million under each UC Agreement. We will also be required to pay the UC Regents a royalty on net sales of licensed products, services and methods covered by the patents licensed under the UC Agreements at a percentage in the low single-digit percentage rate, subject to certain specified reductions. Under the UC Agreements, a specified minimum annual royalty will also be due to the UC Regents beginning the first calendar year after the year in which any net sales of a licensed product first occur, such minimum royalty amount to increase on an annual basis, but not to exceed $0.1 million in the aggregate under both UC Agreements. Under each UC Agreement, royalties are payable until the expiration of the last-to-expire licensed patent right covering the licensed product, service or method, which will expire on June 28, 2038 (the “UC Royalty Term”). Milestone, royalty and sublicense revenue payments will be due to the UC Regents under only one of the UC Agreements covering any licensed product, regardless of the number of patents covering a given licensed product.

Each UC Agreement will expire at the end of the UC Royalty Term. The UC Regents may terminate each of the UC Agreements if we fail to cure a breach of such UC Agreement within 60 days of notice. If we fail to meet our diligence obligations, the UC Regents has the right to either terminate the UC Agreement or to reduce our exclusive license to a non-exclusive license, after giving us 60 days to cure or request arbitration. We may terminate either UC Agreement at-will in its entirety or with respect to any portion of the licensed patent rights upon 90 days prior written notice. Each UC Agreement will terminate immediately if we or a third party on our behalf files a claim asserting that the licensed patent rights are invalid or unenforceable.

Cystic Fibrosis Foundation

In 2016, we received a grant from Cystic Fibrosis Foundation (“CFF”) in the amount of $525,000 to support discovery and development of product candidates to treat cystic fibrosis. The grant was increased to $3.5 million in 2017 and was subsequently amended to allocate the $3.5 million to different milestones. The grant provides for repayment to CFF upon the commercialization of any product developed under the grant. The repayment is capped at nine times multiple of the grant actually paid to us.

In April 2020, CFF made a $10.0 million investment in our Series C redeemable convertible preferred stock financing. In return for the investment, CFF received shares of our Series C redeemable convertible preferred stock, and we and CFF entered into a Funding Agreement (the Funding Agreement). Pursuant to the terms of the Funding Agreement, we agreed to use the proceeds of the CFF investment to support development of 4D-710, our product candidate for the treatment of cystic fibrosis, and to match CFF’s support for the product candidate. Upon acceptance by the FDA of an IND for 4D-710 (“Acceptance”), CFF will make an additional $4.0 million investment (the “Subsequent Investment”), except in the event of a change of control transaction occurring prior to Acceptance or Acceptance occurring after April 29, 2026. At the time of Acceptance, CFF will receive shares of common stock priced at the 10-day average reported closing price of our common stock for the date of Acceptance. We have agreed to use the additional $4.0 million from the Subsequent Investment to support development of 4D-710 and to match CFF’s support of the product candidate. Under the terms of the Funding Agreement, neither the $10.0 million investment in the Series C redeemable convertible preferred stock nor the $4.0 million of funding upon Acceptance are restricted as to withdrawal or usage.

Government Regulation

The FDA and other regulatory authorities at federal, state, and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring, and post-approval reporting of biological product candidates such as those we are developing. We, along with third-party contractors, will be required to navigate the various preclinical, clinical and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidates. The process of obtaining regulatory approvals and

the subsequent compliance with applicable federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

U.S. Biologics Regulation

In the United States, biological products are subject to regulation under the Federal Food, Drug, and Cosmetic Act, the Public Health Service Act, and other federal, state, local and foreign statutes and regulations. The process required by the FDA before biologic product candidates may be marketed in the United States generally involves the following:

• satisfactory completion of an FDA Advisory Committee review, if applicable;

Prior to beginning the first clinical trial with a product candidate in the United States, we must submit an IND to the FDA. An IND is a request for authorization from the FDA to administer an investigational new drug product to humans. The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical trials. The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product; chemistry, manufacturing, and controls information; and any available human data or literature to support the use of the investigational product. An IND must become effective before human clinical trials may begin. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises safety concerns or questions about the proposed clinical trial. In such a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin. Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.

In addition to the submission of an IND to the FDA, under the National Institutes of Health, or NIH, Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines), supervision of certain human gene transfer trials may also require evaluation and assessment by an institutional biosafety committee (“IBC”), a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution. The IBC assesses the safety of the research and identifies any potential risk to the public health or the environment, and such assessment may result in some delay before initiation of a clinical trial. While the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving NIH funding of recombinant or synthetic nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them.

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical study. Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated. A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments. Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site and must monitor the study until completed. Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives. Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy. There are also requirements governing the reporting of ongoing clinical studies and clinical study results to public registries.

For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

FDMT US Equity

FDMT · 10-K · period ended 2020-12-31

Item 1. Business.

FDMT US Equity☆

FDMT · 10-K · period ended 2020-12-31

Item 1. Business.

FDMT US Equity