4D Molecular Therapeutics, Inc. (FDMT) Business

Item 1. Business.

Overview

We are a leading late-stage biotechnology company advancing durable and disease-targeted therapeutics with the potential to transform treatment paradigms and provide unprecedented benefits to patients. Our products are developed with customized and evolved adeno-associated virus (“AAV”) vectors invented from our proprietary vector discovery platform, Therapeutic Vector Evolution (“TVE”) which was designed to generate vectors with properties that overcome the limitations of conventional AAV vectors. TVE applies the principles of directed evolution in non-human primate (“NHP”) models to select vectors that target tissues of diseases with high unmet need using routine and local routes of administration. We are focused on clinical-stage product candidates in retina and lung utilizing vectors invented with TVE and believe the clinical results to date validate the platform.

Our lead product candidate 4D-150 utilizes our proprietary R100 vector and a transgene encoding anti-VEGF biologics (inhibitors of vascular endothelial growth factor): aflibercept (targeting VEGF-A, VEGF-B and placental growth factor) and an RNA interference (RNAi) approach targeting VEGF-C. The goal for our development and potential commercialization of 4D-150 is to transform the standard of care for large market retinal vascular diseases with a safe, in-office, and durable lifelong backbone therapy, substantially reducing treatment burden and improving long-term vision outcomes. 4D-150 is initially being developed for the treatment of wet age-related macular degeneration (“wet AMD”) and diabetic macular edema (“DME”).

Our other pipeline programs include 4D-710, which we believe is the first known genetic medicine to demonstrate successful delivery and durable expression of the cystic fibrosis transmembrane conductance regulator (“CFTR”) transgene in the lungs of people with cystic fibrosis ("CF") and is currently in Phase 2 development. We believe these results will translate into durable clinical improvements in people with CF, including improved lung function and quality of life.

We believe we are well positioned to discover, develop, manufacture and if approved, commercialize targeted genetic medicines with the potential to transform the lives of patients suffering from debilitating diseases.

Our Product Candidate Pipeline & Strategy

We have developed a pipeline of product candidates in two therapeutic areas, retina and pulmonology, focusing on disease areas of high unmet need and commercial potential. Our strategy focuses on advancing our lead product candidate 4D-150 through Phase 3 trials in wet AMD and DME and if successful, commercialization, while advancing our early-stage programs in retina and pulmonology through clinical proof-of-concept. We believe these product candidates are differentiated and can not only provide meaningful benefit to patients, but also are suitable for scalable, global adoption by physicians and payors.

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Below is a summary of our product candidate pipeline:

Retina Therapeutic Area

Introduction

We are developing product candidates to treat severe retinal diseases with our customized and evolved vector, R100. R100 was developed for in-office intravitreal injection to deliver transgene payloads to all major cell layers of the retina, with potentially lifelong transgene expression. We believe leveraging the same novel vector in multiple product candidates will increase product development efficiencies, decrease development risks and inform the clinical development of subsequent product candidates using the same vector. We believe our product candidates targeting large-market retina diseases such as wet AMD and DME have the potential to reshape the standard of care, resulting in substantial benefit for patients.

Our lead retina product candidate 4D-150 is currently in Phase 3 development for wet AMD and is preparing to enter Phase 3 development in DME.

Our second retina product candidate is 4D-175 for geographic atrophy and has an open IND. Further development for 4D-175 is currently pending financing, including potential strategic partnerships.

4D-150 for Wet AMD and DME

Disease Background, Unmet Medical Need, and Target Patient Population

Wet AMD is a highly prevalent disease with an estimated 5 million patients affected in the United States, major European markets, and Japan, and is expected to continue growing with the aging global 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. CNV causes swelling and edema of the retina, bleeding and scarring, which can result in visual distortion and reduced acuity. The proliferation and leakage of abnormal blood vessels is stimulated by protein members of the VEGF family, such as VEGF-A, -B, -C, and placental growth factor (“PIGF”). This process distorts and can potentially destroy central vision and may progress to blindness without treatment.

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Diabetic eye disease (diabetic retinopathy, including DME) is the leading cause of vision loss and blindness in working-age adults in developed countries. Diabetic retinopathy is a complication of diabetes that arises from chronic hyperglycemia–induced damage to retinal blood vessels, leading to increased vascular permeability and angiogenic signaling. Specifically, DME affects an estimated 4 million patients in the United States, major European markets, and Japan, and is expected to grow with the rapidly increasing prevalence of diabetes. DME is a vision-threatening complication of diabetic retinopathy characterized by macular fluid accumulation. The development of DME is driven by upregulation of VEGF and inflammatory mediators that promote vascular leakage and macular edema, ultimately leading to vision loss.

The current treatment paradigm for both wet AMD and DME requires frequent intravitreal bolus injections of patients with anti-VEGF biologics that inhibit blood vessel leakage and proliferation of new blood vessels, reducing edema and bleeding risk, and allowing in many instances some visual acuity to be recovered. Each anti-VEGF injection requires an in-office visit, which carries significant burden and discomfort to patients, and when patients miss injections, they may experience vision decline due to undertreatment. Based on real world data for wet AMD, approximately 40% of patients discontinue treatment by year one, and early vision gains are followed by steady long-term vision decline, which is associated with declining injection frequency. Even with frequent treatment, the disease can often be under poor control, with higher variability in retina anatomy associated with vision loss. Bolus anti-VEGF treatment of retinal vascular diseases represents global branded therapeutic markets of over $16 billion, with wet AMD and DME comprising approximately $14 billion.

We believe these major chronic retinal vascular diseases are ideal applications for genetic medicines. Multiple products on the market validate the efficacy of the anti-VEGF biologics therapeutic approach. A single dose genetic medicine delivering potentially lifelong expression of anti-VEGF biologics as a backbone therapy delivered with a routine in-office intravitreal injection could transform the standard of care for these diseases. In addition, we expect the relatively low doses required to allow for favorable manufacturing scalability, cost of goods sold, and pricing flexibility compared to conventional IV genetic medicines.

Our Solution

4D-150 is a genetic medicine designed to be a backbone therapy for chronic retinal vascular diseases.

The product candidate combines our proprietary R100 vector designed for efficient intravitreal delivery to the retina with a dual transgene payload expressing aflibercept and VEGF-C RNAi. Sustained expression of 4D-150 transgenes has the potential to reduce the treatment burden of repeated visits for anti-VEGF injections required to maintain optimal visual outcomes. Intravitreal delivery of biologics into the eye is a routine in-office injection, which we believe allows for seamless adoption into retina clinic workflows.

Differentiation of 4D-150

AAV genetic medicine approaches are being developed by several companies to treat wet AMD by delivering a copy of a transgene encoding an anti-VEGF biologic by either subretinal surgery or suprachoroidal 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 toxicities. In comparison, our customized and evolved vectors are invented and tested in primates whose eyes more closely resemble the anatomy of the human eye than of mouse eyes. Compared to subretinal or suprachoroidal delivery, we believe that our R100 vector-based products provide comprehensive retinal coverage via an intravitreal injection, while delivering an improved tolerability profile with limited inflammation compared to other intravitreal approaches.

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In addition, to our knowledge, 4D-150 is the first genetic medicine product candidate for the eye designed to directly inhibit four different angiogenic growth factor targets, VEGF A, B, and C plus PlGF. We therefore believe there is significant differentiation between our genetic medicine product candidate and other AAV genetic medicines in development in this therapeutic area.

In addition to genetic medicine approaches, other product candidates designed for extended durability are in development, with the potential to extend dosing intervals by several weeks. We believe a backbone therapy, like 4D-150, designed to provide potentially lifelong benefit with a one-time treatment, would be paradigm-shifting and highly differentiated from interval extension approaches.

We have received Regenerative Medicine Advanced Therapy ("RMAT") from the U.S. Food and Drug Administration ( the “FDA”) and PRIority MEdicine ("PRIME") designation from the European Medicines Agency (the “EMA”) for 4D-150 for the treatment of wet AMD and RMAT designation for 4D-150 for treatment of DME, which highlights recognition from regulatory bodies of the potential of 4D-150 to address significant unmet medical needs for both wet AMD and DME.

Clinical Development of 4D-150 in Wet AMD: PRISM Phase 1/2 and 4FRONT Phase 3 Program

4D-150 is currently being evaluated in wet AMD in the ongoing PRISM Phase 1/2 clinical trial and ongoing 4FRONT global Phase 3 registrational program, which includes two Phase 3 clinical trials (4FRONT-1 and 4FRONT-2).

PRISM enrolled patients with severe, recalcitrant disease with high anti-VEGF treatment burden (Phase 1/2a, 25 patients dosed with Phase 3 dose of 3E10 vg/eye) and with broad disease activity and treatment burden (Phase 2b, 30 patients dosed with Phase 3 dose). Within the Phase 2b Phase 3 dose arm, a subgroup of 15 recently diagnosed patients were enrolled, which is most comparable to our Phase 3 population. In addition, 16 patients were dosed with 3E10 vg/eye in the Phase 2 Alternate Steroids cohort. In total, 71 patients have been dosed with the Phase 3 dose of 3E10 vg/eye.

Interim Data from 4D-150 PRISM Clinical Trial in Wet AMD

In November 2025, we reported positive long-term interim results from Phase 1/2a and 2b of PRISM. As of the most recent data cutoff date (August 22, 2025):

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4D-150 demonstrated consistent and durable benefit across all three patient cohorts as evidenced by maintenance of visual acuity, control of retinal anatomy and reduction of treatment burden at all time points with up to 2 years of follow-up. Treatment burden reduction results were as follows:

1Compared to projected aflibercept 2mg Q8 weeks (Phase 3 comparator)

2Compared to mean injections in prior 12 months

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Durability was Maintained Consistently Across 6-Month Intervals Through 1.5 to 2 Years:

*Week –1 in Phase 1/2a, Week –1 & 4 in Phase 2b

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4D-150 continued to be well tolerated with no new safety or intraocular inflammation findings, with up to 3.5 years of follow-up

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Within approximately the first 28 weeks post-4D-150 dosing, 2.8% (2 of 71) of patients had 4D-150-related 1+ (mild) intraocular inflammation (IOI) (SUN/NEI scales), which were transient 1+ vitreous cells noted at a single timepoint

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Following the first 28 weeks post-4D-150 dosing, no new cases of inflammation with approximately 1.5 to more than 3.5 years of follow-up on all patients as of the data cutoff

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99% (70 of 71) completed steroid prophylaxis taper on schedule and remained completely off steroids

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No 4D-150-related hypotony, endophthalmitis, vasculitis, occlusive/non-occlusive retinal vasculitis or choroidal effusions observed to date

4FRONT Global Phase 3 Registration Program in Wet AMD

The 4FRONT global Phase 3 registration program consists of two multicenter, randomized, double masked, aflibercept Q8W comparator-controlled trials, with the primary endpoint of BCVA noninferiority of 4D-150 3E10 vg/eye to aflibercept 2mg Q8W at 52 weeks. The first trial 4FRONT-1 is being conducted in North America and is enrolling a treatment-naïve population and the second trial 4FRONT-2 is being conducted globally and is enrolling both treatment-naïve and previously treated, recently diagnosed population. Target enrollment per study is 480 patients randomized 1:1 to 4D-150 or the aflibercept comparator arm, providing approximately 90% power with a noninferiority margin of 4 letters as aligned with the Japan Pharmaceuticals and Medical Devices Agency and EMA and over 90% power with a noninferiority margin of 4.5 letters per FDA guidance.

In March 2025, we initiated 4FRONT-1. Subsequently in February 2026, we announced enrollment completion within an approximately 11-month period, ahead of initial projections, with the trial overenrolled and expected to exceed 500 patients randomized, reflecting strong interest from investigators and patients. We continue to anticipate topline data with the 52-week primary endpoint in the first half of 2027.

In June 2025, we initiated 4FRONT-2, with enrollment completion expected in the second half of 2026. We anticipate topline data with the 52-week primary endpoint in the second half of 2027.

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Clinical Development of 4D-150 in DME: SPECTRA Phase 1/2 Clinical Trial

The SPECTRA Phase 1/2 clinical trial assesses 4D-150 in patients with DME. The trial design consists of a Dose Confirmation cohort (Part 1) followed by a randomized, masked Dose Expansion cohort (Part 2). In the Dose Confirmation cohort, patients were sequentially enrolled to one of three dose arms of 4D-150 (5E9, 1E10 and 3E10 vg/eye). In the Dose Expansion cohort (Part 2, N=54), patients were to be randomized 1:1:1 to one of two doses of 4D-150 or aflibercept. In January 2025, we announced FDA feedback that based on interim data and plans reviewed to-date, we may proceed into Phase 3 and Part 2 was no longer necessary. We do not currently intend to enroll Part 2.

Interim Data from Part 1 of 4D-150 SPECTRA Clinical Trial in DME

In July 2025, we announced positive 60-week topline interim data from Part 1 of the SPECTRA clinical trial. Based on the results, 3E10 vg/eye was selected as the Phase 3 dose. As of the most recent data cutoff date (May 2, 2025):

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Safety (n=22):

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4D-150 was well tolerated with no intraocular inflammation at any timepoint

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All patients completed the 16-week topical corticosteroid taper on schedule and remained completely off steroids

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No hypotony, endophthalmitis, vasculitis, choroidal effusions or retinal artery occlusions

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Efficacy Results Through 60 Weeks:

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Phase 3 Dose (N=9):

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Sustained gain of BCVA of +9.7 letters

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Sustained reduction of CST, as measured by OCT, of -174 µm

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Supplemental injections:

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Post-aflibercept loading doses (3), patients treated with Phase 3 dose required substantially fewer supplemental injections compared to patients receiving lower doses (1E10 and 5E9 vg/eye, N=11 evaluable) or projected on-label aflibercept 2mg Q8W (expected Phase 3 comparator):

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Mean injections per patient:

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Phase 3 dose: 1.6

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Lower doses: 3.7

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Projected on-label aflibercept 2mg Q8W: 7.0

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Dose response observed for Phase 3 dose vs. lower doses (58% fewer injections)

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Phase 3 dose demonstrated a reduction of 78% vs. projected on-label aflibercept 2mg Q8W

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0-1 injections:

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5 of 9 overall (Phase 3 dose) vs. 2 of 11 (lower doses)

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Injection-free:

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4 of 9 overall (Phase 3 dose) vs. 1 of 11 overall (lower doses)

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In January 2025, we also announced alignment with the FDA that a single Phase 3 clinical trial would be acceptable as the basis of a biologics license application (“BLA”) submission for 4D-150 in DME. This decision was based on the data generated for 4D-150 in both the SPECTRA and PRISM clinical trials combined with data from the two planned Phase 3 clinical trials in the 4FRONT wet AMD program. Per FDA feedback, we may proceed to Phase 3 and are aligned with key design elements of a Phase 3 clinical trial with approximately 300-400 patients total with a primary endpoint of BCVA noninferiority vs. on-label aflibercept 2mg (5 loading doses and Q8W), and revised supplemental injection criteria (less stringent compared to Part 1 SPECTRA, in line with prior successful Phase 3 DME clinical trials). Protocol alignment across global agencies is ongoing and a single global Phase 3 clinical trial is expected to initiate in the third quarter of 2026.

Pulmonology Therapeutic Area

Introduction

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

Our first pulmonology product candidate is 4D-710 for cystic fibrosis lung disease. We are currently enrolling the Phase 2 portion of the AEROW Phase 1/2 clinical trial in people with CF with funding from and in collaboration with the CF Foundation.

Our second pulmonology product candidate is 4D-725 for alpha-1 antitrypsin deficiency lung disease. 4D-725 is currently in preclinical development and fully funded by the California Institute for Regenerative Medicine through IND filing.

4D-710 for Cystic Fibrosis Lung Disease

Disease Background, Unmet Medical Need, and Target Patient Population

CF is the most common fatal inherited disease in the United States and results from mutations in the CFTR gene. CF 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 CF, and the median age of death for people is approximately 40 years in developed countries. CF is considered a rare, or orphan, disease by both the FDA and the EMA.

According to the CF Foundation, nearly 40,000 people in the United States and an estimated 105,000 people worldwide are living with CF, and approximately 1,000 new cases are diagnosed in the United States each year. People with CF require lifelong treatment with multiple daily medications, frequent hospitalizations and, ultimately, lung transplants. The quality of life for people with CF is further 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 people with CF were only designed to treat the manifestations of CF, 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.

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More recently, a new class of drugs called modulators target CFTR for people with certain gene variants. 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 CF. In 2019, the FDA approved a triple drug therapy with Trikafta (elexacaftor/ivacaftor/tezacaftor), which Vertex believes would be applicable for up to 90% of people with CF, 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 people, and these chronic therapies require daily dosing for the person’s lifetime. In addition, the existing CF drugs have been associated with tolerability issues, thus limiting their use in some people.

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 people with CF, including people 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 people whose disease is not amenable to CFTR modulators (estimated to include approximately 15% of people with CF who have null variants or are unable to tolerate modulators), and to explore single agent or combination therapy with CFTR modulators for the remaining approximately 85% of people with CF.

Our Solution

We are developing 4D-710 as a durable, redosable, variant-agnostic disease-modifying therapy for people with CF lung disease. 4D-710 is designed for efficient aerosol delivery to the proximal and distal airways and alveoli, subsequent mucus barrier penetration, lung epithelial cell transduction, and resistance to pre-existing antibodies. The intended result is to achieve CFTR expression within lung epithelial cells for correction of CF lung disease. 4D-710 is comprised of our customized and evolved vector, A101, and a codon-optimized version of a synthetic truncated CFTR transgene CFTRΔR. CFTRΔR 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, and is shown to have normal function and regulation in nonclinical studies. Based on nonclinical and clinical studies with other AAV programs, we expect redosing 4D-710 will be feasible.

Initially, we plan to focus on the approximately 15% of all people with CF who are not amenable to CFTR modulators as we believe these people have the highest unmet need. In people with CFTR variants that are amenable to modulators, many do not regain or cannot preserve lung function. Further, these chronic therapies require daily dosing for the person’s lifetime. We therefore expect to eventually develop 4D-710 in this population, as a single agent and/or in combination with these CFTR modulators.

4DMT Differentiation: AAV Genetic Medicines for Cystic Fibrosis Lung Disease

A number of biotechnology companies have pursued genetic medicine solutions to treat cystic fibrosis. We believe these prior attempts to deliver AAV genetic medicine to the lungs of people with CF 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 efficacy, as the mucosal immune system actively transports large quantities of antibodies into all mucus secretions, including on the lung mucosa.

While a number of companies are currently pursuing other genetic medicine solutions utilizing liposomes, herpesvirus, 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 primates 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 genetic medicine product candidate in development designed specifically with a vector selected for aerosol delivery in primates, including humans, and with resistance to antibodies in the human population.

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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 features:

1.
Corrective mechanism-of-action: An aerosol dose of 4D-710 is designed to result in therapeutic levels of the CFTR protein directly within target cells lining the airway.

2.
Long duration therapy: Unlike CFTR-targeted small molecules that require daily dosing for a person’s entire life or liposomal and herpesvirus delivered genetic medicines that are being studied for dosing every few days to weeks, 4D-710 is designed for significantly less frequent dosing.

3.
CFTR mutation-independent efficacy: Unlike CFTR-targeted small molecules that are only effective against specific mutations, 4D-710 is designed to be used in people with CF with any mutation, including in the approximately 15% of people whose disease is not amenable to standard medical therapy.

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Resistance to AAV antibodies: Unlike conventional AAV vectors, which are sensitive to anti-AAV antibody inhibition, 4D-710 utilizes A101, a vector invented for resistance to human antibody inhibition.

Clinical Development: AEROW Phase 1/2 Clinical Trial

The AEROW Phase 1/2 clinical trial is a multicenter, open-label, dose-escalation and dose-expansion trial of 4D-710 in people with cystic fibrosis who are ineligible for CFTR modulator therapy or who have discontinued therapy due to adverse effects. The primary endpoint of the trial is safety and tolerability. Secondary endpoints include assessments of clinical activity including lung function, quality of life, and transgene delivery and CFTR expression as measured from bronchoscopic samples. The trial is being conducted within the Cystic Fibrosis Therapeutics Development Network, the largest CF clinical trials network in the world.

Interim Data from Phase 1 Stage of 4D-710 AEROW Clinical Trial in Cystic Fibrosis

In December 2025, we announced positive interim clinical data. The interim clinical data focused on safety, transgene expression, and clinical activity for 16 participants enrolled across four Phase 1 dose cohorts (2E15, 1E15, 5E14 and 2.5E14 vg).

The interim results, with best available data through December 1, 2025, included:

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Safety Data

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No new pulmonary or other safety events occurred since previous update in higher-dose cohorts (1E15 and 2E15 vg) with up to 3.5 years of follow-up

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In lower-dose cohorts (4 to 24 months of follow-up), 4D-710-related adverse events were generally mild, transient and resolved by 2 months, with no 4D-710-related severe adverse events

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Biopsy Data

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In biopsies collected approximately 4 weeks post-dosing, consistent and dose-dependent CFTR transgene RNA levels at or above physiologically relevant levels in non-CF control samples across all dose levels

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In 2.5E14 vg dose cohort, results met target expression profile

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Durable CFTR transgene expression within or above target therapeutic range through at least 1 year across all dose levels as measured from optional paired biopsies collected at or beyond 1 year post-dosing

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In 2.5E14 vg dose cohort, consistent evidence of clinically meaningful activity detected in all endpoints, including ppFEV1, LCI2.5 and quality of life (CFQ-R-R) through 1 year

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Based on evaluation of safety, tissue expression and efficacy data, 2.5E14 vg was selected as the Phase 2 dose

The 4DMT Therapeutic Vector Evolution Platform: One Billion Synthetic Capsid Sequences for Targeted Genetic Medicines

Genetic medicines hold tremendous promise as a transformative therapeutic class. However, the majority of genetic medicines 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 to treat diseases involving those 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 genetic medicines utilizing conventional AAV vectors.

The first step of directed evolution involves the generation of a diverse library of biological variants. Leveraging a wide range of molecular biology techniques, we have developed a collection of highly diverse and 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 TVE 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. Subsequently, we characterize and evaluate a lead targeted and evolved vector for delivery and transgene expression through extensive studies in NHPs and human cell and organotypic tissue assays.

We believe our proprietary vectors will allow us to overcome known limitations of conventional AAV vectors, and to potentially address a broad range of diseases that affect both large and rare patient populations that cannot be addressed with conventional vectors.

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.

Since our founding in 2013, we have developed and industrialized our Therapeutic Vector Evolution Platform to invent customized and evolved vectors for use in human therapeutic products. In addition, we have developed significant experience in performing TVE programs in NHPs. We have patent applications and issued patents covering hundreds of proprietary, unique AAV capsid vectors. We believe these proprietary customized vectors will give us significant competitive advantages to develop product candidates for a broad range of large market and rare disease patient populations, including those other genetic medicines cannot address.

Diverse Sub-Libraries of Synthetic Capsid Sequences

Each sub-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 also apply bioinformatics, emerging technologies, experience and know-how resulting from previous discovery programs to continually improve and expand our libraries and improve our ability to invent customized 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 genetic medicines.

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The Target Vector Profile Followed by Competitive Vector Selection

We employ a rigorous approach to inventing customized and evolved vectors based on what we consider an optimal vector and product profile, which we term the Target Vector Profile, for any disease or set of diseases affecting the same tissue(s). The Target Vector Profile includes any combination of the following: the target cell(s), the desired distribution of vector transduction within the target organ(s), the optimal route of administration for targeting the specific tissue(s), the optimal dose range, overall biodistribution, and resistance to human pooled antibodies.

We use our Therapeutic Vector Evolution Platform to select the “fittest” customized and evolved capsid that best matches our Target Vector Profile. We achieve this through serial rounds of “selection,” or discovery, in vivo in primates with each round of selection funneling down to fewer and fewer remaining 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.

We believe this deliberate approach to selection in vivo in primates and in human tissues should lead to identification of customized and evolved vectors with a higher likelihood of therapeutic benefit in humans.

Vector Invention Results to Date

We have completed 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: intravitreal, aerosol, intravenous, and intrathecal. 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, resulting in hundreds of unique and proprietary customized and evolved vectors.

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

Vector hits are typically characterized by three major criteria: manufacturability, 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 pooled human antibodies. In order to perform characterization studies, vectors are armed with marker transgene payloads such as enhanced green fluorescent protein (“EGFP”). A lead vector is selected after evaluation of these hits.

Competition

We are aware of several companies focused on developing genetic medicines 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.

We consider our most direct competitors in late-stage development with respect to 4D-150 for the treatment of retinal vascular diseases including wet AMD and DME to be late-stage AAV-based anti-VEGF genetic medicine programs including ABBV-RGX-314 from AbbVie Inc. and REGENXBIO Inc. (subretinal delivery in Phase 3 for wet AMD; suprachoroidal delivery initiating Phase 3 for diabetic retinopathy and in Phase 2 for wet AMD) and  Ixo-Vec from Adverum Biotechnologies Inc., now a subsidiary of Eli Lilly and Company (intravitreal delivery in Phase 3 for wet AMD, previously discontinued in diabetic populations). We also face competition from late-stage sustained release VEGF receptor tyrosine kinase

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inhibitor programs at EyePoint Inc. and Ocular Therapeutix Inc., anti-VEGF and IL-6 antibody biopolymer conjugate programs from Kodiak Sciences Inc, and Wnt signaling-pathway tri-specific antibody program from Merck & Company Inc. Currently marketed products include EYLEA (aflibercept) from Regeneron Pharmaceuticals Inc., which is the current standard of care, and a combination of antibody-based programs including, but not limited to, LUCENTIS, SUSVIMO, VABYSMO from Roche, and EYLEA HD from Regeneron Pharmaceuticals Inc.

We consider our most direct competitors with respect to 4D-175 for the treatment of geographic atrophy to be Apellis Pharmaceuticals Inc.’s C3 inhibitor SYFOVRE (approved by FDA in 2023) and Astellas Pharma Inc.’s C5 inhibitor IZERVAY (approved by FDA in 2023). We are also aware of other mid- to late-stage programs including but not limited to Annexon Biosciences, Inc.’s C1q inhibitor ANX007, Belite Bio, Inc’s retinol binding protein 4 binder tinlarebant, Johnson & Johnson’s AAV genetic medicine encoding CD59 JNJ-81201887, Regeneron Pharmaceuticals Inc.’s anti-C5 antibody pozelimab developed in combination with Alnylam Pharmaceuticals, Inc.’s RNAi therapeutic targeting C5 cemdisiran, Sanofi’s AAV genetic medicine encoding C1s and Bb inhibitors SAR446597, and Stealth BioTherapeutics Inc.’s mitochondrial cardiolipin binder elamipretide.

We consider our most direct competitors with respect to 4D-710 for the treatment of CF lung disease to be Vertex Pharmaceuticals Incorporated, which has several approved CFTR modulators, as well as other companies in preclinical/early-clinical development of CF products, including Vertex Pharmaceuticals Incorporated, Sionna Therapeutics Inc., Krystal Biotech Inc., Arcturus Therapeutics Holdings Inc. and Recode Therapeutics, 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 current Good Manufacturing Practices (“cGMP”) manufacturing, we have designed and are continually developing and scaling our in-house manufacturing platform for both GMP and non-GMP manufacturing. While many companies in the AAV genetic medicine field outsource their process development and manufacturing to 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 late-phase clinical trials, IND-enabling Good Laboratory Practice (“GLP”) toxicology studies, and research candidate production. We also collaborate with contract development and manufacturing organizations (“CDMOs”) to supplement our internal capacity, and expect to rely on CDMOs for potential commercial supply.

cGMP Capabilities

Our team has extensive experience with the manufacturing and analytical testing of numerous unique AAV capsids. Our team has internally manufactured over 300 unique AAV vectors, including both proprietary evolved 4DMT capsid variants and naturally occurring capsids. Our team has manufactured over 500 total lots of AAV vectors for research or clinical use. This total also includes multiple lots of product candidate material for GLP toxicology and biodistribution studies. We have in-house cGMP manufacturing capabilities for clinical trial material production. Our manufacturing team has completed and released 28 lots of clinical trial material for six product candidates in current or previous clinical development. 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.

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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 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. 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, including both adherent and suspension processes.

Manufacturing Facilities

Our manufacturing facilities are on site at company headquarters in Emeryville, California and include process development labs, an analytical development lab, QC lab, and a cGMP manufacturing facility. These process development facilities are designed for production of material for GLP toxicology and biodistribution studies. In addition, our cGMP facilities run at commercial scale (including adherent bioreactors and suspension stirred-tank reactors) and have provided materials for Phase 1 through Phase 3 clinical trial material.

Manufacturing Team

Our team of highly trained individuals is led by our Chief Technical Officer, Dr. Katy Barglow, and includes multiple 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. As of March 2026, our team had submitted 7 INDs, all of which have been granted clearance by the U.S. FDA, enabling our clinical candidates to advance to Phase 3 clinical development. Our team also has experience prior to 4DMT with manufacturing multiple viral vectors from preclinical studies through to multiple Phase 3 trials.

External Manufacturing

In addition to our in-house facilities, we have established a partnership with a leading global commercial CDMO for potential commercialization of 4D-150. We have successfully completed the tech transfer of produced and released Phase 3 batches using our intended commercial processes at this CDMO.

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. In particular, our patent strategy includes the filing of patent applications covering unique gene sequences selected through our TVE process. 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 and certain foreign countries and through the World Intellectual Property Organization that are directed to compositions of matter, dosing regimens, methods of treatment, medical uses, and formulations. We have also licensed several non-provisional patent applications, granted patents and international patent applications relating to our targeted and evolved vector, A101, which is used in 4D-710 and 4D-725, and to other AAV-based technologies.

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As of February 14, 2026, our solely owned patent portfolio includes eighteen granted U.S. patents and one hundred and thirty-five granted foreign patents; each of these patents is expected to expire between May 2037 and April 2042,,excluding any additional term from patent term adjustment or patent term extension if appropriate maintenance and other governmental fees are paid. Our solely owned patent portfolio also includes sixteen pending U.S. non-provisional applications and one hundred and sixty-nine pending foreign applications. We expect that United States and European patents, if issued from pending applications in our solely owned portfolio, would expire between May 2037 and September 2045, 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. Similarly, in the European Union member countries, a supplementary protection certificate, if obtained, provides up to an additional five years of market exclusivity. Our solely owned patent portfolio also includes nine pending U.S. provisional patent applications.

In other jurisdictions (currently, Argentina, Australia, Bahrain, Brazil, Canada, Chile, China, Colombia, Costa Rica, Egypt, Hong Kong, India, Indonesia, Iran, Israel, Japan, Korea, Kuwait, Malaysia, Mexico, New Zealand, Oman, Peru, Philippines, Qatar, Russia, Saudi Arabia, Singapore, South Africa, Taiwan, Thailand, United Arab Emirates, Ukraine, and Vietnam), patents, if issued on pending applications in our solely owned patent portfolio, where applicable, relating to our product and lead optimization candidates, including composition of matter, dosing regimen, method of treatment, medical uses, and formulations are expected to expire between May 2037 and September 2045, 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 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 February 14, 2026, our in-licensed U.C. Berkeley patent portfolio, relating to our vector, A101, and other AAV-based technologies, includes five granted U.S. patents and twenty-one granted foreign patents; each of these patents is expected to expire between August 2027 and June 2038, excluding any additional term from patent term adjustment or patent term extension if appropriate maintenance and other governmental fees are paid. Our in-licensed U.C. Berkeley patent portfolio also includes one pending U.S. non-provisional patent application and ten pending foreign patent applications. We expect that United States and European patents, if issued from applications in our in-licensed U.C. Berkeley portfolio would expire between August 2027 and June 2038, excluding any additional term from patent term adjustment or patent term extension if appropriate maintenance and other governmental fees are paid.

As of February 14 2026, our in-licensed University of Pennsylvania patent portfolio includes two granted U.S. patents and ten granted foreign patents; each of these patents is expected to expire in September 2036, excluding any additional term from patent term adjustment or patent term extension if appropriate maintenance and other governmental fees are paid. Our in-licensed University of Pennsylvania patent portfolio also includes one pending U.S. non-provisional patent application and seven pending foreign patent applications. We expect that United States and European patents, if issued from applications in our in-licensed portfolio would expire in September 2036, excluding any additional term from patent term adjustment or patent term extension if appropriate maintenance and other governmental fees are paid.

In other jurisdictions (currently, for our in-licensed U.C. Berkeley patent portfolio, Australia, Brazil, Canada, China, Hong Kong, India, Japan, Korea and Mexico, and for our in-licensed University of Pennsylvania patent portfolio, Australia, Brazil, Canada, China, Israel, Japan, Korea and Hong Kong), patents, if issued on pending applications in our in-licensed patent portfolio, where applicable, relating to our product 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 August 2027 and June 2038 for our in-licensed U.C. Berkeley patent portfolio, and expire in September 2036 for our in-licensed University of Pennsylvania patent portfolio, 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

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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 trade secrets and other 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 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

Otsuka Pharmaceutical Co., Ltd.

On October 31, 2025, we entered into a Collaboration and License Agreement (“Otsuka Collaboration and License Agreement”) with Otsuka Pharmaceutical Co., Ltd. (“Otsuka”), pursuant to which we granted Otsuka exclusive rights to develop and commercialize 4D-150 for retinal vascular diseases, including wet AMD and DME, in Japan, China, Australia, and other Asia-Pacific (“APAC”) markets. Otsuka has agreed to lead all regulatory and commercialization activities in its licensed territories. We agreed to continue to lead all Phase 3 clinical activities globally, including within the APAC region. Otsuka made an upfront cash payment of $85.0 million and has agreed to provide certain cost sharing for global development activities. In addition, we are eligible for up to $335.5 million in potential regulatory and commercial milestone payments and tiered double-digit royalties depending on net sales in Otsuka’s licensed territories. We retain full development and commercialization rights for 4D-150 outside the APAC region, including the United States, Latin America, and Europe.

The Otsuka Collaboration and License Agreement remains in effect, unless earlier terminated, on a country-by-country basis, until the date that Otsuka is no longer developing or commercializing the licensed product in such country within the licensed territory. Each party has the right to terminate the Otsuka Collaboration and License Agreement for the other party’s material breach of its obligations under the Otsuka Collaboration and License Agreement, subject to the right to cure such breach. Additionally, Otsuka may terminate the Otsuka Collaboration and License Agreement for convenience, on a country-by-country basis, upon sufficient prior written notice, or due to safety reasons or the failure of certain of our related clinical trials to achieve their primary endpoints. We may also terminate the Otsuka Collaboration and License Agreement upon notice if Otsuka challenges the patentability, enforceability, or validity of any

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licensed patent, unless Otsuka withdraws the challenge within a specified period, or if Otsuka ceases all development activities and commercialization of all licensed products in Japan for an agreed upon period and does not resume such activities or commercialization within a specified notice period, unless such cessation is substantially attributable to specified circumstances. Upon termination, any license granted by us to Otsuka will terminate.

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. In August 2023, the grant agreement was further amended, which modified the research plan, increased the aggregate milestone payments from $3.5 million to $6.3 million and extended the estimated project completion date. The grant provides for repayment to CFF upon the commercialization of any product developed under the grant. In August 2023, we executed an amendment to the CF Foundation agreement increasing the funding commitment under that agreement by $2.8 million to a total of $6.3 million, which covers anticipated spend for further development of our aerosolized lung epithelium gene delivery vectors. The repayment is capped at nine times 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. As provided under the Funding Agreement, following acceptance by the FDA in October 2021 of our IND for 4D-710 (“Acceptance”), CFF made an additional $4.0 million investment (the “Subsequent Investment”), in exchange for 125,715 shares of our common stock. 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.

In October 2025, CFF purchased 776,398 shares of our common stock for $7.5 million. We agreed to use the proceeds of this investment to support continued development of 4D-710. We also agreed with CFF to form a Joint Steering Committee, with senior clinical development and regulatory expertise to enhance strategic planning, guidance, and coordination of 4D-710’s development. In addition, this agreement between CFF and us in October 2025 provides that CFF will invest an additional $3.6 million in exchange for shares of our common stock subject to achievement of specific clinical milestones and at our option. This agreement between us and CFF in October 2025 does not modify our prior agreements with CFF.

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.

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U.S. Biologics Regulation

In the United States, biological products are subject to regulation under the Federal Food, Drug, and Cosmetic Act (“FDCA”), 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:

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completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s GLPs;

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submission to the FDA of an IND, which must become effective before clinical trials may begin;

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approval by an Institutional Review Board ("IRB") or ethics committee at each clinical site before the trial is commenced;

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performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the proposed biologic product candidate for its intended purpose;

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preparation of and submission to the FDA of a BLA after completion of all pivotal clinical trials;

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

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a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;

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satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with current GMP and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency, and of selected clinical investigation sites to assess compliance with Good Clinical Practices (“GCP”); and

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FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the United States.

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 be allowed to proceed by the FDA before human clinical trials may begin. The IND automatically goes into effect within 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 proceed. 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 (“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.

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Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCP, 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:

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Phase 1—The investigational product is initially introduced into healthy human subjects or patients with the target disease or condition. These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

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Phase 2—The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks. Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.

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Phase 3—The investigational product is administered to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product labeling.

In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product within the approved indication. These so-called Phase 4 studies, in addition to other post-marketing clinical trials, registry studies or comparable post-marketing commitments or requirements, may also be made a condition to approval of the BLA.

While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report, among other information, must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the drug, findings from animal or in vitro testing suggesting a significant risk to humans exposed to the drug, and any clinically important increased rate of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

Concurrent with clinical trials, companies may complete additional animal studies and develop additional information about the biological characteristics of the product candidate and must finalize a process for manufacturing the product in commercial quantities in accordance with cGMP. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, sponsors must develop methods for testing the identity, strength, quality, and

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purity of the final product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

BLA Submission and Review by the FDA

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, including results from nonclinical studies and clinical trials are submitted to the FDA as part of a BLA requesting approval to market the product for one or more indications. The BLA must include all relevant data available from preclinical and clinical studies, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things. Data can come from company-sponsored clinical studies intended to test the safety and effectiveness of a use of the product, or from a number of alternative sources, including studies initiated by investigators. The submission of a BLA requires payment of a substantial user fee to FDA, and the sponsor of an approved BLA is also subject to an annual program fee. A waiver of user fees may be obtained under certain limited circumstances. Additionally, no user fees are assessed on BLAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

In addition, the Pediatric Research Equity Act (“PREA”), requires a BLA sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration. Under PREA, original BLAs and certain supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver. The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is deemed safe and effective. The sponsor or FDA may request a deferral of pediatric clinical trials for some or all of the pediatric subpopulations. A deferral may be granted for several reasons, including a finding that the drug is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric clinical trials begin.

Within 60 days following submission of the application, the FDA reviews a BLA submitted to determine if it is substantially complete before the FDA accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA must be resubmitted with the additional information. Once a BLA has been accepted for filing, the FDA’s goal is to review standard applications within ten months after the filing date, or, if the application qualifies for priority review, six months after the filing date. Priority review designation will direct overall attention and resources to the evaluation of applications for products that, if approved, would represent significant improvements in the safety or effectiveness in the treatment, diagnosis, or prevention of serious conditions. In both standard and priority reviews, the review process can be extended by three months for the FDA to review and respond to new information deemed a major amendment to the application. The FDA reviews a BLA to determine, among other things, whether a product is safe, pure and potent and the facility in which it is manufactured, processed, packed, or held meets standards designed to assure the product’s continued safety, purity and potency. The FDA may also convene an advisory committee to provide clinical insight on application review questions. The FDA is not bound by recommendations of an advisory committee, but it considers such recommendations when making decisions regarding approval.

Before approving a BLA, the FDA will typically inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP and adequate to assure consistent production of the product within required specifications. Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

After the FDA evaluates a BLA and conducts inspections of manufacturing facilities where the investigational product and/or its drug substance will be produced, the FDA may issue an approval letter or a Complete Response Letter (“CRL”). An approval letter authorizes commercial marketing of the product

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with specific prescribing information for specific indications. A CRL will generally describe all of the deficiencies that the FDA has identified in the BLA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the CRL without first conducting required inspections, testing submitted product lots, and/or reviewing proposed labeling. In issuing the CRL, the FDA may recommend actions that the applicant might take to place a resubmitted BLA in condition for approval, including requests for additional clinical trials, or other significant and time-consuming requirements related to clinical trials, nonclinical studies or manufacturing. The FDA may delay or refuse approval of a BLA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.

If regulatory approval of a product is granted, such approval will be granted for particular indications and may entail limitations on the indicated uses for which such product may be marketed. For example, the FDA may approve the BLA with a Risk Evaluation and Mitigation Strategy (“REMS”), to ensure the benefits of the product outweigh its risks. A REMS is a safety strategy to manage a known or potential serious risk associated with a medicine and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries, and other risk minimization tools. The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls and specifications. Once approved, the FDA may withdraw the product approval if compliance with pre- and post-marketing requirements is not maintained or if problems occur after the product reaches the marketplace. The FDA may also require one or more Phase IV post-market studies and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization and may limit further marketing of the product based on the results of these post-marketing studies.

Expedited Development and Review Programs

A sponsor may seek approval of its product candidate under programs designed to accelerate FDA’s review and approval of drugs and biological products that meet certain criteria. Specifically, biological product candidates are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. Fast track designation applies to the combination of the product candidate and the specific indication for which it is being studied. The sponsor of a fast track product candidate has opportunities for more frequent interactions with the applicable FDA review team during product development and, once a BLA is submitted, the application may be eligible for priority review. For a fast track product candidate, the FDA may consider sections of the BLA for review on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines that the schedule is acceptable and the sponsor pays any required user fees upon submission of the first section of the application. A fast track designated product candidate may also qualify for priority review, under which the FDA sets the target date for FDA action on the BLA at six months after the FDA accepts the application for filing.

A product candidate intended to treat a serious or life-threatening disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review. A product candidate can receive breakthrough therapy designation if preliminary clinical evidence indicates that the product candidate, alone or in combination with one or more other drugs or biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product candidate, including involvement of senior managers.

In 2017, the FDA established the regenerative medicine advanced therapy (“RMAT”) designation as part of its implementation of the 21st Century Cures Act. The RMAT designation program is intended to fulfill the 21st Century Cures Act requirement that the FDA facilitate an efficient development program for,

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and expedite review of, any drug or biologic that meets the following criteria: (i) the drug or biologic qualifies as a RMAT, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, with limited exceptions; (ii) the drug or biologic is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and (iii) preliminary clinical evidence indicates that the drug or biologic has the potential to address unmet medical needs for such a disease or condition. Based on the FDA’s current interpretation of Section 506(g) of the FDCA (as added by Section 3033 of the 21st Century Cures Act), certain human gene therapies and xenogeneic cell products may also meet the definition of a regenerative medicine therapy. RMAT designation provides all the benefits of breakthrough therapy designation, including more frequent meetings with the FDA to discuss the development plan for the product candidate and eligibility for rolling review and priority review. Product candidates granted RMAT designation may also be eligible for accelerated approval on the basis of a surrogate or intermediate endpoint reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of clinical trial sites, including through expansion of trials to additional sites.

Any marketing application for a drug or biologic submitted to the FDA for approval, including a product candidate with a fast track designation, RMAT designation and/or breakthrough therapy designation, may be eligible for other types of FDA programs intended to expedite the FDA review and approval process, such as priority review and accelerated approval. A product candidate is eligible for priority review if it is designed to treat a serious or life-threatening disease or condition, and if approved, would provide a significant improvement in safety or effectiveness compared to available alternatives for such disease or condition. For original BLAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date (as compared to ten months under standard review). Under the accelerated approval program, the FDA may approve a BLA on the basis of either a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. Post-marketing studies or completion of ongoing studies after marketing approval are generally required to verify the biologic’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit. In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product. FDA may withdraw approval of a biologic or indication approved under accelerated approval on an expedited basis if, for example, the sponsor fails to conduct required post-marketing trials in a timely manner or if such trials fail to verify the predicted clinical benefit of the product.

Fast Track designation, priority review, accelerated approval, RMAT designation and breakthrough therapy designation do not change the standards for approval but may expedite the development or approval process. Even if a product candidate qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

We have obtained RMAT designation for 4D-150 for the treatment of neovascular (wet) AMD, and we plan to seek additional expedited designations for some or all of our product candidates in which there is a medically plausible basis for the use of these products.

Orphan Drug Designation and Exclusivity

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 individuals in the United States, or a patient population greater than 200,000 individuals in the United States and when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the United States will be recovered from sales in the United States for that drug or biologic. Orphan drug designation must be requested before submitting a BLA. After the FDA grants orphan drug designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

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If a product that has orphan drug designation subsequently receives the first FDA approval for a particular active ingredient for the rare disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same biologic for the same approved use or indication within such rare disease or condition for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs relating to the approved use or indication of patients with the rare disease or condition for which the drug was designated. Orphan drug exclusivity does not prevent the FDA from approving a different drug or biologic for the same approved use or indication within the relevant rare disease or condition, or the same drug or biologic for any use or indication within a different disease or condition. Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the BLA application user fee.

A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the disease or condition for which it received orphan designation. In addition, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or, as noted above, if the second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity within the relevant approved use or indication or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs relating to the approved use or indication of patients with the relevant rare disease or condition. We have obtained orphan drug designation for 4D-710 for the treatment of cystic fibrosis.

Rare Pediatric Disease Priority Review Voucher Program

In 2012, the U.S. Congress authorized the FDA to award priority review vouchers to Sponsors of certain rare pediatric disease product applications. This program is designed to encourage development of new drug and biological products for prevention and treatment of certain rare pediatric diseases. Specifically, under this program, a sponsor who receives an approval for a drug or biologic for a “rare pediatric disease” may qualify for a voucher that can be redeemed to receive priority review of a subsequent marketing application for a different product. The Sponsor of a rare pediatric disease drug product receiving a priority review voucher may transfer (including by sale) the voucher to another sponsor. The voucher may be further transferred any number of times before the voucher is used, as long as the Sponsor making the transfer has not yet submitted the application. The FDA may also revoke any priority review voucher if the rare pediatric disease drug for which the voucher was awarded is not marketed in the U.S. within one year following the date of approval.

For purposes of this program, a “rare pediatric disease” is a (a) serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years, including age groups often called neonates, infants, children, and adolescents; and (b) rare diseases or conditions within the meaning of the Orphan Drug Act. Congress has only authorized the Rare Pediatric Disease Priority Review Voucher program until September 30, 2029. Consequently, unless Congress reauthorizes the program, the sponsor of the marketing application for a drug that receives Rare Pediatric Disease Designation will only be eligible to receive a voucher if the FDA grants the designation on or before September 30, 2029.

Post-Approval Requirements

Biologics are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing, annual program fees for any marketed products. Biologic manufacturers and their subcontractors are required to register their establishments with the FDA

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and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon us and our third-party manufacturers. Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting requirements upon us and any third-party manufacturers that we may decide to use. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical studies to assess new safety risks; or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

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restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;

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fines, warning letters, or untitled letters;

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clinical holds on clinical studies;

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refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product license approvals;

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product seizure or detention, or refusal to permit the import or export of products;

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consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs;

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mandated modification of promotional materials and labeling and the issuance of corrective information;

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the issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other safety information about the product; or

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injunctions or the imposition of civil or criminal penalties.

The FDA closely regulates the marketing, labeling, advertising and promotion of biologics. A company can make only those claims relating to safety and efficacy, purity and potency that are approved by the FDA and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses. Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties. Physicians may prescribe legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. Such off-label uses are common across medical specialties. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.

Biosimilars and Exclusivity

The Affordable Care Act, signed into law in 2010, includes a subtitle called the BPCIA, which created an abbreviated approval pathway for biological products that are biosimilar to or interchangeable with an FDA-licensed reference biological product. The FDA has issued several guidance documents outlining an approach to review and approval of biosimilars. Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity,

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and potency, can be shown through analytical studies, animal studies, and a clinical study(ies). Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA. In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed. During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product. The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products. At this juncture, it is unclear whether products deemed “interchangeable” by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law.

A biological product can also obtain pediatric market exclusivity in the United States. Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms. This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.

Other Healthcare Laws

Pharmaceutical companies are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business. Such laws include, without limitation, U.S. federal and state anti-kickback, fraud and abuse, false claims, pricing reporting, and transparency laws and regulations with respect to payments and other transfers of value made to physicians and other healthcare professionals, as well as similar foreign laws in the jurisdictions outside the U.S. Violation of any of such laws or any other governmental regulations that apply may result in significant penalties, including, without limitation, administrative civil and criminal penalties, damages, disgorgement fines, additional reporting requirements and oversight obligations, contractual damages, the curtailment or restructuring of operations, exclusion from participation in government healthcare programs, and imprisonment.

Data Privacy and Security Laws

Pharmaceutical companies may be subject to domestic and foreign privacy, security and data breach notification laws, which are rapidly evolving in many jurisdictions worldwide. In the United States, federal and state health information laws may govern the collection, use, disclosure and protection of health-related and other personal information. In addition, certain foreign laws govern the privacy and security of personal data, including health-related data. Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts, and can result in investigations, proceedings, or actions that lead to significant civil and/or criminal penalties and restrictions on data processing.

Coverage and Reimbursement

Sales of any pharmaceutical product depend, in part, on the extent to which such product will be reimbursed by third-party payors, such as federal, state and foreign government healthcare programs, commercial insurance and managed healthcare organizations, and the level of reimbursement for such product by third-party payors. Significant uncertainty exists as to the coverage and reimbursement status of any newly approved product, particularly for genetic medicine products where the Centers for Medicare & Medicaid Services (“CMS”) and other third-party payors in the United States have not yet established a

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uniform policy of coverage and reimbursement. Decisions regarding the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis. One third-party payor’s decision to cover a particular product does not ensure that other payors will also provide coverage for the product. As a result, the coverage determination process can require manufacturers to provide scientific and clinical support for the use of a product to each payor separately and can be a time-consuming process, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance. For products administered under the supervision of a physician, obtaining coverage and adequate reimbursement may be particularly difficult because of the higher prices often associated with such drugs. Additionally, separate reimbursement for the product itself or the treatment or procedure in which the product is used may be limited, which may impact physician utilization.

In addition, third-party payors are increasingly reducing reimbursements for pharmaceutical products and services. The U.S. government and state legislatures have continued implementing cost-containment programs, including price controls, restrictions on coverage and reimbursement and requirements for substitution of generic products. Third-party payors are increasingly challenging the prices charged, examining the medical necessity and reviewing the cost effectiveness of pharmaceutical products, in addition to questioning their safety and efficacy. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit sales of any product. Decreases in third-party reimbursement for any product or a decision by a third-party payor not to cover a product could reduce physician usage and patient demand for the product.

In international markets, reimbursement and healthcare payment systems vary significantly by country, and many countries have instituted price ceilings on specific products and therapies. For example, the European Union provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. A member state may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of us placing the medicinal product on the market. Pharmaceutical products may face competition from lower-priced products in foreign countries that have placed price controls on pharmaceutical products and may also compete with imported foreign products. Furthermore, there is no assurance that a product will be considered medically reasonable and necessary for a specific indication, will be considered cost-effective by third-party payors, that an adequate level of reimbursement will be established even if coverage is available, or that the third-party payors’ reimbursement policies will not adversely affect the ability for manufacturers to sell products profitably.

Healthcare Reform

In the United States and certain foreign jurisdictions, there have been, and we expect there will continue to be, a number of legislative and regulatory changes to the healthcare system. In March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively the “ACA”) was signed into law, which substantially changed the way healthcare is financed by both governmental and private insurers in the United States. The ACA contains a number of provisions, including those governing enrollment in federal healthcare programs, reimbursement adjustments and fraud and abuse changes. Additionally, the ACA increased the minimum level of Medicaid rebates payable by manufacturers of brand name drugs from 15.1% to 23.1%; required collection of rebates for drugs paid by Medicaid managed care organizations; imposed a non-deductible annual fee on pharmaceutical manufacturers or importers who sell certain “branded prescription drugs” to specified federal government programs, implemented a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted, or injected; expanded eligibility criteria for Medicaid programs; created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research; and established a Center for Medicare & Medicaid Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.

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Since its enactment, there have been judicial, executive and Congressional challenges to certain aspects of the ACA. On June 17, 2021, the U.S. Supreme Court dismissed the most recent judicial challenge to the ACA without specifically ruling on the constitutionality of the ACA.

Other legislative changes have been proposed and adopted since the ACA was enacted, including aggregate reductions of Medicare payments to providers, which will remain in effect through 2032, with the exception of a temporary suspension from May 1, 2020 through March 31, 2022, absent additional Congressional action. In addition, on March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminates the statutory cap on drug manufacturers’ Medicaid drug rebate program liability, beginning January 1, 2024. The rebate was previously capped at 100% of a drug’s average manufacturer price.

Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted legislation designed, among other things, to bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs and reform government program reimbursement methodologies for pharmaceutical products. On August 16, 2022, the Inflation Reduction Act of 2022, or IRA, was signed into law. Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare, with prices that can be negotiated subject to a cap; imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023); and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025). The IRA permits the Secretary of the Department of Health and Human Services (“HHS”) to implement many of these provisions through guidance, as opposed to regulation, for the initial years. CMS has published the negotiated prices for the initial ten drugs, which went into effect in January 2026, and the subsequent 15 drugs, which will first be effective in 2027, as well as the next set of 15 drugs that will be subject to price negotiations. HHS has issued and will continue to issue guidance implementing the IRA, although the Medicare drug price negotiation program is currently subject to legal challenges. While the impact of the IRA on the pharmaceutical industry cannot yet be fully determined, it is likely to be significant.

The One Big Beautiful Bill Act, which was enacted in July 2025, imposes significant reductions in the funding of the Medicaid program. Such reductions are expected to decrease the number of persons enrolled in Medicaid and reduce the services covered by Medicaid, which could adversely affect our sales of any product candidate that we commercialize.

The Trump administration is pursuing a two-fold strategy to reduce drug costs in the U.S. While it is unclear whether and how the Trump proposals will be implemented, the Trump policies are likely to have a negative impact on the pharmaceutical industry and on our ability to receive adequate revenues for any product candidate that we commercialize. On the one hand, President Trump has threatened to impose significant tariffs on pharmaceutical manufacturers that do not adopt pricing policies such as most favored nation pricing, which would tie the price for drugs in the U.S. to the lowest price in a group of other countries. In response, multiple manufacturers have reportedly entered into confidential pricing agreements with the federal government. On the other hand, the Trump administration is pursuing traditional regulatory pathways to impose drug pricing policies, and published two proposed regulations in December 2025, referred to as Globe and Guard. If finalized, these regulations would implement mandatory payment models under which manufacturers of eligible drugs would be required to pay rebates to the federal government on a portion of the units of their drugs that are reimbursed by Medicare, with the rebate amount based on most favored nation pricing. Imposing a rebate in the U.S. that is based on drug prices outside the U.S. would mark a drastic and unprecedented shift in the U.S. pharmaceutical market, and while the impact of the Globe and Guard proposed regulations, if finalized, cannot yet be determined, it is likely to be significant. Even regulatory proposals or executive actions that are ultimately deemed unlawful could negatively impact the U.S. pharmaceutical sector and our business.

Individual states in the United States have also become increasingly active in implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access, marketing cost disclosure, drug

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price reporting and other transparency measures. Some states have enacted legislation creating so-called prescription drug affordability boards, which ultimately may attempt to impose price limits on certain drugs in these states, and at least one state board is imposing an upper payment limit. Some states are also seeking to implement general, across the board price caps for pharmaceuticals, or are seeking to regulate drug distribution. Some measures are designed to encourage importation from other countries. These types of initiatives may result in additional reductions in Medicare, Medicaid, and other healthcare funding, and may otherwise affect the prices we may obtain for our investigational products that receive approval. Furthermore, there has been increased interest by third-party payors and governmental authorities in reference pricing systems and publication of discounts and list prices. Adoption of other new legislation or regulation at the federal, state, or foreign level could further limit reimbursement for pharmaceuticals, including our product candidates, if approved.

Employees and Human Capital

As of March 6, 2026, we had 196 full-time employees. Of these employees, 144 are engaged in research and development and 39 hold M.D. or Ph.D. degrees. Our employees are not represented by labor unions or covered by collective bargaining agreements. We consider our relationship with our employees to be good.

Our human resources objectives include, as applicable, identifying, recruiting, developing, managing, retaining, incentivizing and integrating our employees. The principal purposes of our equity incentive plans are to attract, retain and motivate selected employees, consultants, and directors through the granting of stock-based compensation awards and cash-based performance bonus awards.

Facilities

We lease approximately 91,000 square feet of office, research and development, engineering, laboratory and warehouse space in Emeryville, California under lease agreements that expire between August 2026 and December 2030. We believe that our facilities are adequate to meet our current needs, and that suitable additional alternative spaces will be available in the future on commercially reasonable terms, if required.

Corporate Information

We were formed on September 12, 2013 as a Delaware limited liability company under the name 4D Molecular Therapeutics, LLC. On March 11, 2015, 4D Molecular Therapeutics, Inc. was incorporated as a Delaware corporation. On March 20, 2015, 4D Molecular Therapeutics, LLC merged with 4D Molecular Therapeutics, Inc., with 4D Molecular Therapeutics, Inc. being the surviving entity. Our principal executive offices are located at 5858 Horton Street #455, Emeryville, California 94608, and our telephone number is (510) 505-2680.

Available Information

Our website address is www.4dmoleculartherapeutics.com. The information on, or that can be accessed through, our website is not part of this Annual Report on Form 10-K. The U.S. Securities and Exchange Commission (“SEC”) maintains an internet site that contains reports, proxy and information statements, and other information regarding issuers that file electronically with the SEC at www.sec.gov. Our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934, as amended, (the “Exchange Act”) are also available free of charge on our investor relations website as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC.