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What changed in 4D Molecular Therapeutics, Inc.'s 10-K — 2024 vs 2025

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Paragraph-level year-over-year comparison of 4D Molecular Therapeutics, Inc.'s 2024 and 2025 10-K annual filings, covering the Business, Risk Factors, Legal Proceedings, Cybersecurity, MD&A and Market Risk sections. Every new, removed and edited paragraph is highlighted side-by-side so you can see exactly what management changed in the 2025 report.

+531 added−488 removedSource: 10-K (2026-03-18) vs 10-K (2025-02-28)

Top changes in 4D Molecular Therapeutics, Inc.'s 2025 10-K

531 paragraphs added · 488 removed · 390 edited across 6 sections

Item 1. Business

Business — how the company describes what it does

129 edited+47 added−39 removed147 unchanged
Biggest changeThe presentation focused on safety, tolerability, delivery and expression of the 4D-710 CFTR∆R transgene in lung tissue samples, and clinical activity for 10 patients enrolled across four dose cohorts: • 2E15 vg Cohort: n=4 • 1E15 vg Cohort: n=3 • 5E14 vg Cohort: n=2 • 2.5E14 vg Cohort: n=1 The interim results, with best available data from May 2024, included: • Safety Data o High Dose – 2E15 vg (n=4): o One reported serious adverse event (SAE) (pneumonitis not otherwise specified); ppFEV1 in this participant improved by 6% from baseline to month 12 (last timepoint assessed) o Lung biopsy results: ▪ No evidence of inflammation or toxicity from histological analysis of tissue samples ▪ Widespread expression of CFTR protein compared to normal (non-CF) lung samples and no increase vs. 1E15 vg dose ▪ Evidence of consistent CFTR protein expression in all major airway epithelial cell types, as well as in interstitial tissue cells; interstitial CFTR expression was not detected in normal lung control samples o Based on all available data for 2E15 and 1E15 vg dose level participants, 2E15 vg dose will not be further evaluated • Lower Doses – 2.5E14 to 1E15 vg (n=6): o 4D-710 was well tolerated, with no 4D-710–related adverse events after administration, no dose-limiting toxicities, and no SAEs • CFTR Biomarker Data o Biomarker analyses demonstrated robust, consistent and widespread CFTRΔR transgene mRNA and CFTR protein expression throughout all lung biopsy samples from all participants at all four dose levels o Dose-dependent CFTR∆R transgene RNA expression, with the mean % of airway epithelial cells testing positive ranging from 14% to 53% o Robust, widespread and above-normal CFTR protein expression at all doses 10 o Protein levels in lung tissue from 4D-710–treated participants 2–4 fold higher than in normal (non-CF) samples, and ~8-12 fold higher than in CF lung samples o Protein expression observed in multiple airway epithelial cell types, including basal cells o Pre-existing AAV immunity that cross-reacted with A101 did not affect transgene expression, biological activity or safety; transgene expression levels, clinical activity and safety were similar regardless of pre-existing immunity • Interim Clinical Activity Data o All participants in 2E15 vg and 1E15 vg Cohorts had at least 12 months of follow up (maximum duration of ppFEV1 assessments per original protocol) and had generally stable or improved in ppFEV1 at 12 months o Two of three participants with baseline mild to moderate lung function impairment (ppFEV1 40-80%) showed clinically meaningful improvement in ppFEV1 at 12 months: ▪ 2E15 vg Cohort: +6% ▪ 1E15 vg Cohort: +5% o Quality of Life ("CFQ-R-R") scores in 1E15 vg Cohort showed durable and clinically meaningful mean improvement throughout 12 months 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.
Biggest changeThe interim results, with best available data through December 1, 2025, included: • Safety Data o 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 o 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 • Biopsy Data o 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 ▪ In 2.5E14 vg dose cohort, results met target expression profile o 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 9 • In 2.5E14 vg dose cohort, consistent evidence of clinically meaningful activity detected in all endpoints, including ppFEV 1 , LCI 2.5 and quality of life (CFQ-R-R) through 1 year • 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.
We expect that United States and European patents, if issued from applications in our in-licensed portfolio would expire 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.
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, and expire September 2036 for our in-licensed University of Pennsylvania patent portfolio, if the appropriate maintenance, renewal, annuity, and other government fees are paid.
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.
The process required by the FDA before biologic product candidates may be marketed in the United States generally involves the following: • completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s GLPs; • submission to the FDA of an IND, which must become effective before clinical trials may begin; • approval by an Institutional Review Board ("IRB") or ethics committee at each clinical site before the trial is commenced; • 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; • preparation of and submission to the FDA of a BLA after completion of all pivotal clinical trials; • satisfactory completion of an FDA Advisory Committee review, if applicable; • a determination by the FDA within 60 days of its receipt of a BLA to file the application for review; • 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 17 • FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the United States.
The process required by the FDA before biologic product candidates may be marketed in the United States generally involves the following: • completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s GLPs; • submission to the FDA of an IND, which must become effective before clinical trials may begin; • approval by an Institutional Review Board ("IRB") or ethics committee at each clinical site before the trial is commenced; • 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; • preparation of and submission to the FDA of a BLA after completion of all pivotal clinical trials; • satisfactory completion of an FDA Advisory Committee review, if applicable; • a determination by the FDA within 60 days of its receipt of a BLA to file the application for review; • 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 • FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the United States.
Other potential consequences include, among other things: • restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls; • fines, warning letters, or untitled letters; • clinical holds on clinical studies; 23 • refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product license approvals; • product seizure or detention, or refusal to permit the import or export of products; • consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs; • mandated modification of promotional materials and labeling and the issuance of corrective information; • the issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other safety information about the product; or • injunctions or the imposition of civil or criminal penalties.
Other potential consequences include, among other things: • restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls; • fines, warning letters, or untitled letters; • clinical holds on clinical studies; • refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product license approvals; • product seizure or detention, or refusal to permit the import or export of products; • consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs; • mandated modification of promotional materials and labeling and the issuance of corrective information; • the issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other safety information about the product; or • injunctions or the imposition of civil or criminal penalties.
The RMAT designation program is intended to fulfill the 21st Century Cures Act requirement that the FDA facilitate an efficient development program for, 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.
The RMAT designation program is intended to fulfill the 21st Century Cures Act requirement that the FDA facilitate an efficient development program for, 20 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.
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. • 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 18 schedule and to identify possible adverse side effects and safety risks.
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. • 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.
In order to perform characterization studies, vectors are armed with marker transgene payloads 12 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.
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.
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 21 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.
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.
The upstream manufacturing step involves triple plasmid transfections in an adherent HEK293 mammalian production cell line. Downstream manufacturing steps for purification and concentration include multiple orthogonal column chromatography steps and tangential flow filtration. The downstream purification columns used in our process are from stable sources. Using internally developed manufacturing processes and testing, we characterize our novel capsids and payloads.
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.
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 24 on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.
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.
Decreases in third-party reimbursement for any product or a decision 25 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.
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.
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 the company’s 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.
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.
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 do mouse eyes.
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.
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 patients whose disease is not amenable to standard medical therapy. 4.
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. 4.
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 uniform policy of coverage and reimbursement.
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 24 uniform policy of coverage and reimbursement.
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 with specific prescribing information for specific indications.
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 19 with specific prescribing information for specific indications.
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 the Company’s common stock.
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.
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 massively diverse library of biological variants.
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.
We have obtained orphan drug designation for 4D-710 for the treatment of cystic fibrosis. 22 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.
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.
A deferral may be granted for several reasons, including a 19 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.
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.
Biologic manufacturers and their subcontractors are required to register their establishments with the FDA 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.
Biologic manufacturers and their subcontractors are required to register their establishments with the FDA 22 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.
Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical study(ies).
Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, 23 and potency, can be shown through analytical studies, animal studies, and a clinical study(ies).
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. 28
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. 27
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 purity of the final product.
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 18 purity of the final product.
The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources. U.S.
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. 16 U.S.
Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap; imposes rebates under Medicare Part B and Medicare Part D to penalize price 26 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).
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).
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 corporation under the name 4D Molecular Therapeutics, LLC.
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.
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 March 2043, if the appropriate maintenance, renewal, annuity, and other government fees are paid.
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.
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 study is safety and 9 tolerability.
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.
The current treatment paradigm for both wet AMD and DME requires frequent intravitreal bolus injections of patients with anti-VEGF proteins 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.
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.
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. 13 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.
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. 12 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.
In addition, on March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminates the statutory Medicaid drug rebate cap, beginning January 1, 2024. The rebate was previously capped at 100% of a drug’s average manufacturer price.
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.
The intended result is to achieve CFTR expression within lung epithelial cells for correction of cystic fibrosis 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.
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 .
As of February 14 2025, our in-licensed University of Pennsylvania patent portfolio includes two granted U.S. patents and six granted foreign patents; each of these patents is expected to expire September 2036, 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.
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 or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.
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.
Our in-licensed University of Pennsylvania patent portfolio also includes one pending U.S. non-provisional patent application and eleven pending foreign patent applications.
Our in-licensed University of Pennsylvania patent portfolio also includes one pending U.S. non-provisional patent application and seven pending foreign patent applications.
Our team has internally manufactured over 290 unique AAV vectors, including both proprietary evolved 4DMT capsid variants and naturally occurring capsids. Our team has manufactured over 400 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.
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.
Berkeley patent portfolio, relating to our vector, A101, and other AAV-based technologies, includes four granted U.S. patents and nine 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, 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.
We expect that United States and European patents, if issued from pending applications in our solely owned portfolio, would expire between May 2037 and March 2043, excluding any additional term from patent term adjustment or patent term extension if appropriate maintenance and other governmental fees are paid.
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.
We then deploy Therapeutic Vector Evolution with our capsid libraries in NHPs and use competitive selection to identify targeted and evolved vectors from our libraries that demonstrate the strongest match to the Target Vector Profile.
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.
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.
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. 25 Since its enactment, there have been judicial, executive and Congressional challenges to certain aspects of the ACA.
In 2019, the FDA approved triple drug therapy with Trikafta (elexacaftor/ivacaftor/tezacaftor), which Vertex believes would be applicable for up to 90% of people with cystic fibrosis, leaving at least 10% with no CFTR-targeted options.
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.
Currently marketed products include Eylea (aflibercept) from Regeneron, which is the current wet AMD 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.
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.
This decision is based on the data generated to date 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.
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.
We expect to explore single agent therapy with 4D-710 initially in patients whose disease is not amenable to CFTR modulators (estimated to include approximately 15% of people with cystic fibrosis who have null mutations 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 cystic fibrosis.
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.
As of February 2024, 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. For example, Dr.
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.
Per FDA feedback, the Company may proceed to Phase 3 (SPECTRA Part 2 no longer needed) and is 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).
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).
We believe there is a clinical need and market opportunity for a durable aerosolized therapy, delivered by breath-actuated nebulizer, that can restore normal CFTR function across all cystic fibrosis patient subgroups, including patients who are receiving combination CFTR-modulator therapies and/or do not have appreciable CFTR protein expression and are therefore not amenable to CFTR modulators.
We 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.
While these therapies improve lung function, they fall short of restoring it to the normal range in most patients, and these chronic therapies require daily dosing for the patient’s lifetime. In addition, the existing cystic fibrosis drugs have been associated with tolerability issues, thus limiting their use in some patients.
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.
There is no cure for cystic fibrosis, and the median age of death for patients is approximately 40 years in developed countries. Cystic fibrosis is considered a rare, or orphan, disease by both the FDA and the EMA.
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.
Berkeley patent portfolio also includes two pending U.S. non-provisional patent applications and twelve pending foreign patent applications. We expect that United States and European patents, if issued from applications in 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.
Our Product Candidate Pipeline & Strategy We have developed a broad pipeline of product candidates in two therapeutic areas, large market ophthalmology and pulmonology, focusing on disease areas of high unmet need and commercial potential.
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.
In addition, we have developed significant experience in performing Therapeutic Vector Evolution programs 11 in NHPs. We have patent applications and issued patents covering hundreds of proprietary, unique AAV capsid vectors.
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.
As of February 14, 2025, our in-licensed U.C.
As of February 14, 2026, our in-licensed U.C.
We believe that this modular product approach, utilizing A101 for multiple product candidates by switching the therapeutic transgene insert, will increase product development efficiencies, decrease development risks and help inform the clinical development of subsequent product candidates using the same vector. Our first pulmonology product candidate is 4D-710 for cystic fibrosis lung disease.
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 consider our most direct competitors with respect to 4D-710 for the treatment of cystic fibrosis lung disease to be Vertex, which has several approved CFTR modulators, as well as other companies in preclinical/early-clinical development of cystic fibrosis products, including Vertex, Sionna, Krystal, Spirovant, Arcturus, and ReCode.
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 Team Our team of approximately 50 highly trained individuals is led by our President and Chief Operating Officer, Dr. Fred Kamal, and includes 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.
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.
Our solely owned patent portfolio also 14 includes thirteen pending U.S. non-provisional applications and one hundred and twenty-nine pending foreign applications.
Our solely owned patent portfolio also includes sixteen pending U.S. non-provisional applications and one hundred and sixty-nine pending foreign applications.
If a product that has orphan drug designation subsequently receives the first FDA approval for a particular active ingredient for the disease 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 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 of patients with the disease or condition for which the drug was designated.
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. 21 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.
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 and marketing cost disclosure and transparency measures and, in some cases, mechanisms to encourage importation from other countries and bulk purchasing.
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 26 price reporting and other transparency measures.
As of the most recent data cutoff date (December 13, 2024), 21 patients were evaluable: • Safety (n=21) : o 4D-150 was well tolerated with no intraocular inflammation at any timepoint o All patients completed the 16-week topical corticosteroid taper on schedule and remained completely off steroids o No hypotony, endophthalmitis, vasculitis, choroidal effusions or retinal artery occlusions • Efficacy Results Through 32 Weeks (3E10 vg/eye arm): o Sustained gain of BCVA of +8.4 letters 6 o Sustained reduction of CST, as measured by OCT, of -194 µm o Supplemental injections : ▪ Post-aflibercept loading doses (3), 3E10 vg/eye achieved substantially fewer supplemental injections compared to 1E10 vg/eye and projected on-label aflibercept 2mg Q8W: ▪ Mean injections per patient: • 3E10 vg/eye: 0.6, 1E10 vg/eye: 1.4, projected on-label aflibercept 2mg Q8W: 4.0 • 3E10 vg/eye demonstrated a reduction of 61% vs. 1E10 vg/eye • 3E10 vg/eye demonstrated a reduction of 86% vs. projected on-label aflibercept 2mg Q8W ▪ 0-1 injections: • 8 of 9 overall (3E10 vg/eye) vs. 5 of 10 (1E10 vg/eye, 1 patient missed Week 24-32 visits) ▪ Injection-free: • 5 of 9 overall (3E10 vg/eye) vs. 2 of 10 overall (1E10 vg/eye) 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 BLA submission for 4D-150 in DME.
As of the most recent data cutoff date (May 2, 2025): • Safety (n=22): o 4D-150 was well tolerated with no intraocular inflammation at any timepoint o All patients completed the 16-week topical corticosteroid taper on schedule and remained completely off steroids o No hypotony, endophthalmitis, vasculitis, choroidal effusions or retinal artery occlusions • Efficacy Results Through 60 Weeks: o Phase 3 Dose (N=9): ▪ Sustained gain of BCVA of +9.7 letters ▪ Sustained reduction of CST, as measured by OCT, of -174 µm o Supplemental injections : ▪ 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): • Mean injections per patient: o Phase 3 dose: 1.6 o Lower doses: 3.7 o Projected on-label aflibercept 2mg Q8W: 7.0 o Dose response observed for Phase 3 dose vs. lower doses (58% fewer injections) o Phase 3 dose demonstrated a reduction of 78% vs. projected on-label aflibercept 2mg Q8W • 0-1 injections: o 5 of 9 overall (Phase 3 dose) vs. 2 of 11 (lower doses) • Injection-free: o 4 of 9 overall (Phase 3 dose) vs. 1 of 11 overall (lower doses) 6 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.
We therefore expect to eventually develop 4D-710 in this patient population, as a single agent and/or in combination with these CFTR modulator small molecule medicines. 4DMT Differentiation: AAV Genetic Medicines for Cystic Fibrosis Lung Disease A number of biotechnology companies have pursued genetic medicine solutions to treat cystic fibrosis.
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.
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).
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).
More recently, a new class of drugs called modulators target CFTR for patients with certain gene mutations. Several therapies from Vertex Pharmaceuticals Inc. have been approved for marketing in the United States and the European Union based on their ability to improve lung function in genetically defined subsets of cystic fibrosis patients.
Accordingly, antibiotics are frequently used along with mucus-thinning drugs. 7 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.
Until recently, approved therapies to treat people with cystic fibrosis were only designed to treat the manifestations of cystic fibrosis, for example by preventing and controlling infections that occur in the lungs, rather than addressing the underlying cause of the disease. Accordingly, antibiotics are frequently used along with mucus-thinning drugs.
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.
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.
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.
These patents and patent applications (if applicable), depending on the national laws, may benefit from extension of patent term in individual countries if regulatory approval of any of our product or lead optimization candidates is obtained in those countries. For example, in Japan, the term of a patent may be extended by a maximum of five years in certain circumstances.
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 14 product or lead optimization candidates is obtained in those countries.
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.
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.
Our second pulmonology product candidate is 4D-725 for alpha-1 antitrypsin deficiency lung disease; 4D-725 is currently in preclinical development. 7 4D-710 for Cystic Fibrosis Lung Disease Disease Background, Unmet Medical Need, and Target Patient Population Cystic fibrosis is the most common fatal inherited disease in the United States and results from mutations in the cystic fibrosis transmembrane conductance regulator (“CFTR”) gene.
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.
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).
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. 10 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).
In August 2023, the Company 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 16 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.
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.
Interim Data from Part 1 of 4D-150 SPECTRA Clinical Trial in Wet AMD In January 2025, we announced positive 32-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.
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.
After September 30, 2026, FDA may not award any Rare Pediatric Disease Priority Review Voucher. 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.
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.
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.
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.
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.
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.
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.
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).
Clinical Development of 4D-150 in Wet AMD: PRISM Phase 1/2 Clinical Trial and 4FRONT Phase 3 Program 4D-150 is currently being evaluated in an on-going PRISM Phase 1/2 clinical trial in wet AMD.
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).
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.
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. 8 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.
In particular, our patent strategy includes the filing of patent applications covering unique gene sequences selected through our Therapeutic Vector Evolution 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 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.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeAmong the provisions of the ACA, those of greatest importance to the pharmaceutical and biotechnology industries include the following: 57 • an annual, non-deductible fee payable by any entity that manufactures or imports certain branded prescription drugs and biologic agents (other than those designated as orphan drugs), which is apportioned among these entities according to their market share in certain government healthcare programs; • new requirements to report certain financial arrangements with physicians and teaching hospitals, including reporting “transfers of value” made or distributed to prescribers and other healthcare providers and reporting investment interests held by physicians and their immediate family members; • an increase to the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and an extension the rebate program to individuals enrolled in Medicaid managed care organizations; • 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; • expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability; • a licensure framework for follow-on biologic products; • 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 • establishment of a Center for Medicare & Medicaid Innovation (“CMMI”) at the Centers for Medicare & Medicaid Services (“CMS”) to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.
Biggest changeAmong the provisions of the ACA of importance to our business, including, without limitation, our ability to commercialize and to obtain adequate prices for any product candidates approved for sale, are the following: • an annual, non-deductible fee payable by any entity that manufactures or imports certain branded prescription drugs and biologic agents (other than those designated as orphan drugs), which is apportioned among these entities according to their market share in certain government healthcare programs; • expansion of manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic drugs, revising the “average manufacturer price” definition, and extending rebate liability from fee-for-service Medicaid utilization to include the utilization of Medicaid managed care organizations as well; and • establishment of a Center for Medicare & Medicaid Innovation (“CMMI”) at the Centers for Medicare & Medicaid Services (“CMS”) to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.
The IBC assesses the safety of the research and identifies any potential risk to the public health or the environment, and such review may result in some delay before initiation of a clinical trial.
The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such review may result in some delay before initiation of a clinical trial.
The role of the CAT is to prepare a draft opinion on an application for marketing authorization for ATMP candidate that is submitted to the EMA. In the EU, the development and evaluation of an ATMP must be considered in the context of the relevant EU guidelines.
The role of the CAT is to prepare a draft opinion on an application for marketing authorization for an ATMP candidate that is submitted to the EMA. In the EU, the development and evaluation of an ATMP must be considered in the context of the relevant EU guidelines.
We may encounter substantial delays in our clinical trials or may not be able to conduct or complete our clinical trials on the timelines we expect, if at all. Clinical testing is expensive, time consuming, and subject to uncertainty. We cannot guarantee that any clinical trials will be initiated or conducted as planned or completed on schedule, if at all.
We may encounter substantial delays in our clinical trials or may not be able to conduct or complete our clinical trials on the timelines we expect, if at all. Clinical testing is expensive, time consuming, and subject to uncertainty. We cannot guarantee that any clinical trials will be initiated, conducted as planned or completed on schedule, if at all.
If we experience any delays in completing these trials, due to delays in enrollment or other factors, it could result in serious harm our business.
If we experience any delays in completing these trials, due to delays in enrollment or other factors, it could result in serious harm to our business.
Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States, or from selling or importing products made using our inventions in and into the United States or other jurisdictions.
Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States, or from selling or importing products made using our inventions in and into the United States or other jurisdictions.
Patent and Trademark Office (“USPTO”) and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other provisions during the patent process, the noncompliance with which can result in abandonment or lapse of a patent or patent application, and partial or complete loss of patent rights in the relevant jurisdiction; • patent applications may not result in any patents being issued; • patents that may be issued or in-licensed may be challenged, invalidated, modified, revoked, circumvented, found to be unenforceable or otherwise may not provide any competitive advantage; • our competitors, many of whom have substantially greater resources than we do and many of whom have made significant investments in competing technologies, may seek or may have already obtained patents that will limit, interfere with or eliminate our ability to make, use and sell our potential product candidates; • other parties may have designed around our claims or developed technologies that may be related or competitive to our platform, may have filed or may file patent applications and may have received or may receive patents that overlap or conflict with our patent applications, either by claiming the same methods or devices or by claiming subject matter that could dominate our patent position; • any successful opposition to any patents owned by or licensed to us could deprive us of rights necessary for the practice of our technologies or the successful commercialization of any products or product candidates that we may develop; • because patent applications in the United States and most other countries are confidential for a period of time after filing, we cannot be certain that we or our licensors were the first to file any patent application related to our product candidates, proprietary technologies and their uses; • an interference proceeding can be provoked by a third party or instituted by the USPTO to determine who was the first to invent any of the subject matter covered by the patent claims of our licensors’ patent applications for any patent application with an effective filing date before March 16, 2013; • there may be significant pressure on the U.S. government and international governmental bodies to limit the scope of patent protection both inside and outside the United States for 67 disease treatments that prove successful, as a matter of public policy regarding worldwide health concerns; and • countries other than the United States may have patent laws less favorable to patentees than those upheld by U.S. courts, allowing foreign competitors a better opportunity to create, develop and market competing product candidates.
Patent and Trademark Office (“USPTO”) and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other provisions during the patent process, the noncompliance with which can result in abandonment or lapse of a patent or patent application, and partial or complete loss of patent rights in the relevant jurisdiction; • patent applications may not result in any patents being issued; • patents that may be issued or in-licensed may be challenged, invalidated, modified, revoked, circumvented, found to be unenforceable or otherwise may not provide any competitive advantage; • our competitors, many of whom have substantially greater resources than we do and many of whom have made significant investments in competing technologies, may seek or may have already obtained patents that will limit, interfere with or eliminate our ability to make, use and sell our potential product candidates; • other parties may have designed around our claims or developed technologies that may be related or competitive to our platform, may have filed or may file patent applications and may have received or may receive patents that overlap or conflict with our patent applications, either by claiming the same methods or devices or by claiming subject matter that could dominate our patent position; • any successful opposition to any patents owned by or licensed to us could deprive us of rights necessary for the practice of our technologies or the successful commercialization of any products or product candidates that we may develop; • because patent applications in the United States and most other countries are confidential for a period of time after filing, we cannot be certain that we or our licensors were the first to file any patent application related to our product candidates, proprietary technologies and their uses; • an interference proceeding can be provoked by a third party or instituted by the USPTO to determine who was the first to invent any of the subject matter covered by the patent claims of our licensors’ patent applications for any patent application with an effective filing date before March 16, 2013; • there may be significant pressure on the U.S. government and international governmental bodies to limit the scope of patent protection both inside and outside the United States for disease treatments that prove successful, as a matter of public policy regarding worldwide health concerns; and • countries other than the United States may have patent laws less favorable to patentees than those upheld by U.S. courts, allowing foreign competitors a better opportunity to create, develop and market competing product candidates.
Physician Payments Sunshine Act and its implementing regulations, which requires certain manufacturers of drugs, devices, biologics and medical supplies that are reimbursable under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to CMS information related to certain payments and other transfers of value to physicians (as defined by statute), certain other non-physician practitioners (including physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, anesthesiology assistants, and certified nurse midwives) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members; • analogous U.S. state laws and regulations, including: state anti-kickback and false claims laws, which may apply to our business practices, including but not limited to, research, distribution, sales and marketing arrangements and claims involving healthcare items or services reimbursed by any third-party payor, including private insurers; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the U.S. federal government, or otherwise restrict payments that may be made to healthcare providers and other potential referral sources; state laws and regulations that require drug manufacturers to file reports relating to pricing and marketing information, which requires tracking gifts and other remuneration and items of value provided to healthcare professionals and entities; and state and local laws requiring the registration of pharmaceutical sales representatives; and • similar healthcare laws in the EU and other jurisdictions, including reporting requirements detailing interactions with and payments to healthcare providers.
Physician Payments Sunshine Act and its implementing regulations, which require certain manufacturers of drugs, devices, biologics and medical supplies that are reimbursable under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to CMS information related to certain payments and other transfers of value to physicians (as defined by statute), certain other non-physician practitioners (including physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, anesthesiology assistants, and certified nurse midwives) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members; • analogous U.S. state laws and regulations, including: state anti-kickback and false claims laws, which may apply to our business practices, including but not limited to, research, distribution, sales and marketing arrangements and claims involving healthcare items or services reimbursed by any third-party payor, including private insurers; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the U.S. federal government, 60 or otherwise restrict payments that may be made to healthcare providers and other potential referral sources; state laws and regulations that require drug manufacturers to file reports relating to pricing and marketing information, which requires tracking gifts and other remuneration and items of value provided to healthcare professionals and entities; and state and local laws requiring the registration of pharmaceutical sales representatives; and • similar healthcare laws in the EU and other jurisdictions, including reporting requirements detailing interactions with and payments to healthcare providers.
These fluctuations may occur due to a variety of factors, many of which are outside of our control and may be difficult to predict, including: • the timing and success or failure of preclinical studies and clinical trials for our product candidates or competing product candidates, or any other change in the competitive landscape of our industry, including consolidation among our competitors or collaboration partners; • the timing and cost of, and level of investment in research, development and commercialization activities, which may change from time to time; • the timing of receipt of approvals from regulatory authorities in the United States and internationally; • the timing and status of enrollment and safety and efficacy readouts for our clinical trials; • the cost of manufacturing, as well as building out our supply chain, which may vary depending on the quantity of production, the cost of continuing to establish and scale up our internal manufacturing capabilities, and the terms of any agreements we enter into with third-party suppliers; • timing and amount of any option, milestone, royalty or other payments due under any current or future collaboration or license agreement; • coverage and reimbursement policies with respect to our genetic medicine product candidates and potential future drugs that compete with our products, if approved; • expenditures that we may incur to acquire, develop or commercialize additional products and technologies; • the level of demand for our genetic medicine products, if approved, which may vary significantly over time; • future accounting pronouncements or changes in our accounting policies; and • the impact from general macroeconomic trends, such as higher inflation, tariffs and increased interest rates.
These fluctuations may occur due to a variety of factors, many of which are outside our control and may be difficult to predict, including: • the timing and success or failure of preclinical studies and clinical trials for our product candidates or competing product candidates, or any other change in the competitive landscape of our industry, including consolidation among our competitors or collaboration partners; • the timing, cost, and level of investment in research, development and commercialization activities, which may change from time to time; • the timing of receipt of approvals from regulatory authorities in the United States and internationally; • the timing and status of enrollment and safety and efficacy readouts for our clinical trials; • the cost of manufacturing, as well as building out our supply chain, which may vary depending on the quantity of production, the cost of continuing to establish and scale up our manufacturing capabilities, and the terms of any agreements we enter into with third-party suppliers; • the timing and amount of any option, milestone, royalty or other payments due under any current or future collaboration or license agreement; • coverage and reimbursement policies with respect to our genetic medicine product candidates and potential future drugs that compete with our products, if approved; • expenditures that we may incur to acquire, develop or commercialize additional products and technologies; • the level of demand for our genetic medicine products, if approved, which may vary significantly over time; • future accounting pronouncements or changes in our accounting policies; and • the impact from general macroeconomic trends, such as higher inflation, tariffs and increased interest rates.
The degree of market acceptance of any product candidates we may develop, if approved for commercial sale, will depend on a number of factors, including: • the efficacy and safety of such product candidates as demonstrated in pivotal clinical trials and published in peer-reviewed journals; • the potential and perceived advantages compared to alternative treatments; • the ability to offer our products for sale at competitive prices; • the ability to offer appropriate patient access programs, such as co-pay assistance; • sufficient third-party coverage or reimbursement; • the extent to which physicians recommend our products to their patients; • convenience and ease of dosing and administration compared to alternative treatments; • the clinical indications for which the product candidate is approved by FDA, EMA or other regulatory agencies; • product labeling or product insert requirements of the FDA, EMA or other comparable foreign regulatory authorities, including any limitations, contraindications or warnings contained in a product’s approved labeling; • restrictions on how the product is distributed; • the timing of market introduction of competitive products; • publicity concerning our products or competing products and treatments; • the strength of marketing and distribution support; and 47 • the prevalence and severity of any side effects.
The degree of market acceptance of any product candidates we may develop, if approved for commercial sale, will depend on a number of factors, including: • the efficacy and safety of such product candidates as demonstrated in pivotal clinical trials and published in peer-reviewed journals; • the potential and perceived advantages compared to alternative treatments; • the ability to offer our products for sale at competitive prices; • the ability to offer appropriate patient access programs, such as co-pay assistance; • sufficient third-party coverage or reimbursement; • the extent to which physicians recommend our products to their patients; • convenience and ease of dosing and administration compared to alternative treatments; • the clinical indications for which the product candidate is approved by FDA, EMA or other regulatory agencies; • product labeling or product insert requirements of the FDA, EMA or other comparable foreign regulatory authorities, including any limitations, contraindications or warnings contained in a product’s approved labeling; • restrictions on how the product is distributed; • the timing of market introduction of competitive products; • publicity concerning our products or competing products and treatments; • the strength of marketing and distribution support; and • the prevalence and severity of any side effects.
Factors that may inhibit our efforts to commercialize any approved product on our own include: • our inability to recruit and retain adequate numbers of effective sales, marketing, reimbursement, compliance, customer service, medical affairs and other support personnel; • our inability to recruit and build a commercial infrastructure; • the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe any future approved products; • the inability of reimbursement professionals to negotiate arrangements for formulary access, reimbursement, and other acceptance by payors; 46 • the inability to price our products at a sufficient price point to ensure an adequate and attractive level of profitability; • restricted or closed distribution channels that make it difficult to distribute our products to segments of the patient population; • the lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and • unforeseen costs and expenses associated with creating an independent commercialization organization.
Factors that may inhibit our efforts to commercialize any approved product on our own include: • our inability to recruit and retain adequate numbers of effective sales, marketing, reimbursement, compliance, customer service, medical affairs and other support personnel; • our inability to recruit and build a commercial infrastructure; • the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe any future approved products; • the inability of reimbursement professionals to negotiate arrangements for formulary access, reimbursement, and other acceptance by payors; • the inability to price our products at a sufficient price point to ensure an adequate and attractive level of profitability; • restricted or closed distribution channels that make it difficult to distribute our products to segments of the patient population; • the lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and • unforeseen costs and expenses associated with creating an independent commercialization organization.
Collaborations are subject to numerous risks, which may include that: • collaborators have significant discretion in determining the efforts and resources that they will apply to collaborations; • collaborators may not pursue development and commercialization of our product candidates or may elect not to continue or renew development or commercialization programs based on trial or test results, changes in their strategic focus due to the acquisition of competitive products, availability of funding or other external factors, such as a business combination that diverts resources or creates competing priorities; • collaborators could independently develop, or develop with third parties, products and product candidates that compete directly or indirectly with our product candidates; • a collaborator with marketing, manufacturing and distribution rights to one or more products and product candidates may not commit sufficient resources to or otherwise not perform satisfactorily in carrying out these activities; • we could grant exclusive rights to our collaborators that would prevent us from collaborating with others; 75 • collaborators may not properly maintain or defend our intellectual property rights or may use our intellectual property or proprietary information in a way that gives rise to actual or threatened litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential liability; • disputes may arise between us and a collaborator that causes the delay or termination of the research, development or commercialization of our current or future product candidates or that results in costly litigation or arbitration that diverts management attention and resources; • collaborations may be terminated, and, if terminated, may adversely affect the price of our common stock and may result in a need for additional capital to pursue further development or commercialization of the applicable current or future product candidates; • collaborators may own or co-own intellectual property covering our product candidates that results from our collaborating with them, and in such cases, we would not have the exclusive right to develop or commercialize such intellectual property; and • a collaborator’s sales and marketing activities or other operations may not be in compliance with applicable laws resulting in civil or criminal proceedings.
Collaborations are subject to numerous risks, which may include that: • collaborators have significant discretion in determining the efforts and resources that they will apply to collaborations; • collaborators may not pursue development and commercialization of our product candidates or may elect not to continue or renew development or commercialization programs based on trial or test results, changes in their strategic focus due to the acquisition of competitive products, 74 availability of funding or other external factors, such as a business combination that diverts resources or creates competing priorities; • collaborators could independently develop, or develop with third parties, products and product candidates that compete directly or indirectly with our product candidates; • a collaborator with marketing, manufacturing and distribution rights to one or more products and product candidates may not commit sufficient resources to or otherwise not perform satisfactorily in carrying out these activities; • we could grant exclusive rights to our collaborators that would prevent us from collaborating with others; • collaborators may not properly maintain or defend our intellectual property rights or may use our intellectual property or proprietary information in a way that gives rise to actual or threatened litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential liability; • disputes may arise between us and a collaborator that causes the delay or termination of the research, development or commercialization of our current or future product candidates or that results in costly litigation or arbitration that diverts management attention and resources; • collaborations may be terminated, and, if terminated, may adversely affect the price of our common stock and may result in a need for additional capital to pursue further development or commercialization of the applicable current or future product candidates; • collaborators may own or co-own intellectual property covering our product candidates that results from our collaborating with them, and in such cases, we would not have the exclusive right to develop or commercialize such intellectual property; and • a collaborator’s sales and marketing activities or other operations may not be in compliance with applicable laws resulting in civil or criminal proceedings.
Collaborations involving our product candidates we may develop, pose the following risks to us: • collaborators generally have significant discretion in determining the efforts and resources that they will apply to these collaborations; • collaborators may not properly obtain, maintain, enforce or defend intellectual property or proprietary rights relating to our product candidates or may use our proprietary information in 64 such a way as to expose us to potential litigation or other intellectual property related proceedings, including proceedings challenging the scope, ownership, validity and enforceability of our intellectual property; • collaborators may own or co-own intellectual property covering our product candidates that result from our collaboration with them, and in such cases, we may not have the exclusive right to commercialize such intellectual property or such product candidates; • disputes may arise with respect to the ownership of intellectual property developed pursuant to collaborations; • we may need the cooperation of our collaborators to enforce or defend any intellectual property we contribute to or that arises out of our collaborations, which may not be provided to us; • collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability; • disputes may arise between the collaborators and us that result in the delay or termination of the research, development or commercialization of our product candidates or that result in costly litigation or arbitration that diverts management attention and resources; • collaborators may decide not to pursue development and commercialization of any product candidates we develop or may elect not to continue or renew development or commercialization programs based on clinical trial results, changes in the collaborator’s strategic focus or available funding or external factors such as an acquisition that diverts resources or creates competing priorities; • collaborators may delay clinical trials, provide insufficient funding for a clinical trial, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials, or require a new formulation of a product candidate for clinical testing; • collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours; • collaborators with marketing and distribution rights to one or more product candidates may not commit sufficient resources to the marketing and distribution of such product candidates; • we may lose certain valuable rights under circumstances identified in our collaborations, including if we undergo a change of control; • collaborators may undergo a change of control and the new owners may decide to take the collaboration in a direction which is not in our best interest; • collaborators may become party to a business combination transaction and the continued pursuit and emphasis on our development or commercialization program by the resulting entity under our existing collaboration could be delayed, diminished or terminated; • collaborators may become bankrupt, which may significantly delay our research or development programs, or may cause us to lose access to valuable technology, devices, materials, know-how or intellectual property of the collaborator relating to our products and product candidates; • key personnel at our collaborators may leave, which could negatively impact our ability to productively work with our collaborators; • collaborations may require us to incur short and long-term expenditures, issue securities that dilute our stockholders, or disrupt our management and business; 65 • collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development or commercialization of the applicable product candidates or our Therapeutic Vector Evolution platform technology; and • collaboration agreements may not lead to development or commercialization of product candidates in the most efficient manner or at all.
Collaborations involving our product candidates we may develop, pose the following risks to us: • collaborators generally have significant discretion in determining the efforts and resources that they will apply to these collaborations; • collaborators may not properly obtain, maintain, enforce or defend intellectual property or proprietary rights relating to our product candidates or may use our proprietary information in such a way as to expose us to potential litigation or other intellectual property related proceedings, including proceedings challenging the scope, ownership, validity and enforceability of our intellectual property; • collaborators may own or co-own intellectual property covering our product candidates that result from our collaboration with them, and in such cases, we may not have the exclusive right to commercialize such intellectual property or such product candidates; • disputes may arise with respect to the ownership of intellectual property developed pursuant to collaborations; • we may need the cooperation of our collaborators to enforce or defend any intellectual property we contribute to or that arises out of our collaborations, which may not be provided to us; • collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability; • disputes may arise between the collaborators and us that result in the delay or termination of the research, development or commercialization of our product candidates or that result in costly litigation or arbitration that diverts management attention and resources; • collaborators may decide not to pursue development and commercialization of any product candidates we develop or may elect not to continue or renew development or commercialization programs based on clinical trial results, changes in the collaborator’s strategic focus or available funding or external factors such as an acquisition that diverts resources or creates competing priorities; • collaborators may delay clinical trials, provide insufficient funding for a clinical trial, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials, or require a new formulation of a product candidate for clinical testing; • collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours; • collaborators with marketing and distribution rights to one or more product candidates may not commit sufficient resources to the marketing and distribution of such product candidates; • we may lose certain valuable rights under circumstances identified in our collaborations, including if we undergo a change of control; • collaborators may undergo a change of control and the new owners may decide to take the collaboration in a direction which is not in our best interest; • collaborators may become party to a business combination transaction and the continued pursuit and emphasis on our development or commercialization program by the resulting entity under our existing collaboration could be delayed, diminished or terminated; • collaborators may become bankrupt, which may significantly delay our research or development programs, or may cause us to lose access to valuable technology, devices, 63 materials, know-how or intellectual property of the collaborator relating to our products and product candidates; • key personnel at our collaborators may leave, which could negatively impact our ability to productively work with our collaborators; • collaborations may require us to incur short and long-term expenditures, issue securities that dilute our stockholders, or disrupt our management and business; • collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development or commercialization of the applicable product candidates or our Therapeutic Vector Evolution platform technology; and • collaboration agreements may not lead to development or commercialization of product candidates in the most efficient manner or at all.
A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation; • the U.S. federal civil and criminal false claims and civil monetary penalties laws, including the civil federal False Claims Act, which can be enforced through civil whistleblower or qui tam actions, which prohibit, among other things, individuals or entities from knowingly presenting, 61 or causing to be presented, to the U.S. federal government, claims for payment or approval that are false or fraudulent, knowingly making, using or causing to be made or used, a false record or statement material to a false or fraudulent claim, or from knowingly making a false statement to avoid, decrease or conceal an obligation to pay money to the U.S. federal government.
A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation; • the U.S. federal civil and criminal false claims and civil monetary penalties laws, including the civil federal False Claims Act, which can be enforced through civil whistleblower or qui tam actions, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, to the U.S. federal government, claims for payment or approval that are false or fraudulent, knowingly making, using or causing to be made or used, a false record or statement material to a false or fraudulent claim, or from knowingly making a false statement to avoid, decrease or conceal an obligation to pay money to the U.S. federal government.
For example, the FDA may determine that a BLA, even if ultimately approved, does not meet the eligibility criteria for a priority review voucher, including for the following reasons: 56 • the product no longer meets the definition of a rare pediatric disease; • the product contains an active ingredient (including any ester or salt of the active ingredient) that has been previously approved in another marketing application; • the application does not rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population; • the application is approved for a different adult indication than the rare pediatric disease for which the product is designated Moreover, Congress included a sunset provision in the statute authorizing the rare pediatric disease priority review voucher program.
For example, the FDA may determine that a BLA, even if ultimately approved, does not meet the eligibility criteria for a priority review voucher, including for the following reasons: • the product no longer meets the definition of a rare pediatric disease; • the product contains an active ingredient (including any ester or salt of the active ingredient) that has been previously approved in another marketing application; • the application does not rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population; • the application is approved for a different adult indication than the rare pediatric disease for which the product is designated Moreover, Congress included a sunset provision in the statute authorizing the rare pediatric disease priority review voucher program.
A medicinal product may be designated as orphan if its sponsor can establish that (i) the product is intended for the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating condition; (ii) either (a) such condition affects no more than five in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify investment; and (iii) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the medicinal product will be 54 of significant benefit to those affected by the condition.
A medicinal product may be designated as orphan if its sponsor can establish that (i) the product is intended for the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating condition; (ii) either (a) such condition affects no more than five in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify investment; and (iii) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the medicinal product will be of significant benefit to those affected by the condition.
As a result, we may fail to capitalize on viable commercial products or profitable market opportunities, be required to forego or delay pursuit of opportunities with other product candidates or other diseases that may later prove to have greater commercial potential than those we choose to pursue, or relinquish valuable rights to such product candidates through collaboration, licensing or other royalty arrangements in cases in which it would have been advantageous for us to invest additional resources to retain sole development and commercialization rights.
As a result, we may fail to capitalize on viable 30 commercial products or profitable market opportunities, be required to forego or delay pursuit of opportunities with other product candidates or other diseases that may later prove to have greater commercial potential than those we choose to pursue, or relinquish valuable rights to such product candidates through collaboration, licensing or other royalty arrangements in cases in which it would have been advantageous for us to invest additional resources to retain sole development and commercialization rights.
The degree of future protection for our proprietary rights is uncertain, and we cannot ensure that: • any of our patents, or any of our pending patent applications, if issued, or those of our licensors, will include claims having a scope sufficient to protect our product candidates; • any of our pending patent applications or those of our licensors may issue as patents; 68 • others will not or may not be able to make, use, offer to sell, or sell products that are the same as or similar to our own but that are not covered by the claims of the patents that we own or license; • we will be able to successfully commercialize our product candidates on a substantial scale, if approved, before the relevant patents that we own or license expire; • we or our licensors were the first to make the inventions covered by each of the patents and pending patent applications that we own or license; • we or our licensors were the first to file patent applications for these inventions; • others will not develop similar or alternative technologies that do not infringe the patents we own or license; • any of the patents we own or license will be found to ultimately be valid and enforceable; • any patents issued to us or our licensors will provide a basis for an exclusive market for our commercially viable products or will provide us with any competitive advantages; • a third party may not challenge the patents we own or license and, if challenged, a court would hold that such patents are valid, enforceable and infringed; • we may develop or in-license additional proprietary technologies that are patentable; • the patents of others will not have an adverse effect on our business; • our competitors do not conduct research and development activities in countries where we do not have enforceable patent rights and then use the information learned from such activities to develop competitive products for sale in our major commercial markets; • we will develop additional proprietary technologies or product candidates that are separately patentable; or • our commercial activities or products will not infringe upon the patents of others.
The degree of future protection for our proprietary rights is uncertain, and we cannot ensure that: • any of our patents, or any of our pending patent applications, if issued, or those of our licensors, will include claims having a scope sufficient to protect our product candidates; • any of our pending patent applications or those of our licensors may issue as patents; • others will not or may not be able to make, use, offer to sell, or sell products that are the same as or similar to our own but that are not covered by the claims of the patents that we own or license; • we will be able to successfully commercialize our product candidates on a substantial scale, if approved, before the relevant patents that we own or license expire; • we or our licensors were the first to make the inventions covered by each of the patents and pending patent applications that we own or license; • we or our licensors were the first to file patent applications for these inventions; • others will not develop similar or alternative technologies that do not infringe the patents we own or license; • any of the patents we own or license will be found to ultimately be valid and enforceable; • any patents issued to us or our licensors will provide a basis for an exclusive market for our commercially viable products or will provide us with any competitive advantages; 67 • a third party may not challenge the patents we own or license and, if challenged, a court would hold that such patents are valid, enforceable and infringed; • we may develop or in-license additional proprietary technologies that are patentable; • the patents of others will not have an adverse effect on our business; • our competitors do not conduct research and development activities in countries where we do not have enforceable patent rights and then use the information learned from such activities to develop competitive products for sale in our major commercial markets; • we will develop additional proprietary technologies or product candidates that are separately patentable; or • our commercial activities or products will not infringe upon the patents of others.
Foreign Corrupt Practices Act of 1977, as amended, which prohibits, among other things, U.S. companies and their employees and agents from authorizing, promising, offering, or providing, directly or indirectly, corrupt or improper payments or anything else of value to foreign government officials, employees of public international organizations and foreign government owned or affiliated entities, candidates for foreign political office, and foreign political 62 parties or officials thereof, and federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers.
Foreign Corrupt Practices Act of 1977, as amended, which prohibits, among other things, U.S. companies and their employees and agents from authorizing, promising, offering, or providing, directly or indirectly, corrupt or improper payments or anything else of value to foreign government officials, employees of public international organizations and foreign government owned or affiliated entities, candidates for foreign political office, and foreign political parties or officials thereof, and federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers.
An biological product candidate is eligible for RMAT designation if: (1) it meets the definition of a regenerative medicine therapy, which the FDA defines 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; (2) the candidate is intended to treat, modify, reverse, or cure a serious disease or condition; and (3) preliminary clinical evidence indicates that the candidate has the potential to address unmet medical needs for such disease or condition.
A biological product candidate is eligible for RMAT designation if: (1) it meets the definition of a regenerative medicine therapy, which the FDA defines 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; (2) the candidate is intended to treat, modify, reverse, or cure a serious disease or condition; and (3) preliminary clinical evidence indicates that the candidate has the potential to address unmet medical needs for such disease or condition.
As we look to respond to evolving standards for identifying, measuring, and reporting ESG metrics, our efforts may result in a significant increase in costs and may nevertheless not meet investor or other stakeholder expectations and evolving standards or regulatory requirements, which may negatively impact our financial results, our reputation, our ability to attract or retain employees, our attractiveness as an investment or business partner, or expose us to government enforcement actions, private litigation, and actions by stockholders or stakeholders. 94
As we look to respond to evolving standards for identifying, measuring, and reporting ESG metrics, our efforts may result in a significant increase in costs and may nevertheless not meet investor or other stakeholder expectations and evolving standards or regulatory requirements, which may negatively impact our financial results, our reputation, our ability to attract or retain employees, our attractiveness as an investment or business partner, or expose us to government enforcement actions, private litigation, and actions by stockholders or stakeholders.
Patient enrollment, a determinative factor in the timing of clinical trials, is affected by many factors including the severity of and difficulty of diagnosing the disease under investigation, knowledge of the disease in the medical community and availability of effective diagnostic methods, size and distribution of the patient population and process for identifying subjects, access of patients to medical professionals experienced in their disease, our ability to effectively disseminate information about our clinical trials to the patient population and access of patients to such information, eligibility and exclusion criteria for the trial in question, design of the trial protocol, availability, efficacy of, and our ability to compete with approved and standard of care therapies or other clinical trials for the disease or condition under investigation, perceived 39 risks and benefits of the product candidate under trial or testing, availability of genetic testing for potential patients, efforts to facilitate timely enrollment in clinical trials, patient referral practices of physicians, ability to obtain and maintain subject consent, the risk that enrolled subjects will drop out before completion of the trial, the ability to monitor patients adequately during and after treatment, the time and financial commitments required of patients to enroll in our trials beyond the costs covered by the company, and the proximity and availability of and access to clinical trial sites for prospective patients.
Patient enrollment, a determinative factor in the timing of clinical trials, is affected by many factors including the severity and difficulty of diagnosing the disease under investigation, knowledge of the disease in the medical community and availability of effective diagnostic methods, size and distribution of the patient population and process for identifying subjects, access of patients to medical professionals experienced in their disease, our ability to effectively disseminate information about our clinical trials to the patient population and access of patients to such information, eligibility and exclusion criteria for the trial in 37 question, design of the trial protocol, availability, efficacy of, and our ability to compete with approved and standard of care therapies or other clinical trials for the disease or condition under investigation, perceived risks and benefits of the product candidate under trial or testing, availability of genetic testing for potential patients, efforts to facilitate timely enrollment in clinical trials, patient referral practices of physicians, ability to obtain and maintain subject consent, the risk that enrolled subjects will drop out before completion of the trial, the ability to monitor patients adequately during and after treatment, the time and financial commitments required of patients to enroll in our trials beyond the costs covered by the company, and the proximity and availability of and access to clinical trial sites for prospective patients.
Future growth will impose significant added responsibilities on members of management, including: • identifying, recruiting, integrating, retaining and motivating additional employees; • managing our internal development efforts effectively, including the clinical and FDA review process for our current and future product candidates, while complying with our contractual obligations to contractors and other third parties; • expanding our operational, financial and management controls, reporting systems and procedures; and • managing increasing operational and managerial complexity.
Future growth will impose significant added responsibilities on members of management, including: • identifying, recruiting, integrating, retaining and motivating additional employees; 80 • managing our internal development efforts effectively, including the clinical and FDA review process for our current and future product candidates, while complying with our contractual obligations to contractors and other third parties; • expanding our operational, financial and management controls, reporting systems and procedures; and • managing increasing operational and managerial complexity.
This choice of forum provision may limit a stockholder’s ability to bring a claim in a judicial forum that it finds favorable for disputes with us or any of our directors, officers, other employees or stockholders, which may discourage lawsuits with respect to such claims, although our stockholders will not be deemed 91 to have waived our compliance with federal securities laws and the rules and regulations thereunder.
This choice of forum provision may limit a stockholder’s ability to bring a claim in a judicial forum that it finds favorable for disputes with us or any of our directors, officers, other employees or stockholders, which may discourage lawsuits with respect to such claims, although our stockholders will not be deemed to have waived our compliance with federal securities laws and the rules and regulations thereunder.
Misconduct by these parties could include intentional, reckless and negligent conduct that fails to: comply with the laws of the FDA, EMA and other comparable foreign regulatory authorities; provide true, complete and accurate information to the FDA, EMA and other comparable foreign regulatory authorities; comply with manufacturing standards we have established; comply with healthcare fraud and abuse laws in the United States and similar foreign fraudulent misconduct laws; or report financial information or data accurately or to disclose unauthorized activities to us.
Misconduct by these parties could include intentional, reckless and negligent conduct that fails to: comply with the laws of the FDA, EMA and other comparable foreign 93 regulatory authorities; provide true, complete and accurate information to the FDA, EMA and other comparable foreign regulatory authorities; comply with manufacturing standards we have established; comply with healthcare fraud and abuse laws in the United States and similar foreign fraudulent misconduct laws; or report financial information or data accurately or to disclose unauthorized activities to us.
If one of our product candidates is approved, it will be subject to ongoing regulatory requirements for manufacturing, labeling, packaging, storage, advertising, promotion, sampling, record-keeping, conduct of post-marketing studies, and submission of safety, efficacy, and other post- market information, including both federal and state requirements in the United States and requirements of comparable foreign regulatory authorities.
If one of our product candidates is approved, it will be subject to ongoing regulatory requirements for manufacturing, labeling, packaging, storage, advertising, promotion, sampling, record-keeping, conduct 50 of post-marketing studies, and submission of safety, efficacy, and other post- market information, including both federal and state requirements in the United States and requirements of comparable foreign regulatory authorities.
The patent application process is subject to numerous risks and uncertainties, and there can be no assurance that we or any of our actual or potential future collaborators or licensors will be successful in protecting our product candidates, proprietary technologies and their uses by obtaining and defending patents. These risks and uncertainties include the following: • the U.S.
The patent application process is subject to numerous risks and uncertainties, and there can be no assurance that we or any of our actual or potential future collaborators or licensors will be successful in 65 protecting our product candidates, proprietary technologies and their uses by obtaining and defending patents. These risks and uncertainties include the following: • the U.S.
Our competitors in both the United States and abroad, many of which have substantially greater resources and 77 have made substantial investments in patent portfolios and competing technologies, may have applied for or obtained or may in the future apply for and obtain, patents that will prevent, limit or otherwise interfere with our ability to make, use and sell our product candidates.
Our competitors in both the United States and abroad, many of which have substantially greater resources and have made substantial investments in patent portfolios and competing technologies, may have applied for or obtained or may in the future apply for and obtain, patents that will prevent, limit or otherwise interfere with our ability to make, use and sell our product candidates.
Our limited operating history as a company and early stage of drug development make any assessment of our future success and viability subject to significant uncertainty. We will encounter risks and difficulties frequently experienced by early-stage biopharmaceutical companies in rapidly evolving fields, and we have not yet demonstrated an ability to successfully overcome such risks and difficulties.
Our limited operating history as a company and stage of drug development make any assessment of our future success and viability subject to significant uncertainty. We will encounter risks and difficulties frequently experienced by biopharmaceutical companies in rapidly evolving fields, and we have not yet demonstrated an ability to successfully overcome such risks and difficulties.
In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several types of providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several types of providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of 55 limitations period for the government to recover overpayments to providers from three to five years.
We or our independent registered public accounting firm may not be able to conclude on an ongoing basis that we have effective internal control over financial reporting, which could harm our operating results, cause investors to lose confidence in our reported financial information and cause the trading price of our stock to fall.
We or our independent registered public accounting firm may not 89 be able to conclude on an ongoing basis that we have effective internal control over financial reporting, which could harm our operating results, cause investors to lose confidence in our reported financial information and cause the trading price of our stock to fall.
Certain Chinese biotechnology companies, CROs and contract development and manufacturing organizations may become subject to trade restrictions, sanctions, other regulatory requirements, or proposed legislation by the U.S. government, which could potentially impact services available for our research and development or our ability to secure the materials we need for our product candidates.
Certain Chinese biotechnology companies, CROs and contract development and manufacturing organizations may become subject to trade restrictions, sanctions, other regulatory requirements, or proposed legislation by the U.S. government, which could potentially impact services available for our research and development or our ability to secure the materials we need for our product candidates. For example, the U.S.
Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy profile despite having progressed through preclinical studies and initial clinical trials. A number of companies in the biopharmaceutical industry have suffered significant setbacks in advanced clinical trials due to lack of efficacy or unacceptable safety issues, notwithstanding promising 43 results in earlier trials.
Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy profile despite having progressed through preclinical studies and initial clinical trials. A number of companies in the biopharmaceutical industry have suffered significant setbacks in advanced clinical trials due to lack of efficacy or unacceptable safety issues, notwithstanding promising results in earlier trials.
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 through reliance upon data obtained from a 55 meaningful number of sites, including through expansion of clinical trials to a sufficient number sites, as appropriate.
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 through reliance upon data obtained from a meaningful number of sites, including through expansion of clinical trials to a sufficient number of sites, as appropriate.
Seeking foreign regulatory approvals could result in significant delays, difficulties and costs for us and may require additional preclinical studies or clinical trials which would be costly and time consuming. Regulatory requirements can vary widely from country to 60 country and could delay or prevent the introduction of our products in those countries.
Seeking foreign regulatory approvals could result in significant delays, difficulties and costs for us and may require additional preclinical studies or clinical trials which would be costly and time consuming. Regulatory requirements can vary widely from country to country and could delay or prevent the introduction of our products in those countries.
In addition, the uncertainties associated with litigation could have a material adverse effect on our ability to raise the funds necessary to continue our clinical trials, continue our research programs, license necessary technology from third parties or enter into development or manufacturing partnerships that would help us bring our product candidates to market.
In addition, 78 the uncertainties associated with litigation could have a material adverse effect on our ability to raise the funds necessary to continue our clinical trials, continue our research programs, license necessary technology from third parties or enter into development or manufacturing partnerships that would help us bring our product candidates to market.
Even if regulatory approval is secured for any of our product candidates, the terms of such approval may limit the scope and use of our product candidate, which may also limit its commercial potential. In addition, the FDA’s and other regulatory authorities’ policies with respect to clinical trials may change and additional government regulations may be enacted.
Even if regulatory approval is secured for any of 41 our product candidates, the terms of such approval may limit the scope and use of our product candidate, which may also limit its commercial potential. In addition, the FDA’s and other regulatory authorities’ policies with respect to clinical trials may change and additional government regulations may be enacted.
An adverse determination in any such submission, proceeding or litigation could reduce the scope or enforceability of, or invalidate, our patent rights, which could adversely affect our competitive position. This could have a negative impact on some of our intellectual property and could increase uncertainties surrounding obtaining and enforcement or defense of 70 our issued patents.
An adverse determination in any such submission, proceeding or litigation could reduce the scope or enforceability of, or invalidate, our patent rights, which could adversely affect our competitive position. This could have a negative impact on some of our intellectual property and could increase uncertainties surrounding obtaining and enforcement or defense of our issued patents.
Any patent-related legal action against us claiming damages and seeking to enjoin commercial activities relating to our product candidates or proprietary technologies could subject us to potential liability for damages, including treble damages if we were determined to willfully infringe, and require us to obtain a license to manufacture or market our product candidates or any future products.
Any patent-related legal action against us claiming damages and seeking to enjoin commercial activities relating to our product candidates or proprietary technologies could subject us to 77 potential liability for damages, including treble damages if we were determined to willfully infringe, and require us to obtain a license to manufacture or market our product candidates or any future products.
Any acquisition or strategic partnership may entail numerous risks, including: • increased operating expenses and cash requirements; • the assumption of indebtedness or contingent liabilities; • the issuance of our equity securities which would result in dilution to our stockholders; • assimilation of operations, intellectual property, products and product candidates of an acquired company, including difficulties associated with integrating new personnel; • the diversion of our management’s attention from our existing product candidates and initiatives in pursuing such an acquisition or strategic partnership; • retention of key employees, the loss of key personnel, and uncertainties in our ability to maintain key business relationships; • risks and uncertainties associated with the other party to such a transaction, including the prospects of that party and their existing products or product candidates and regulatory approvals; and 82 • our inability to generate revenue from acquired intellectual property, technology and/or products sufficient to meet our objectives or even to offset the associated transaction and maintenance costs.
Any acquisition or strategic partnership may entail numerous risks, including: • increased operating expenses and cash requirements; • the assumption of indebtedness or contingent liabilities; 81 • the issuance of our equity securities which would result in dilution to our stockholders; • assimilation of operations, intellectual property, products and product candidates of an acquired company, including difficulties associated with integrating new personnel; • the diversion of our management’s attention from our existing product candidates and initiatives in pursuing such an acquisition or strategic partnership; • retention of key employees, the loss of key personnel, and uncertainties in our ability to maintain key business relationships; • risks and uncertainties associated with the other party to such a transaction, including the prospects of that party and their existing products or product candidates and regulatory approvals; and • our inability to generate revenue from acquired intellectual property, technology and/or products sufficient to meet our objectives or even to offset the associated transaction and maintenance costs.
Any failure or perceived failure by 84 us to comply with federal, state or foreign laws or regulation, our internal policies and procedures or our contracts governing our processing of personal information could result in negative publicity, government investigations and enforcement actions, claims by third parties and damage to our reputation, any of which could seriously harm our business.
Any failure or perceived failure by us to comply with federal, state or foreign laws or regulation, our internal policies and procedures or our contracts governing our processing of personal information could result in negative publicity, government investigations and enforcement actions, claims by third parties and damage to our reputation, any of which could seriously harm our business.
Our efforts to enforce or protect our proprietary rights related to trademarks, trade names, trade secrets, domain names, copyrights or other intellectual property may be ineffective and could result in substantial costs and diversion of resources and could seriously harm our business. 74 Intellectual property rights do not necessarily address all potential threats to our competitive advantage.
Our efforts to enforce or protect our proprietary rights related to trademarks, trade names, trade secrets, domain names, copyrights or other intellectual property may be ineffective and could result in substantial costs and diversion of resources and could seriously harm our business. Intellectual property rights do not necessarily address all potential threats to our competitive advantage.
We may also be subject to claims that patents and applications we have filed to protect inventions of our employees or consultants, even those related to one or more of our product candidates, 80 are rightfully owned by their former or concurrent employer or former or current client. Litigation may be necessary to defend against these claims.
We may also be subject to claims that patents and applications we have filed to protect inventions of our employees or consultants, even those related to one or more of our product candidates, are rightfully owned by their former or concurrent employer or former or current client. Litigation may be necessary to defend against these claims.
Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies. Our inability to promptly obtain coverage and profitable payment rates from both government-funded and private payors for any approved products we may develop could seriously harm our business.
Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies. Our 58 inability to promptly obtain coverage and profitable payment rates from both government-funded and private payors for any approved products we may develop could seriously harm our business.
The incurrence of indebtedness would result in increased fixed payment obligations and could involve restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business.
The incurrence of indebtedness would result in increased fixed payment obligations and could involve restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell or license intellectual property rights and other operating restrictions that could adversely 88 impact our ability to conduct our business.
Failure of a product candidate may occur at any stage of preclinical or clinical development, and, because our product candidates and our Therapeutic Vector Evolution platform technology are in an early stage of development, there is a relatively higher risk of failure, and we may never succeed in developing marketable products or generating product revenue.
Failure of a product candidate may occur at any stage of preclinical or clinical development, and, because most of our product candidates and our Therapeutic Vector Evolution platform technology are in an early stage of development, there is a relatively higher risk of failure, and we may never succeed in developing marketable products or generating product revenue.
If the top-line or interim data that we report differ from final results, or if others, including regulatory authorities, disagree with the conclusions reached, our ability to obtain approval for, and commercialize, product candidates may be harmed, which could seriously harm our business.
If the top-line or interim data that we report differ from final results, or if others, including regulatory authorities, disagree with the 42 conclusions reached, our ability to obtain approval for, and commercialize, product candidates may be harmed, which could seriously harm our business.
In addition, our rights in such inventions may be subject to certain requirements to manufacture products embodying such inventions in the United States. Any exercise by the government of such rights could seriously harm our business. 69 The lives of our patents may not be sufficient to effectively protect our product candidates and business. Patents have a limited lifespan.
In addition, our rights in such inventions may be subject to certain requirements to manufacture products embodying such inventions in the United States. Any exercise by the government of such rights could seriously harm our business. The lives of our patents may not be sufficient to effectively protect our product candidates and business. Patents have a limited lifespan.
These agreements are complex, and certain provisions in such agreements may be susceptible to multiple interpretations which could lead to disputes, including but not limited to those regarding: • the scope of rights granted under the license agreement and other interpretation-related issues; • the extent to which our proprietary technology and product candidates infringe on intellectual property of the licensor that is not subject to the licensing agreement; • the sublicensing of patent and other rights; • diligence obligations under the license agreement and what activities satisfy those diligence obligations; 76 • the ownership of inventions and know-how resulting from the creation or use of intellectual property by us or our counterparties, alone or jointly; • the scope and duration of our payment obligations; • rights upon termination of such agreement; and • the scope and duration of exclusivity obligations of each party to the agreement.
These agreements are complex, and certain provisions in such agreements may be susceptible to multiple interpretations which could lead to disputes, including but not limited to those regarding: 75 • the scope of rights granted under the license agreement and other interpretation-related issues; • the extent to which our proprietary technology and product candidates infringe on intellectual property of the licensor that is not subject to the licensing agreement; • the sublicensing of patent and other rights; • diligence obligations under the license agreement and what activities satisfy those diligence obligations; • the ownership of inventions and know-how resulting from the creation or use of intellectual property by us or our counterparties, alone or jointly; • the scope and duration of our payment obligations; • rights upon termination of such agreement; and • the scope and duration of exclusivity obligations of each party to the agreement.
We will be unable to use our NOLs or other tax attributes if we do not attain profitability sufficient to offset our available NOLs or other tax attributes prior to their expiration, to the extent subject to expiration. Changes in tax laws or regulations that are applied adversely to us or our customers may seriously harm our business.
We will be unable to use our NOLs or other tax attributes if we do not 86 attain profitability sufficient to offset our available NOLs or other tax attributes prior to their expiration, to the extent subject to expiration. Changes in tax laws or regulations that are applied adversely to us or our customers may seriously harm our business.
We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.
We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the 70 intellectual property that we develop or license.
If a security breach or other incident were to result in the unauthorized access to or unauthorized use, disclosure, release or other processing of clinical trial data or personal data, it may be necessary to 83 notify individuals, governmental authorities, supervisory bodies, the media, and other parties pursuant to privacy and security laws.
If a security breach or other incident were to result in the unauthorized access to or unauthorized use, disclosure, release or other processing of clinical trial data or personal data, it may be necessary to notify individuals, governmental authorities, supervisory bodies, the media, and other parties pursuant to privacy and security laws.
Despite these efforts, we cannot provide any assurances that all such agreements have been duly executed, and any of these parties may breach the agreements and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches.
Despite these efforts, we cannot 71 provide any assurances that all such agreements have been duly executed, and any of these parties may breach the agreements and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches.
Over the long term, if we are unable to establish name recognition based on our trademarks and trade names, then we may not be able to compete effectively and our business may be adversely affected. We may license our trademarks and trade names, to the extent any are registered, to third parties, such as distributors.
Over the long term, if we are unable to establish name recognition based on our trademarks and trade names, then we may not be able to compete effectively and our business may be adversely affected. We may license our trademarks 73 and trade names, to the extent any are registered, to third parties, such as distributors.
If we or our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA or others, we will not be able to obtain 49 and/or maintain regulatory approval for our products as manufactured at their manufacturing facilities.
If our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA or others, we will not be able to obtain and/or maintain regulatory approval for our products as manufactured at their manufacturing facilities.
Currently, the AWA imposes a wide variety of specific regulations that govern the humane handling, care, treatment and transportation of certain animals by producers and users of research animals, most notably relating to personnel, facilities, sanitation, cage size, and feeding, watering and shipping conditions.
Currently, the AWA imposes a wide variety of specific regulations that govern the humane 61 handling, care, treatment and transportation of certain animals by producers and users of research animals, most notably relating to personnel, facilities, sanitation, cage size, and feeding, watering and shipping conditions.
In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common 79 stock.
In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.
There can also be no assurance that our and our collaborators’, future CROs’ and other contractors’ and consultants’ cybersecurity risk management program and processes, including policies, controls or procedures, will be fully implemented, complied with or effective in protecting our systems, networks and Confidential Information.
There can also be no assurance that our and our collaborators’, future CROs’ and other contractors’ and 82 consultants’ cybersecurity risk management program and processes, including policies, controls or procedures, will be fully implemented, complied with or effective in protecting our systems, networks and Confidential Information.
If our revenue or operating results fall below or if operating expenses or other costs are higher than the expectations of analysts or investors or below or above, as the case may 33 be, any forecasts we may provide to the market, or if the forecasts we provide to the market are below the expectations of analysts or investors, the price of our common stock could decline substantially.
If our revenue or operating results fall below or if operating expenses or other costs are higher than the expectations of analysts or investors or below or above, as the case may be, any forecasts we may provide to the market, or if the forecasts we provide to the market are below the expectations of analysts or investors, the price of our common stock could decline substantially.
In addition, even if we or our collaborators were to obtain approval, regulatory authorities may approve any of our product candidates for fewer or more limited indications than we request, may impose significant limitations in the form of narrow indications, warnings, or a REMS.
In addition, even if we or our collaborators were to obtain approval, regulatory authorities may approve any of our product candidates for fewer or more limited indications than we request, may impose 49 significant limitations in the form of narrow indications, warnings, or a REMS.
A failure to obtain accelerated approval or any other form of expedited development, review or approval for our product candidate would result in a longer 52 time period to commercialization of such product candidate, if any, could increase the cost of development of such product candidate and could harm our competitive position in the marketplace.
A failure to obtain accelerated approval or any other form of expedited development, review or approval for our product candidate would result in a longer time period to commercialization of such product candidate, if any, could increase the cost of development of such product candidate and could harm our competitive position in the marketplace.
Any government investigation of alleged violations of law could require us to expend significant time and resources in response and could generate negative publicity. Any failure to comply with ongoing regulatory requirements may adversely affect our ability to commercialize and generate revenue from our 53 products.
Any government investigation of alleged violations of law could require us to expend significant time and resources in response and could generate negative publicity. Any failure to comply with ongoing regulatory requirements may adversely affect our ability to commercialize and generate revenue from our products.
New income, sales, use or other tax laws, statutes, rules, regulations or ordinances could be enacted at any time, which could affect the tax treatment of any of our future domestic and foreign earnings. Any new taxes could adversely affect our domestic and international business operations, and our business and 86 financial performance.
New income, sales, use or other tax laws, statutes, rules, regulations or ordinances could be enacted at any time, which could affect the tax treatment of any of our future domestic and foreign earnings. Any new taxes could adversely affect our domestic and international business operations, and our business and financial performance.
Our product candidates require processing steps that are more complex than those required for most chemical and protein pharmaceuticals. Moreover, unlike chemical pharmaceuticals, the physical and chemical properties of a biologic such as ours generally cannot be fully characterized.
Our product candidates require processing steps that are 45 more complex than those required for most chemical and protein pharmaceuticals. Moreover, unlike chemical pharmaceuticals, the physical and chemical properties of a biologic such as ours generally cannot be fully characterized.
Our security measures may not prevent an employee, consultant, collaborator or third party from misappropriating our trade secrets 72 and providing them to a competitor, and recourse we take against such misconduct may not provide an adequate remedy to protect our interests fully.
Our security measures may not prevent an employee, consultant, collaborator or third party from misappropriating our trade secrets and providing them to a competitor, and recourse we take against such misconduct may not provide an adequate remedy to protect our interests fully.
Should any of these events occur, they could seriously harm our business. Any collaboration arrangements that we may enter into in the future may not be successful, which could adversely affect our ability to develop and commercialize our products. Any future collaborations that we enter into may not be successful.
Should any of these events occur, they could seriously harm our business. Our existing collaborations and any collaboration arrangements that we may enter into in the future may not be successful, which could adversely affect our ability to develop and commercialize our products.
If holders of these 88 pre-funded warrants exercise these securities, existing shareholders will suffer dilution to their voting power and the Company may experience dilution in its earnings per share, as well as a negative impact on its share price.
If holders of these pre-funded warrants exercise these securities, existing shareholders will suffer dilution to their voting power and the Company may experience dilution in its earnings per share, as well as a negative impact on its share price.
If we obtain FDA approval of any of our product candidates and begin commercializing those products in the United States, our potential exposure under such laws will increase significantly, and our costs associated 93 with compliance with such laws are also likely to increase.
If we obtain FDA approval of any of our product candidates and begin commercializing those products in the United States, our potential exposure under such laws will increase significantly, and our costs associated with compliance with such laws are also likely to increase.
If we or any of our licensors is forced to grant a license to third parties with respect to any patents relevant to our business, our business may be seriously harmed. 71 We may be subject to claims challenging the inventorship or ownership of our patents and other intellectual property.
If we or any of our licensors is forced to grant a license to third parties with respect to any patents relevant to our business, our business may be seriously harmed. We may be subject to claims challenging the inventorship or ownership of our patents and other intellectual property.
These and other licenses we may enter into in the future may not provide adequate rights to use such intellectual property and technology in all relevant fields of use or in all territories in which we may wish to develop or commercialize our technology and product candidates in the future.
These and other licenses we may enter into in the future may not provide adequate rights to use such intellectual property and technology in all relevant fields of use or in all territories in which we may wish to develop or commercialize our technology and product candidates in the 72 future.
These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our product candidates.
These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient 43 registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our product candidates.
Our ability to generate revenue from these arrangements with commercial entities will depend on our collaborators’ abilities to successfully perform the functions assigned to them in these arrangements. We cannot predict the success of any collaboration that we enter into.
Our ability to generate revenue from these arrangements with commercial entities will depend on our collaborators’ abilities to 62 successfully perform the functions assigned to them in these arrangements. We cannot predict the success of any collaboration that we enter into.
If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may be subject to enforcement action and we may not achieve or sustain profitability.
If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or 51 if we are not able to maintain regulatory compliance, we may be subject to enforcement action and we may not achieve or sustain profitability.
There can be no 81 assurance that the services of these independent organizations, advisors and consultants will continue to be available to us on a timely basis when needed, or that we can find qualified replacements.
There can be no assurance that the services of these independent organizations, advisors and consultants will continue to be available to us on a timely basis when needed, or that we can find qualified replacements.
Negative public perception about the use of AAV technology in human therapeutics, whether related to our technology or a competitor’s technology, could result in increased governmental regulation, delays in the development and commercialization of product candidates or decreased demand for the resulting products, any of which may seriously harm our business. 35 Our product candidates may cause undesirable side effects or have other properties that could halt their clinical development, prevent their regulatory approval, limit their commercial potential or result in significant negative consequences.
Negative public perception about the use of AAV technology in human therapeutics, whether related to our technology or a competitor’s technology, could result in increased governmental regulation, delays in the development and commercialization of product candidates or decreased demand for the resulting products, any of which may seriously harm our business. 33 Our product candidates may cause undesirable side effects or have other properties that could halt their clinical development, prevent their regulatory approval, limit their commercial potential or result in significant negative consequences.
In many countries, any product candidate for human use must be approved for reimbursement before it can be approved for sale in that country. In some cases, the intended price for such product is also subject to approval.
In many countries, any product candidate for human 54 use must be approved for reimbursement before it can be approved for sale in that country. In some cases, the intended price for such product is also subject to approval.
Nothing in our amended and restated certificate of incorporation and amended and restated bylaws precludes stockholders that assert claims under the Exchange Act from bringing such claims in state or federal court, subject to applicable law.
Nothing in our 91 amended and restated certificate of incorporation and amended and restated bylaws precludes stockholders that assert claims under the Exchange Act from bringing such claims in state or federal court, subject to applicable law.
Conducting trials in smaller subject populations increases the risk that any safety or efficacy issues observed in only a few patients could prevent such trials from reaching statistical significance or otherwise meeting their specified endpoints, which could require us to conduct additional clinical trials, or delay or prevent our product candidates from receiving regulatory approval, which would seriously harm our business. 40 Research and development of biopharmaceutical products is inherently risky.
Conducting trials in smaller subject populations increases the risk that any safety or efficacy issues observed in only a few patients could prevent such trials from reaching statistical significance or otherwise meeting their specified endpoints, which could require us to conduct additional clinical trials, or delay or prevent our product candidates from receiving regulatory approval, which would seriously harm our business. 38 Research and development of biopharmaceutical products is inherently risky.
In addition, we may not be successful in entering into arrangements with third parties to commercialize our product candidates or may be unable to do so on terms that are favorable to us.
In addition, we may not be successful in entering into arrangements with third parties to commercialize our product candidates or may be unable to 44 do so on terms that are favorable to us.
These laws may constrain the business or financial arrangements and relationships through which we conduct our operations, including how we research, market, sell and distribute our product candidates, if approved.
These laws may constrain 59 the business or financial arrangements and relationships through which we conduct our operations, including how we research, market, sell and distribute our product candidates, if approved.

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Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

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Biggest changeIf applicable, the Company records a liability for such matters when it believes that it is both probable that a liability may be imputed, and the amount of the liability can be reasonably estimated. Significant judgment by the Company is required to determine both probability and the estimated amount.
Biggest changeIf applicable, the Company records a liability for such matters when it believes that it is both probable that a liability may have been incurred, and the amount of the liability can be reasonably estimated. Significant judgment by the Company is required to determine both probability and the estimated amount.

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeHolders of Common Stock As of February 26, 2025, there were approximately 13 holders of record of our common stock.
Biggest changeHolders of Common Stock As of March 16, 2026, there were approximately 11 holders of record of our common stock.

Item 7. Management's Discussion & Analysis

Management's Discussion & Analysis (MD&A) — revenue / margin commentary

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Biggest changeOther Income, Net Our other income, net primarily consists of interest income earned on our cash equivalents and marketable securities and adjustments for the change in the fair value of our derivative liability which must be remeasured at each reporting date. 101 Results of Operations Comparison of the Years Ended December 31, 2024 and 2023 The following table summarizes our results of operations for the periods indicated (dollars in thousands): Year Ended December 31, 2024 2023 $ Change % Change Revenue: Collaboration and license revenue $ 37 $ 20,723 $ (20,686 ) -100 % Operating expenses: Research and development 141,299 97,096 44,203 46 % General and administrative 46,579 36,494 10,085 28 % Total operating expenses 187,878 133,590 54,288 41 % Loss from operations (187,841 ) (112,867 ) (74,974 ) 66 % Other income (expense): Interest income 27,050 12,211 14,839 122 % Other expense, net (77 ) (181 ) 104 -57 % Total other income, net 26,973 12,030 14,943 124 % Net loss $ (160,868 ) $ (100,837 ) $ (60,031 ) 60 % Revenue Revenue for the year ended December 31, 2024 decreased by $20.7 million, or 100%, from the year ended December 31, 2023.
Biggest changeOther Income, Net Our other income, net primarily consists of interest income earned on our cash equivalents and marketable securities and adjustments for the change in the fair value of our derivative liability which must be remeasured at each reporting date. 101 Results of Operations Comparison of the Years Ended December 31, 2025 and 2024 The following table summarizes our results of operations for the periods indicated (dollars in thousands): Year Ended December 31, 2025 2024 $ Change % Change Revenue Collaboration and license revenue $ 85,209 $ 37 $ 85,172 * Operating Expenses: Research and development 195,696 141,299 54,397 38 % General and administrative 49,060 46,579 2,481 5 % Total operating expenses 244,756 187,878 56,878 30 % Loss from operations (159,547 ) (187,841 ) 28,294 (15 )% Other Income, Net 19,438 26,973 (7,535 ) (28 )% Net loss $ (140,109 ) $ (160,868 ) $ 20,759 (13 )% * not meaningful Revenue Revenue for the year ended December 31, 2025 increased by $85.2 million from the year ended December 31, 2024.
We began recognizing revenue related to uniQure in 2020 and recognized the remaining revenue under the agreement during the third quarter of 2023. We recognized immaterial revenue during the during the year ended December 31, 2023 related to this agreement.
We began recognizing revenue related to uniQure in 2020 and recognized the remaining revenue under the agreement during the third quarter of 2023. We recognized immaterial revenue during the year ended December 31, 2023 related to this agreement.
Our future capital requirements will depend on many factors, including: • the progress of our current and future product candidates through preclinical and clinical development; • potential delays in our preclinical studies and clinical trials, whether current or planned; • expanding our manufacturing facilities and working with our contract manufacturers to scale up the manufacturing processes for our product candidates; 104 • continuing our research and discovery activities; • continuing the development of our Therapeutic Vector Evolution platform; • initiating and conducting additional preclinical, clinical or other studies for our product candidates; • changing or adding additional contract manufacturers or suppliers; • seeking regulatory approvals and marketing authorizations for our product candidates; • establishing sales, marketing and distribution infrastructure to commercialize any products for which we obtain approval; • acquiring or in-licensing product candidates, intellectual property and technologies; • making milestone, royalty or other payments due under any current or future collaboration or license agreements; • obtaining, maintaining, expanding, protecting and enforcing our intellectual property portfolio; • attracting, hiring and retaining qualified personnel; • potential delays or other issues related to our operations; • meeting the requirements and demands of being a public company; • defending against any product liability claims or other lawsuits related to our products; and • the lingering impact of the COVID-19 pandemic and adverse macroeconomic conditions such as, but not limited to, higher inflation and increased interest rates, each of which may exacerbate the magnitude of the factors discussed above.
Our future capital requirements will depend on many factors, including: • the progress of our current and future product candidates through preclinical and clinical development; • potential delays in our preclinical studies and clinical trials, whether current or planned; • working with our contract manufacturers to scale up the manufacturing processes for our product candidates; • continuing our research and discovery activities; • continuing the development of our Therapeutic Vector Evolution platform; • initiating and conducting additional preclinical, clinical or other studies for our product candidates; 104 • changing or adding additional contract manufacturers or suppliers; • seeking regulatory approvals and marketing authorizations for our product candidates; • establishing sales, marketing and distribution infrastructure to commercialize any products for which we obtain approval; • acquiring or in-licensing product candidates, intellectual property and technologies; • making milestone, royalty or other payments due under any current or future collaboration or license agreements; • receiving milestone, royalty or other payments under any current or future collaboration or license agreements; • obtaining, maintaining, expanding, protecting and enforcing our intellectual property portfolio; • attracting, hiring and retaining qualified personnel; • potential delays or other issues related to our operations; • meeting the requirements and demands of being a public company; • defending against any product liability claims or other lawsuits related to our products; and • the lingering impact of the COVID-19 pandemic and adverse macroeconomic conditions such as, but not limited to, higher inflation and increased interest rates, each of which may exacerbate the magnitude of the factors discussed above.
Treasury zero-coupon issues whose term is similar in duration to the expected term of the respective stock option. • Expected Dividend Yield —We have not paid and do not currently anticipate paying any dividends on our common stock. Accordingly, we have estimated the dividend yield to be zero.
Treasury zero-coupon issues whose term is similar in duration to the expected term of the respective stock option. 109 • Expected Dividend Yield —We have not paid and do not currently anticipate paying any dividends on our common stock. Accordingly, we have estimated the dividend yield to be zero.
These inputs are subjective and generally require significant analysis and judgment to develop: • Expected Term —The expected term for employee options is calculated using the simplified method as we do not have sufficient historical information to provide a basis for estimate.
These inputs are subjective and generally require significant analysis and judgment to develop: • Expected Term —The expected term for employee stock options is calculated using the simplified method as we do not have sufficient historical information to provide a basis for estimate.
Our significant accounting policies are described in Note 2 to our financial statements included elsewhere in this report. We believe the following accounting policies are critical to the process of making significant judgments and estimates in the preparation of our financial statements and understanding and evaluating our reported financial results.
Our significant accounting policies are described in Note 2, Summary of Significant Accounting Policies, to our financial statements included elsewhere in this report. We believe the following accounting policies are critical to the process of making significant judgments and estimates in the preparation of our financial statements and understanding and evaluating our reported financial results.
We expense all research and development costs in the periods in which they are incurred. We have entered into various agreements with CROs and CMOs. Costs of certain activities are recognized based on an evaluation of the progress to completion of specific tasks.
We expense all research and development costs in the periods in which they are incurred. We have entered into various agreements with CROs and CDMOs. Costs of certain activities are recognized based on an evaluation of the progress to completion of specific tasks.
Our ability to raise additional funds may be adversely impacted by potential worsening global economic conditions and the recent disruptions to, and volatility in, the credit and financial markets in the United States and worldwide resulting from conflicts in the Middle East, the lingering impact of the COVID-19 pandemic, the war in Ukraine, rising interest rates, inflation and otherwise.
Our ability to raise additional funds may be adversely impacted by potential worsening global economic conditions and the recent disruptions to, and volatility in, the credit and financial markets in the United States and worldwide resulting from conflicts in the Middle East, the lingering impact of the COVID-19 pandemic, the war in Ukraine, rising interest rates, tariffs, inflation, government shutdowns and otherwise.
Payments to us under these arrangements typically include one or more of the following: nonrefundable upfront and license fees, research funding, milestone and other contingent payments to us for the achievement of defined collaboration objectives and certain preclinical, clinical, regulatory and sales-based events, as well as royalties on sales of any commercialized products.
Payments to us under these arrangements typically include one or more of the following: nonrefundable upfront and license fees, cost-sharing and other forms of research funding, milestone and other contingent payments to us for the achievement of defined collaboration objectives and certain preclinical, clinical, regulatory and sales-based events, as well as royalties on sales of any commercialized products.
Off-Balance Sheet Arrangements Since our inception, we have not engaged in any off-balance sheet arrangements as defined in the rules and regulations of the SEC. Recent Accounting Pronouncements See Note 2 to our financial statements included elsewhere in this report for information.
Off-Balance Sheet Arrangements Since our inception, we have not engaged in any off-balance sheet arrangements as defined in the rules and regulations of the SEC. Recent Accounting Pronouncements See Note 2, Summary of Significant Accounting Policies, to our financial statements included elsewhere in this report for information.
Our failure to raise capital as and when needed would have a negative impact on our financial condition and our ability to pursue our business strategy. See the section titled “Risk Factors” for additional risks associated with our substantial capital requirements. We do not have any committed external sources of funds.
Our failure to raise capital as and when needed would have a negative impact on our financial condition and our ability to pursue our business strategy. See the section titled “Risk Factors” for additional risks associated with our substantial capital requirements. We have limited committed external sources of funds.
The noncash charges primarily consisted of stock-based compensation expense of $19.7 million, depreciation and amortization of $4.2 million, amortization of operating lease right-of-use assets of $1.5 million and change in fair value of derivative liability of $0.2 million, partially offset by accretion of discount on marketable securities of $1.2 million.
The noncash charges primarily consisted of stock-based compensation expense of $22.0 million, depreciation and amortization of $4.7 million and amortization of operating lease right-of-use assets of $2.9 million, partially offset by accretion of discount on marketable securities of $4.7 million and $0.1 million in change in fair value of derivative liability.
Accordingly, we will be required to obtain further funding through public or private equity offerings, debt financings, collaborations and licensing arrangements or other sources to complete the clinical development for the product candidates for treatment of wet AMD, DME, GA, cystic fibrosis lung disease, alpha-1 antitrypsin deficiency lung disease, Fabry disease cardiomyopathy or any other indication we may pursue.
Accordingly, we will be required to obtain further funding through public or private equity offerings, debt financings, collaborations and licensing arrangements or other sources to complete the clinical development for the product candidates for treatment of wet AMD, DME, geographic atrophy, cystic fibrosis lung disease, alpha-1 antitrypsin deficiency lung disease or any other indication we may pursue.
In June 2024, we entered into a Sales Agreement (the “Leerink Sales Agreement”) with Leerink Partners LLC (“Leerink”) as sales agent to sell shares of our common stock, from time to time, with aggregate gross sales proceeds of up to $250.0 million pursuant to a Registration Statement on Form S-3 that we filed with the SEC in February 2024 as an “at-the-market” offering under the Securities Act (the “2024 ATM Offering Program”).
At-the-Market Offering Program In June 2024, we entered into a Sales Agreement (the “Leerink Sales Agreement”) with Leerink Partners LLC (“Leerink”) as sales agent to sell shares of our common stock, from time to time, with aggregate gross sales proceeds of up to $250.0 million pursuant to a Registration Statement on Form S-3 that we filed with the SEC in February 2024 as an “at-the-market” offering under the Securities Act.
As of December 31, 2024, our principal commitments consisted of obligations under our operating lease for our headquarters. Please see Note 9 to our financial statements included elsewhere in this report. Critical Accounting Policies and Significant Judgments and Estimates Our financial statements have been prepared in accordance with generally accepted accounting principles in the United States.
As of December 31, 2025, our principal commitments consisted of obligations under our operating lease for our headquarters. Please see Note 8, Commitments and Contingencies, to our financial statements included elsewhere in this report. Critical Accounting Policies and Significant Judgments and Estimates Our financial statements have been prepared in accordance with generally accepted accounting principles in the United States.
These expenses include salaries and personnel-related costs, including stock-based compensation of our scientific personnel performing research and development activities; laboratory supplies; research materials; fees paid to CROs to execute preclinical studies and clinical trials; fees paid to CMOs to manufacture materials for preclinical studies and clinical trials; fees related to obtaining technology licenses; consulting costs; costs related to seeking regulatory approval of our product candidates; and allocated facility-related costs, information technology costs, depreciation expense, and other overhead.
These expenses include salaries and personnel-related costs, including stock-based compensation of our clinical, medical, chemistry, manufacturing and controls and scientific personnel performing research and development activities; laboratory supplies; research materials; fees paid to CROs to execute preclinical studies and clinical trials; fees paid to CDMOs to manufacture materials for preclinical studies and clinical trials; fees related to obtaining technology licenses; consulting costs; costs related to seeking regulatory approval of our product 100 candidates; and allocated facility-related costs, information technology costs, depreciation expense, and other overhead.
Payments made prior to the receipt of goods or services that will be used or rendered for future research and development activities are deferred and capitalized as prepaid expenses and other current assets on our balance sheet.
Payments made prior to the receipt of goods or services that will be used or rendered for future research and development activities are deferred and capitalized as prepaid expenses and other current assets on our balance sheet. The capitalized amounts are recognized as expense as the goods are delivered or the related services are performed.
To date, there have been no interest or penalties charged in relation to the unrecognized tax benefits. 109 NOLs and tax credit carryforwards are subject to review and possible adjustment by the Internal Revenue Service and may become subject to an annual limitation in the event of certain cumulative changes in the ownership interest of significant stockholders over a three-year period in excess of 50% as defined under Sections 382 and 383 in the Internal Revenue Code, which could limit the amount of tax attributes that can be utilized annually to offset future taxable income or tax liabilities.
NOLs and tax credit carryforwards are subject to review and possible adjustment by the Internal Revenue Service and may become subject to an annual limitation in the event of certain cumulative changes in the ownership interest of significant stockholders over a three-year period in excess of 50% as defined under Sections 382 and 383 in the Internal Revenue Code, which could limit the amount of tax attributes that can be utilized annually to offset future taxable income or tax liabilities.
The change in operating assets and liabilities was primarily due to a $3.4 million increase in accrued and other liabilities and a $0.9 million increase in accounts payable, offset by a $0.7 million decrease in deferred revenue, $1.5 million decrease in operating lease liabilities and a $1.4 million increase in prepaid expenses and other current assets.
The change in operating assets and liabilities was primarily due to an $8.1 million increase in accrued and other liabilities, a $6.8 million increase in accounts payable, offset by a $3.2 million decrease in operating lease liabilities, a $0.2 decrease in deferred revenue, a $0.4 million increase in prepaid expenses and other current assets and a $4.9 million increase in other assets.
We believe that our existing cash and cash equivalents will allow us to fund our planned operations for at least one year from the date of the issuance of this report.
We believe that our existing cash, cash equivalents and marketable securities will allow us to fund our planned operations for at least one year from the date of the issuance of the financial statements included in this report.
This was due to proceeds from the issuance of common stock upon public offering, net of issuance costs, of $316.1 million, proceeds from the issuance of common stock from the 2022 ATM Offering Program of $15.3 million, proceeds from the issuance of common stock from the exercise of stock options and warrants of $4.6 million and proceeds from the issuance of common stock from purchases from the Company’s 2020 Employee Stock Purchase Plan (“ESPP”) of $1.3 million.
This was due to proceeds from the issuance of common stock upon public offering, net of issuance costs, of $316.1 million, proceeds from the issuance of common stock from the 2022 ATM Offering Program of $15.3 million, proceeds from the issuance of common stock from the exercise of stock options and warrants of $4.6 million and proceeds from the issuance of common stock from purchases from the ESPP of $1.3 million.
As of December 31, 2024, the unrecognized stock-based compensation expense related to stock options was $54.5 million and is expected to be recognized as expense over a weighted-average period of approximately 2.1 years.
As of December 31, 2025, the unrecognized stock-based compensation expense related to stock options and RSUs was $34.2 million and is expected to be recognized as expense over a weighted-average period of approximately 1.7 years.
The capitalized amounts are recognized as expense as the goods are delivered or the related services are performed. 100 We do not allocate our costs by product candidate, as a significant amount of research and development expenses includes internal costs, such as salary and other personnel-related expenses, laboratory supplies and allocated overhead, and external costs, such as fees paid to third parties to conduct research and development activities on our behalf, none of which are tracked by product candidate.
We do not allocate our costs by product candidate, as a significant amount of research and development expenses includes internal costs, such as salary and other personnel-related expenses, laboratory supplies and allocated overhead, and external costs, such as fees paid to third parties to conduct research and development activities on our behalf, none of which are tracked by product candidate.
The intrinsic value of all outstanding stock options as of December 31, 2024 was approximately $0.3 million, of which $0.3 million related to vested options and zero related to unvested options.
The intrinsic value of all outstanding stock options as of December 31, 2025 was approximately $4.6 million, of which $1.0 million related to vested stock options and $3.6 million related to unvested stock options.
Our net losses were $160.9 million and $100.8 million for the years ended December 31, 2024 and 2023, respectively. As of December 31, 2024, we had an accumulated deficit of $576.2 million. We do not expect positive cash flows from operations in the foreseeable future.
Our net losses were $140.1 million and $160.9 million for the years ended December 31, 2025 and 2024, respectively. As of December 31, 2025, we had an accumulated deficit of $716.3 million. We do not expect positive cash flows from operations in the foreseeable future.
In March 2022, we also entered into an Open Market Sales Agreement (the “Sales Agreement”) with Jefferies LLC as sales agent to sell shares of our common stock, from time to time, with aggregate gross sales proceeds of up to $100.0 million pursuant to the S-3 Registration Statement as an “at-the-market” offering under the Securities Act (the “2022 ATM Offering Program”). 1,684,550 shares of the Company’s common stock have been sold pursuant to the Sales Agreement for net proceeds to the Company of $34.4 million, after deducting issuance costs.
For the year ended December 31, 2025, 1,175,000 shares of the Company's common stock were sold pursuant to the Leerink Sales Agreement for net proceeds to the Company of $9.6 million, after deducting issuance costs. 103 In March 2022, we also entered into an Open Market Sales Agreement (the “Sales Agreement”) with Jefferies LLC as sales agent to sell shares of our common stock, from time to time, with aggregate gross sales proceeds of up to $100.0 million pursuant to the S-3 Registration Statement as an “at-the-market” offering under the Securities Act (the “2022 ATM Offering Program”).
We have funded our operations primarily through the sale and issuance of equity securities and to a lesser extent from cash received pursuant to our collaboration and license agreements.
We have funded our operations primarily through the sale and issuance of our equity securities, including Follow-on Offerings and our “at-the-market” offering program, and to a lesser extent from cash received pursuant to our collaboration and license agreements.
Net Cash Provided by (Used in) Investing Activities Net cash used in investing activities was $302.4 million for the year ended December 31, 2024. This was due to purchases of marketable securities of $467.6 million and purchases of property and equipment of $3.8 million, offset by maturities of marketable securities of $169.0 million.
This was due to purchases of marketable securities of $467.6 million and purchases of property and equipment of $3.8 million, offset by maturities of marketable securities of $169.0 million. 106 Net Cash Provided by Financing Activities Net cash provided by financing activities was $113.0 million for the year ended December 31, 2025.
The net proceeds from the 2024 Offering were $281.2 million, after deducting underwriting discounts and commissions and other offering expenses.
The net proceeds from the 2023 Offering were $129.2 million after deducting underwriting discounts and commissions and offering expenses.
Our determination of the fair value of stock options on the date of grant utilizes the Black-Scholes option pricing model. 108 The fair value of the option granted is recognized on a straight-line basis over the period during which an optionee is required to provide services in exchange for the option award, known as the requisite service period, which usually is the vesting period.
The fair value of the option granted is recognized on a straight-line basis over the period during which an optionee is required to provide services in exchange for the option award, known as the requisite service period, which usually is the vesting period.
This was primarily due to the net loss of $160.9 million partially offset by a change of $25.7 million in noncash charges and by a net change of $0.5 million in our operating assets and liabilities.
Net cash used in operating activities was $134.6 million for the year ended December 31, 2024. This was primarily due to the net loss of $160.9 million partially offset by a change of $25.7 million in noncash charges and by a net change of $0.5 million in our operating assets and liabilities.
As a result, we will need significant additional capital to fund our operations, which we may obtain through one or more equity offerings, debt financings or other third-party funding, including potential strategic alliances and licensing or collaboration arrangements.
We expect that our overall research and development and general and administrative expenses will increase. As a result, we will need significant additional capital to fund our operations, which we may obtain through one or more equity offerings, debt financings or other third-party funding, the Otsuka Collaboration and License Agreement, and additional potential strategic alliances and licensing or collaboration arrangements.
Summary Statement of Cash Flows The following is a summary of cash flows for the periods indicated below (in thousands): Year Ended December 31, 2024 2023 Net cash used in operating activities $ (134,585 ) $ (75,792 ) Net cash provided by (used in) investing activities (302,437 ) 115,717 Net cash provided by financing activities 337,250 156,832 Net increase (decrease) in cash and cash equivalents $ (99,772 ) $ 196,757 Net Cash Used in Operating Activities Net cash used in operating activities was $134.6 million for the year ended December 31, 2024.
Summary Statement of Cash Flows The following is a summary of cash flows for the periods indicated below (in thousands): Year Ended December 31, 2025 2024 Net cash used in operating activities $ (109,082 ) $ (134,585 ) Net cash used in investing activities (92,973 ) (302,437 ) Net cash provided by financing activities 112,960 337,250 Net decrease in cash and cash equivalents $ (89,095 ) $ (99,772 ) Net Cash Used in Operating Activities Net cash used in operating activities was $109.1 million for the year ended December 31, 2025.
Insufficient liquidity may also require us to relinquish rights to product candidates at an earlier stage of development or on less favorable terms than we would otherwise choose. We cannot assure you that we will ever be profitable or generate positive cash flow from operating activities.
Insufficient liquidity may also require us to relinquish rights to product candidates at an earlier stage of development or on less favorable terms than we would otherwise choose.
At the end of each reporting period, we re-evaluate the estimated variable consideration included in the transaction price and any related constraint, and if necessary, adjust our estimate of the overall transaction price.
At the end of each reporting period, we re-evaluate the estimated variable consideration included in the transaction price and any related constraint, and if necessary, adjusts its estimate of the overall transaction price. We allocate the total transaction price to each performance obligation based on the estimated standalone selling prices.
Our ability to raise additional capital may be adversely impacted by potential worsening global economic conditions and the recent disruptions to and volatility in the credit and financial markets in the United States and worldwide resulting from the war in Ukraine, conflicts in the Middle East, any expansion of these conflicts, rising interest rates and inflation, natural disasters and pandemics. 105 If we are unable to obtain additional funding, we expect to delay, reduce or eliminate some or all of our research and development programs, product portfolio expansion or investment in internal manufacturing capabilities, which could adversely affect our business.
Our ability to raise additional capital may be adversely impacted by potential worsening global economic conditions and the recent disruptions to and volatility in the credit and financial markets in the United States and worldwide resulting from the war in Ukraine, conflicts in the Middle East, any expansion of these conflicts, rising interest rates and inflation, natural disasters and pandemics.
Stock-Based Compensation Expense We use a fair value-based method to account for all stock-based compensation arrangements with employees and nonemployees including stock options and stock awards.
Stock-Based Compensation Expense We use a fair value-based method to account for all stock-based compensation arrangements with employees and nonemployees including stock options and stock awards. Our determination of the fair value of stock options on the date of grant utilizes the Black-Scholes option pricing model.
Net cash used in operating activities was $$75.8 million for the year ended December 31, 2023. This was primarily due to the net loss of $100.8 million partially offset by a change of $24.4 million in noncash charges and by a net change of $0.6 million in our operating assets and liabilities.
This was primarily due to the net loss of $140.1 million partially offset by a change of $24.8 million in noncash charges and by a net change of $6.2 million in our operating assets and liabilities.
Net cash provided by investing activities was $115.7 million for the year ended December 31, 2023.
Net cash provided by financing activities was $337.3 million for the year ended December 31, 2024.
Revenue Recognition We determine revenue recognition for arrangements within the scope of ASC 606 by performing the following five steps: (i) identification of the promised goods or services in the contract; (ii) determination of whether the promised goods or services are performance obligations including whether they are distinct in the context of the contract; (iii) measurement of the transaction price, including the constraint on variable consideration; (iv) allocation of the transaction price to the performance obligations based on estimated selling prices; and (v) recognition of revenue when (or as) we satisfy each performance obligation. 107 Our revenue is primarily derived through our license, research, development and commercialization agreements.
Revenue Recognition We determine revenue recognition for arrangements within the scope of Accounting Standards Update 2014-09, Revenue from Contracts with Customers (Topic 606) (“ASC 606”) by performing the following five steps: (i) assessment whether a contract with a customer exists; (ii) determination of whether the promised goods or services are performance obligations; (iii) measurement of the transaction price, including the constraint on variable consideration; (iv) allocation of the transaction price to the performance 107 obligations based on estimated standalone selling prices; and (v) recognition of revenue when (or as) we satisfy each performance obligation.
In March 2024, the underwriters exercised their option and purchased 1,259,299 additional shares of common stock resulting in net proceeds of $34.9 million, after deducting underwriting discounts and commissions.
In March 2024, the underwriters exercised their option and purchased 1,259,299 additional shares of common stock resulting in net proceeds of $34.9 million, after deducting underwriting discounts and commissions. In May 2023, we completed the 2023 Offering in which 8,625,000 shares of our common stock were sold at an offering price of $16.00 per share.
See Note 7, Research and Collaboration Agreements, to our financial statements included elsewhere in this report for further discussion regarding the accounting treatment of this agreement. Future collaboration and license revenue is highly dependent on the successful development and commercialization of products by our collaboration partners, which is uncertain, and revenue may fluctuate significantly from period to period.
Future collaboration and license revenue is highly dependent on the successful development and commercialization of products by our collaboration partners, which is uncertain, and revenue may fluctuate significantly from period to period.
As partial consideration for the rights and licenses granted to AGT under the License Agreement, we received an upfront payment of $20.0 million.
As partial consideration for the rights and licenses granted to AGT under the License Agreement, we received an upfront payment of $20.0 million. Future Funding Requirements We have experienced recurring net losses and had an accumulated deficit of $716.3 million at December 31, 2025.
We have strengthened our ophthalmology senior leadership team and announced formation of the Ophthalmology Advisory Board, ahead of first Phase 3 clinical trial initiation for 4D-150 in wet AMD. The process of conducting the necessary clinical research to obtain regulatory approval is costly and time-consuming, and the successful development of our product candidates is highly uncertain.
However, we expect our overall research and development expenses to increase in the near term primarily for 4D-150 Phase 3 trials in wet AMD and DME. The process of conducting the necessary clinical development to obtain regulatory approval is costly and time-consuming, and the successful development of our product candidates is highly uncertain.
Overview We are a leading late-stage biotechnology company advancing durable and disease-targeted therapeutics with potential to transform treatment paradigms and provide unprecedented benefits to patients. Our core pipeline focus is advancing 4D-150 for the treatment of wet AMD and DME through late-stage studies and 4D-710 for treatment of cystic fibrosis through early-stage studies.
Overview We are a leading late-stage biotechnology company advancing durable and disease-targeted therapeutics with potential to transform treatment paradigms and provide unprecedented benefits to patients.
This was due to maturities of marketable securities of $173.3 million offset by purchases of marketable securities of $54.8 million and purchases of property and equipment of $2.8 million. 106 Net Cash Provided by Financing Activities Net cash provided by financing activities was $337.3 million for the year ended December 31, 2024.
Net Cash Used in Investing Activities Net cash used in investing activities was $93.0 million for the year ended December 31, 2025. This was due to purchases of marketable securities of $442.8 million and purchases of property and equipment of $0.5 million, offset by maturities of marketable securities of $350.4 million.
Significant management judgment is required to determine the level of effort required under an arrangement, and the period over which the Company expects to complete its performance obligations under the arrangement. Changes in these estimates can have a material effect on revenue recognized.
Significant management judgment is required to determine the level of effort required under an arrangement and the period over which we expect to complete our performance obligations under the arrangement.
As partial consideration for the rights and licenses granted to AGT under License Agreement, we received an upfront payment of $20.0 million which we recognized as revenue during the third quarter of 2023. In August 2019, we amended our agreement with uniQure and entered into a separate new collaboration and license agreement with uniQure.
Otsuka made an upfront cash payment of $85 million which we recognized as revenue during the fourth quarter of 2025, and agreed to provide certain cost sharing for global development activities. In August 2019, we amended our agreement with uniQure (the "Amended uniQure Agreement") and entered into a separate new collaboration and license agreement with uniQure (the "Second uniQure Agreement").
Research and Development Expenses The following table provides a breakout of research and development expenses for the periods indicated (dollars in thousands): Year Ended December 31, 2024 2023 $ Change % Change Research and development trials and consumables expenses $ 64,757 $ 39,550 $ 25,207 64 % Payroll and personnel expenses 57,383 42,848 14,535 34 % Facilities and other research and development expenses 19,159 14,698 4,461 30 % Total research and development expenses $ 141,299 $ 97,096 $ 44,203 46 % Research and development expenses for the year ended December 31, 2024 increased by $44.2 million, or 46%, from the year ended December 31, 2023.
Research and Development Expenses The following table provides a breakout of research and development expenses for the periods indicated (dollars in thousands): Year Ended December 31, 2025 2024 $ Change % Change Research and development trials and consumables expenses $ 100,220 $ 64,757 $ 35,463 55 % Payroll and personnel expenses 67,345 57,383 9,962 17 % Facilities and other research and development expenses 28,131 19,159 8,972 47 % Total research and development expenses $ 195,696 $ 141,299 $ 54,397 38 % Research and development expenses for the year ended December 31, 2025 increased by $54.4 million, or 38%, from the year ended December 31, 2024.
Accrued Clinical Research Organization Costs We estimate our accrued clinical research organization costs as of each balance sheet date.
Changes in these estimates can have a material effect on revenue recognized. 108 Accrued Clinical Research Organization Costs We estimate our accrued clinical research organization costs as of each balance sheet date.
The net proceeds from the 2023 Offering were $129.2 million after deducting underwriting discounts and commissions and offering expenses. 103 In July 2023, we entered into the License Agreement with AGT where we provided our 4D vector technology to AGT to deliver AGT’s genetic payloads for the treatment of rare monogenic diseases.
Otsuka made an upfront cash payment of $85 million and agreed to provide certain cost sharing for global development activities. In July 2023, we entered into the License Agreement with AGT where we provided our 4D vector technology to AGT to deliver AGT’s genetic payloads for the treatment of rare monogenic diseases.
The increase was due to the following: • a $25.2 million increase in research and development trials and consumables expense mainly due to increased clinical trial activity for our product candidates, primarily 4D-150; • a $14.5 million increase in payroll and personnel expenses due to increased headcount of research and development personnel, including a $4.1 million increase in employee stock-based compensation; and 102 • a $4.5 million increase in consulting services, facilities related expenses, software expenses and other research and development related expenses.
The increase was due to the following: • a $35.5 million increase in research and development trials and consumables expenses mainly due to increased clinical trial activity for our product candidates, primarily 4D-150; • a $10.0 million increase in payroll and personnel expenses primarily due to increased headcount of research and development personnel and one-time severance costs; and • an $8.9 million increase in facilities and other research and development expenses primarily due to higher rent and increased clinical trial activity for our product candidates. 102 General and Administrative Expenses General and administrative expenses for the year ended December 31, 2025 increased by $2.5 million, or 5%, from the year ended December 31, 2024.
The terms of these types of agreements may include (i) licenses to our technology, (ii) research and development services, and (iii) services or obligations in connection with participation in research or steering committees.
Our revenue is primarily derived through its license, research, development and commercialization agreements. The terms of these types of agreements may include (i) licenses to our technology, (ii) research and development services, and (iii) supplies of clinical and commercial materials.
Our second priority product candidate is 4D-710, which we believe is the first known genetic medicine to demonstrate successful delivery and expression of the CFTR transgene in the lungs of people with cystic fibrosis (CF). We believe these results will translate into durable clinical improvements in people with CF, including improved lung function and quality of life.
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.
The decrease in revenue is due to the upfront fees received from the License Agreement with Astellas in 2023.
The increase in revenue was primarily due to the upfront fees received from the Otsuka Collaboration and License Agreement in October 2025.
Royalty payments are recognized when earned or as the sales occur. We record cost reimbursements as accounts receivable when right to consideration is unconditional. A performance obligation is a promise in a contract to transfer a distinct good or service to the customer and is the unit of account in ASC 606.
A performance obligation is a promise in a contract to transfer a distinct good or service to the customer, and is the unit of account in ASC 606. Significant judgment is required to determine whether the individual promised goods or services are distinct.
Chris was most recently SVP & Chief Commercial Officer at Iveric Bio where he led commercial strategy and execution for the launch of IZERVAY. Components of Results of Operations Revenue Our revenue to date has been generated through payments from our collaboration and license agreements, primarily from upfront and milestone payments and expense reimbursement.
Components of Results of Operations Revenue Our revenue to date has been generated through payments from our collaboration and license agreements, primarily from upfront and milestone payments and expense reimbursement. We have not generated any revenue from the sale of approved products and do not expect to do so for the foreseeable future.
On May 31, 2024, we terminated the Sales Agreement and the 2022 ATM Offering Program pursuant to the terms of the Sales Agreement. In May 2023, we completed the 2023 Offering in which 8,625,000 shares of our common stock were sold at an offering price of $16.00 per share.
On May 31, 2024, we terminated the Sales Agreement and the 2022 ATM Offering Program pursuant to the terms of the Sales Agreement. At termination, 1,684,550 shares of our common stock had been sold pursuant to the Sales Agreement for net proceeds to us of $34.4 million, after deducting issuance costs.
Liquidity and Capital Resources Sources of Liquidity We have funded our operations primarily through the sale and issuance of our equity securities, including from the sale of our common stock in our IPO, Follow-on Offerings, and “at-the-market” offerings and the sale of our Series A, Series A-1, Series B and Series C redeemable preferred stock, and to a lesser extent from cash received pursuant to our collaboration and license agreements.
The proceeds of this funding agreement enabled the start of the Phase 2 stage of the AEROW clinical trial, redosing, and Phase 3 readiness activities. We have funded our operations primarily through the sale and issuance of equity securities and to a lesser extent from cash received pursuant to our collaboration and license agreements.
Net cash provided by financing activities was $156.8 million for the year ended December 31, 2023, which was due to proceeds from the issuance of common stock pursuant to public offerings of $129.2 million, proceeds from the issuance of common stock from the ATM offering program of $19.1 million, proceeds from the issuance of common stock upon exercise of stock options of $7.3 million and proceeds from ESPP purchases of $1.2 million.
This was due to proceeds from the issuance of common stock upon underwritten offering, net of issuance costs, of $93.5 million, proceeds from the issuance of common stock from the ATM Offering Program of $9.7 million, proceeds from the issuance of common stock under a stock purchase agreement of $7.5 million, proceeds from the issuance of common stock from purchases from the Company’s 2020 Employee Stock Purchase Plan (“ESPP”) of $1.3 million, and proceeds from the issuance of common stock from the exercise of stock options and warrants of $1.0 million.
In February 2024, we completed an underwritten public offering (the “2024 Offering” and, together with the 2023 Offering and the 2021 Offering (as defined below), the “Follow-on Offerings”) in which 6,586,015 shares of our common stock were sold at an offering price of $29.50 per share, as well as pre-funded warrants to purchase 3,583,476 shares of our common stock at an offering price of $29.4999 per underlying share pursuant to our effective registration statement on Form S-3.
Our recent sources of liquidity include the following transactions: Follow-on Offerings In November 2025, we completed an underwritten offering (the "2025 Offering") in which 8,385,809 shares of our common stock were sold at an offering price of $10.51 per share, as well as pre-funded warrants to purchase 1,128,949 shares of our common stock at an offering price of $10.5099 per underlying share.
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We believe these product candidates are differentiated and can support meaningful near-term and long-term value generation. In January 2025, we implemented a strategic pipeline prioritization designed to prioritize the development of 4D-150 and 4D-710.
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Our primary focus is advancing 4D-150 for wet age-related macular degeneration (“wet AMD”) and diabetic macular edema (“DME”) through late-stage studies and potential commercialization and advancing our other pipeline programs, 4D-175 for geographic atrophy, 4D-710 for CF lung disease, and 4D-725 for A1AT lung disease primarily through external funding including strategic partnerships.
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Further, we will be seeking strategic alternatives, including potential partnering, for our other clinical stage product candidates: 4D-175 for the treatment of geographic atrophy, 4D-725 for the treatment of alpha-1 antitrypsin deficiency, and 4D-310 for the treatment of Fabry disease cardiomyopathy.
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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 lead product candidate 4D-150 utilizes our proprietary R100 vector and a transgene encoding anti-VEGF biologics: aflibercept and an RNA interference (RNAi) approach targeting VEGF-C.
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In addition, we terminated the development of 4D-110 for the treatment of choroideremia and 4D-125 for the treatment of X-linked retinitis pigmentosa.
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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 AMD and DME.
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Our lead product candidate 4D-150 utilizes our proprietary R100 vector and a transgene cassette encoding aflibercept and inhibitory miRNA targeting vascular endothelial growth factor-C (“VEGF-C”). 4D-150 was designed to become the first backbone therapy for the treatment of retinal vascular diseases by providing multi-year sustained production of anti-VEGF from the retina with a single, safe, intravitreal injection, substantially reducing treatment burden and improving long-term patient outcomes. 4D-150 is initially being developed for the treatment of wet age-related macular degeneration (“wet AMD”) and diabetic macular edema (“DME”).
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In March 2025, we initiated 4FRONT-1, our first Phase 3 trial of 4D-150 in wet AMD. Subsequently in February 2026, we announced enrollment completion within an approximately 11-month period, ahead of initial projections, with the clinical trial overenrolled and expected to exceed 500 patients randomized, reflecting strong interest from investigators and patients.
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We also granted the underwriters the option to purchase up to 1,525,423 additional shares of common stock in connection with the offering. 98 In March 2024, the underwriters exercised their option to purchase 1,259,299 additional shares of common stock resulting in net proceeds of $34.9 million, after deducting underwriting discounts and commissions.
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We anticipate topline data with the 52-week primary endpoint in the first half of 2027. Additionally, 4FRONT-2, our second Phase 3 trial of 4D-150 in wet AMD, was initiated in June 2025. 4FRONT-2 is a global clinical trial and is enrolling both treatment-naïve and recently diagnosed, treatment-experienced patients.
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We have incurred significant operating losses and expect that our operating losses will increase significantly as we, among other things, continue to advance our product candidates through preclinical and clinical development, seek regulatory approval, and prepare for, and, if approved, proceed to commercialization; broaden and improve our platform; acquire, discover, validate and develop additional product candidates; maintain, protect and enforce our intellectual property portfolio; and hire additional personnel.
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We expect 52-week topline data for 4FRONT-2 in the second half of 2027.
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Recent Changes to Management / Leadership Team Effective as of January 2, 2024, our Board of Directors (the “Board”) appointed Noriyuki Kasahara, M.D., Ph.D., as Chief Scientific Officer. On January 1, 2024, Dr.
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In November 2025, we announced positive long-term interim results from the ongoing 4D-150 PRISM Phase 1/2 clinical trial in wet AMD. 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 1.5 to 2 years of follow-up.
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Kasahara delivered notice of his resignation from our Board, including his role as a member and the Chair of the Science and Technology Committee of the Board, effective on January 1, 2024. On August 5, 2024, we named Dhaval Desai, PharmD as Chief Development Officer who will oversee late-stage Product Development, Medical Affairs, Scientific Communications, Regulatory and Quality operations.
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In addition, a consistent dose response was observed between 3E10 vg/eye, the selected Phase 3 dose, and the lower dose of 1E10 vg/eye. The Phase 3 dose achieved clinically meaningful reductions in treatment burden. No new cases of intraocular inflammation were reported during this follow-up period with up to approximately 3.5 years of follow-up.
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Dhaval was most recently SVP & Chief Development Officer at Iveric Bio where he led development and approval of IZERVAY. Also on August 5, 2024, we named Carlos Quezada-Ruiz, M.D., FASRS as SVP, Therapeutic Area Head, Ophthalmology who will lead the Ophthalmology franchise and oversee Early- and Late-stage Clinical Development. Dr.
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In July 2025, we presented positive 60-week results from the 4D-150 SPECTRA clinical trial in DME where 4D-150 continued to be well tolerated with no intraocular inflammation observed at any timepoint or dose level.
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Quezada-Ruiz was most recently Group Medical Director, Ophthalmology at Genentech where he led clinical development and approval of VABYSMO and SUSVIMO. 99 Effective September 25, 2024, Christopher Simms joined as Chief Commercial Officer and will oversee Pre-commercial and Commercial organizations, pre-launch preparations and development.

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Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

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Biggest changeAs of December 31, 2024, we had cash, cash equivalents and marketable securities of $505.5 million, consisting of bank deposits, interest-bearing money market funds, and marketable securities, for which the fair value would be affected by changes in the general level of U.S. interest rates.
Biggest changeAs of December 31, 2025, we had cash, cash equivalents and marketable securities of $514.0 million, consisting of bank deposits, interest-bearing money market funds, and marketable securities, for which the fair value would be affected by changes in the general level of U.S. interest rates.

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