Pennsylvania biotech Ocugen advances a modifier gene therapy approach that resets retinal cellular networks rather than replacing individual mutations, positioning OCU400 to address up to 300,000 RP patients in the U.S. and Europe—far beyond the 1-2% eligible for current mutation-specific therapies. Chief Scientific Officer and Head of R&D Arun outlines the company’s clinical progress, CMC strategy, and regulatory positioning for three planned BLA filings over the next three years.

Addressing the Limitations of Mutation-Specific Gene Therapy

Retinitis pigmentosa represents one of the most genetically diverse inherited retinal diseases, with over 100 known gene mutations driving progressive vision loss. Current approved gene therapies target single mutations, leaving the vast majority of patients without treatment options.

Ocugen’s approach fundamentally differs from this mutation-by-mutation strategy. OCU400, the company’s lead candidate currently in the Phase 3 liMeliGhT trial, uses the NR2E3 modifier gene to reset dysfunctional gene networks and support photoreceptor survival across multiple genetic variants. “Unlike traditional gene therapies that target specific gene mutations, our platform uses nuclear hormone receptors to reset cellular homeostasis and create a sustainable environment for non-dividing retinal cells,” Arun explains.

The company’s second program, OCU410ST, applies a similar modifier approach using the RORA gene to address Stargardt disease, an inherited macular dystrophy affecting approximately 100,000 individuals in the U.S. and EU. The candidate received Rare Pediatric Disease Designation from the FDA in May 2025 and dosed its first patient in the Phase 2/3 GARDian3 pivotal confirmatory trial in July 2025. The European Medicines Agency’s Committee for Medicinal Products for Human Use confirmed acceptability of a single U.S.-based trial for Marketing Authorization Application submission.

Developing Functional Endpoints for Genetically Heterogeneous Populations

One of Ocugen’s most significant clinical development challenges involved establishing meaningful endpoints that work across RP’s genetic diversity. The FDA-accepted Multi-Luminance Mobility Test (MLMT) proved insufficient for the broad RP population OCU400 targets.

“The prior FDA accepted test, Multi-Luminance Mobility Test (MLMT), is limited in assessing a broad range of RP patients due to its focus on severe visual impairment, leading to a ceiling effect that misses subtle improvements in those with milder or early-stage disease,” Arun notes. The test’s validation for specific genetic mutations like RPE65 further restricted its applicability to heterogeneous RP populations.

Ocugen addressed this through development of the Luminance Dependent Navigation Assessment (LDNA) test in collaboration with the FDA. LDNA captures functional vision changes across early- to advanced-stage RP patients with various genetic backgrounds, serving as the primary endpoint for the Phase 3 liMeliGhT trial. The company also enhanced surgical safety through key opinion leader collaborations and surgeon training programs, ensuring high transduction efficiency through wider retina coverage using multiple blebs.

Manufacturing Strategy: Strategic Partnerships with Internal Capability Building

Ocugen’s manufacturing approach balances immediate clinical needs with long-term commercial readiness through a phased partnership model.

Current manufacturing activities leverage a strategic partner’s established expertise in AAV-based vector manufacturing and GMP-compliant production. This partnership provides the quality, reliability, and scalability needed for clinical supply, market authorization, and commercial launch across all three gene therapy programs.

In parallel, the company builds internal process development and manufacturing capabilities. “This includes strengthening in-house expertise in process optimization, analytical development, and quality systems to enable clinical and commercial manufacturing,” Arun explains. The dual approach provides operational flexibility during clinical development while establishing independence for sustainable long-term commercialization with significant global capacity.

Achieving Full Capsid Purity at Commercial Scale

AAV-based gene therapy manufacturing presents distinct CMC challenges as programs advance toward commercial production. Ocugen focused on two critical areas: capsid purity and potency assay development.

The company targets full capsid purity exceeding 80% while minimizing contaminants like host cell proteins and DNA. “Contamination from empty capsids, partial assemblies, and process-related impurities (e.g., lipids, proteins) often results in low purity. This is further exacerbated during scale-up, where shear stress and mixing inconsistencies lead to capsid aggregation or degradation, impacting downstream purification efficiency,” Arun notes.

Ocugen’s solution integrated process and analytics development from early stages, building a modular process from Phase 1 and conducting side-by-side runs at various scales to validate equivalence. This approach achieved lower yield variance, higher full capsid content, and reduced process and product-related impurities.

For potency assays—another persistent challenge in gene therapy development—traditional in vitro transduction assays showed high variability (CV >15%) and failed to fully capture in vivo efficacy. “For the BLA, we need assays that are phase-appropriate yet linked to MoA of the product, without over-relying on animal models,” Arun explains. The company implemented a tiered matrix-based approach with cell-based assays correlated to the transgene’s intended biological activity as potency measures for late-stage development and market authorization applications.

Regulatory Positioning for Gene-Agnostic Therapies

Ocugen’s gene-agnostic approach required proactive regulatory engagement to establish appropriate frameworks. The company emphasizes its mechanism-driven, disease-modifying approach that restores retinal homeostasis rather than targeting single-gene mutations.

OCU400 has secured RMAT designation, multiple Orphan Drug Designations, and Expanded Access Program approval from the FDA. The Committee for Advanced Therapies granted positive ATMP classification opinion, providing a clear regulatory pathway through centralized authorization. OCU410ST achieved ATMP classification from EMA, orphan and pediatric designations, and IND clearance for pivotal confirmatory Phase 2/3 trials.

“Ocugen’s regulatory strategy for OCU400 centers on demonstrating that its modifier mechanism provides consistent, clinically meaningful benefits across genetically diverse RP populations,” Arun explains. The approach uses functional endpoints like mobility and vision-based functional assessments to capture real-world clinical benefit beyond genotype limitations, integrates safety and efficacy data from multiple genotypes to support a unified broad indication, and commits to long-term follow-up and post-marketing evidence generation.

The company plans simultaneous BLA and MAA submissions upon successful pivotal outcomes, leveraging alignment achieved under RMAT and ATMP frameworks.

Preparing Distribution Infrastructure for Specialized Ocular Delivery

OCU400 requires a one-time subretinal surgical injection, necessitating specialized treatment center infrastructure. “Our treatment and distribution strategy puts the patient and his or her healthcare provider at the center of the treatment journey,” Arun notes.

The company’s approach includes stringent eligibility criteria, required infrastructure to handle and store gene therapies at appropriate temperatures, and coordinated delivery, reimbursement, and treatment logistics. Ocugen aims to create a frictionless treatment pathway from launch by leveraging the durability of a one-time subretinal injection.

Treatment readiness extends beyond logistics to clinical site capabilities. The company works with approximately ten leading U.S. retinal surgery centers, including Duke University Eye Center, University of Arizona and Associated Retina Consultants, and Gundersen Health System, ensuring surgical precision and patient enrollment capabilities across its trial network.

Platform Expansion Beyond Ocular Indications

With three ocular candidates advancing through late-stage development—OCU400 for RP, OCU410ST for Stargardt disease, and OCU410 for geographic atrophy—Ocugen positions its modifier gene therapy platform for expansion into systemic applications.

“Ocugen aims to evolve the modifier gene therapy platform into a multi-organ, multi-indication therapeutic engine, addressing diseases driven by network dysregulation rather than isolated gene mutations,” Arun explains. The company targets neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease and autism spectrum disorder, with the RORA program (OCU410 platform) serving as the cornerstone for expansion bridging ocular and neurological applications.

The company maintains focus on stand-alone gene therapy rather than combination approaches. “Given the genetic complexity and progressive nature of inherited retinal diseases, Ocugen does not currently see a meaningful role for combination approaches involving gene therapy and small molecules,” Arun notes. The modifier gene therapy design addresses root causes of retinal dysfunction by restoring gene network homeostasis, providing durable, one-time treatment benefit without need for ongoing pharmacologic intervention.

Three BLA Filings Planned Over Next Three Years

Ocugen’s immediate focus centers on advancing all three programs toward regulatory submissions. The FDA recently cleared an IND amendment to begin the Phase 2/3 pivotal confirmatory trial for OCU410ST, marking progress toward the company’s goal of filing three BLAs over the next three years.

The company has raised over $400 million through various funding mechanisms, enabling advancement from early research into late-stage clinical development. This capital directly supported progression of OCU400 and OCU410ST into pivotal registration trials, manufacturing at commercial scale to support late-stage clinical work and BLA/global regulatory filings, and completion of the OCU410 Phase 2 ArMaDa trial targeting geographic atrophy.

As Arun emphasized: “To truly address today’s complex therapeutic challenges, we must move beyond siloed expertise. No single discipline holds all the answers. Interdisciplinary collaboration among clinical, molecular, polymer, and material scientists is essential to overcome barriers like off-target effects and tissue-specific delivery. Equally important is elevating the patient’s perspective. Engaging patients early in the development process helps us design therapies and clinical trials that reflect their real-world needs, not just scientific goals.”