Expanding on his earlier podcast discussion with EPR, Dr Arun Upadhyay, Chief Scientific Officer and Head of Research & Development at Ocugen, discusses the companys promising modifier gene therapy candidates for ophthalmic disorders.

OCU400 is a modifier gene therapy aimed at treating retinitis pigmentosa and Leber congenital amaurosis (LCA).

In April 2024, Ocugen received US Food and Drug Administration (FDA) clearance to initiate the Phase III liMeliGhT clinical trial for OCU400 for retinitis pigmentosa. Shortly thereafter, the European Medicines Agency (EMA) reviewed the study design, endpoints, and planned statistical analysis, and deemed the US-based trial acceptable for a Marketing Authorisation Application (MAA). In December 2023, the FDA granted OCU400 Regenerative Medicine Advanced Therapy (RMAT) designation.

The Phase III study will include 150 participants75 with the RHO gene mutation and 75 that are gene-agnostic. In each arm, participants will be randomised 2:1 to the treatment group (2.5 x 1010 vg/eye of OCU400) and the untreated control group.

Ocugen plans to expand the OCU400 clinical trial in the second half of 2024 to include patients with LCA, contingent on favourable results from the Phase I/II study and alignment with regulatory agencies.

EPR Podcast 24 Developing modifier gene therapy Ocugen

Unlike conventional methodsmodifier gene therapyemphasises the importance of the broader biological system, potentially leading to more effective treatments.

The gene-agnostic mechanism of action for OCU400 provides hope for a larger retinitis pigmentosa patient population and demonstrates the potential to expand the range of indications for which modifier gene therapy could apply.

Unlike conventional methods that typically focus on replacing a mutated gene with a functional copy, modifier gene therapy modifies gene expression using master gene regulators. These master regulators work in a gene-agnostic way and open the possibility for the treatment of diseases caused by different gene mutations.

Modifier gene therapy triggers epigenetic mechanisms to restore homeostasis in the cellular environment and thereby structural and functional improvement in affected cells.

This pragmatic approach emphasises the importance of the broader biological system, potentially leading to more effective treatments.

OCU410 is a modifier gene therapy for the treatment of geographic atrophy, an advanced stage of dry age-related macular degeneration (dAMD). It utilises an adeno-associated virus (AAV) delivery platform for the retinal delivery of the RAR-related orphan receptor A (RORA).

The RORA protein plays a crucial role in stress and metabolism, reducing lipofuscin deposits and oxidative stress, and demonstrates anti-inflammatory properties as well as inhibiting the complement system in in vitro and in vivo studies.

Ocugen is currently enrolling patients in the Phase I/II ArMaDa clinical trial to assess the safety and efficacy of OCU410 for GA secondary to dAMD.

The ArMaDa clinical trial will assess the safety and efficacy of unilateral subretinal administration of OCU410 in subjects with GA and will be conducted in two phases.

OCU410STis a modifier gene therapy utilising an AAV delivery platform (AAV5) for the retinal delivery of the RORA gene for treating the genetic eye disorder Stargardt disease.

The GARDian clinical trial will assess the safety and efficacy of unilateral subretinal administration of OCU410ST in participants and will be conducted in two phases.

In May 2024, Ocugen announced the second cohort (medium dose) completed dosing in the dose-escalation phase. To date, six patients with Stargardt disease have been dosed in the Phase I/II clinical trial. An additional three patients will be dosed with the high dose (cohort 3) in the dose-escalation phase.

Manufacturing of AAV vectors for gene therapy presents several significant challenges, such as:

By leveraging new technologies, [gene therapy] manufacturers can overcome existing challenges, streamline production workflows, and accelerate the development and commercialisation

There has been advancement in many areas related to gene therapy manufacturing, which has played a crucial role in accelerating gene therapy manufacturing by improving efficiency across the production process. By leveraging new technologies, manufacturers can overcome existing challenges, streamline production workflows, and accelerate the development and commercialisation.

Some of these improvements include:

Biopharmaceuticals, Clinical Development, Clinical Trials, Data Analysis, DNA, Drug Development, Drug Safety, Gene therapy, Industry Insight, Research & Development (R&D), Technology, Therapeutics

Read more:
Developing and manufacturing modifier gene therapy - European Pharmaceutical Review

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