STOCKHOLM — Trial results are demonstrating the safety and effectiveness of a novel gene modifier therapy for treating retinitis pigmentosa associated with NR2E3 and RHO mutations.
Researchers speaking here at the American Society of Retina Specialists (ASRS) 2024 Annual Meeting reported that OCU400, developed by Ocugen, was generally well tolerated, with 89% of participants demonstrating stabilization or improvement in visual function measures.
OCU400 is designed to deliver functional copies of the gene NR2E3 to retinal cells using an adeno-associated virus vector. NR2E3 is a nuclear hormone receptor gene that acts as a potent modifier. It regulates several physiologic functions within the retina, including photoreceptor development and maintenance, metabolism, phototransduction, inflammation, and cell survival networks. OCU400 resets disrupted cellular gene networks and reestablishes homeostasis, potentially improving retinal health and function in patients with retinitis pigmentosa.
The Study: Safety and Efficacy Findings
This multicenter, open-label, phase 1/2 clinical trial was designed to evaluate the safety and efficacy of OCU400 in patients with retinitis pigmentosa caused by NR2E3 or RHO mutations. The trial used a 3+3 dose escalation and expansion design, with participants receiving a single unilateral subretinal injection of OCU400 at one of three dose levels (5 × 109, 1 × 1010, or 5 × 1010 vector genomes/eye).
Safety assessments included monitoring adverse events, ophthalmologic changes, and immune and biochemical responses. Efficacy was primarily measured through best corrected visual acuity (BCVA), low luminance visual acuity (LLVA), and multi-luminance mobility testing (MLMT). Additional exploratory endpoints included perimetric and electrophysiologic tests and the NEI-VFQ25 quality-of-life questionnaire.
In a 12-month follow-up of the 18 participants, researchers found that the treatment was generally well tolerated. No serious adverse events were reported in the low- and medium-dose groups. However, two occurred in the high-dose and open-enrollment cohorts: One linked to surgical technique and the other to the surgical procedure and OCU400.
One patient with the NR2E3 gene developed subretinal fluid under the fovea following surgery. The investigators deemed that both the amount of injected fluid during surgery and inflammation from the product contributed to the decreased vision. "A very important lesson from this study is to inject the therapy in the vicinity of the fovea for it to be effective, but avoid the detachment of the fovea," said Benjamin Bakall, MD, PhD, a retina specialist at Associated Retina Consultants in Phoenix and one of the investigators of the trial, told Medscape Medical News.
The second patient had an RHO gene mutation, with a very small number of remaining photoreceptors. The investigators believed that surgery contributed to the decreased function of the remaining photoreceptors.
"We see that patients develop stepwise vision loss when only a few remaining photoreceptors are present," said Bakall. "For the upcoming study, the patients need to have a minimum of a 5-degree visual field to ensure there are sufficient remaining cells to undergo the procedure."
Efficacy assessments showed that 89% of participants (16 out of 18) experienced stabilization or improved visual function in the treated eye, assessed through BCVA, LLVA, or MLMT scores compared to baseline. Specifically, 14 out of 18 patients displayed stabilization or improvement in MLMT scores from baseline; 80% of patients with the RHO mutation showed improvement in mobility tests.
A Great Unmet Need
Retinitis pigmentosa is a group of rare inherited eye disorders that causes the gradual breakdown of cells in the retina, leading to progressive vision loss over time. It can be caused by more than 200 gene mutations that affect the function or survival of photoreceptor cells in the retina.
"There's a great unmet clinical need for retinitis pigmentosa, where most upcoming therapies focus only on a single of the hundreds of causative genes," said Bakall.
Raj Mukherjee, an ophthalmologist based in Leeds, England, told Medscape Medical News that most current gene therapy strategies focus on individual genes associated with retinitis pigmentosa. While these targeted therapies can benefit specific patient populations, they do not address the broader spectrum of retinitis pigmentosa cases caused by the various mutations.
He explained that the incidence of each genetic mutation is small, making it especially challenging to find a therapy targeted to each of the hundreds of subgroups. "Developing one treatment that will be independent of their genetic mutation and treat everybody is helpful," he said. "A gene-agnostic therapy would be accessible for all retinitis pigmentosa patients without needing genetic testing."
Ocugen is currently conducting a phase 3 clinical trial for OCU400, which will enroll 150 participants, including those with RHO gene mutations and patients with gene-agnostic retinitis pigmentosa.
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