Retinitis Pigmentosa Gene Therapy Trial Finishes Dosing Second Cohort


OCU400 utilizes Ocugen’s modifier gene therapy platform, which may allow the product to treat multiple retinal diseases.

A phase 1/2 clinical trial (NCT05203939) of Ocugen’s OCU400, an investigational gene therapy intended to treat inherited retinal diseases, has completed dosing of patients with retinitis pigmentosa (RP) in its second cohort and received recommendation from an independent Data and Safety Monitoring Board (DSMB) to proceed to enrolling patients for the third cohort based on its safety data review of the second cohort.1

OCU400 utilizes Ocugen’s Modifier Gene Therapy Platform, which may allow the product to treat multiple retinal diseases. The therapy is designed to deliver a functional copy of the nuclear hormone receptor gene NR2E3 via an adeno-associated viral (AAV) vector with the intention of resetting retinal homeostasis.2 OCU400 previously received orphan drug designations (ODDs) from the FDA for PDE6B gene mutation-associated retinal diseases, RHO mutation-associated retinal degeneration, NR2E3 mutation-associated retinal degeneration, and CEP290 mutation-associated retinal degeneration. It also was granted orphan medicinal product designation by the European Commission for the treatment of both RP and Leber congenital amaurosis (LCA) in February 2021.3

“I’m very pleased with the progress of the clinical trial,” David Birch, PhD, director, Retina Foundation of the Southwest, and primary investigator for the clinical trial, said in a statement.1 “Currently, patients with inherited retinal degeneration have nothing to address their condition in the long-term. It is imperative to keep working toward a solution for these patients who currently have no hope.”

The multicenter, open-label, dose ranging clinical trial will enroll approximately 18 patients aged 18 years or older who have NR2E3-related RP. Participants are required to have a confirmed genetic diagnosis of either biallelic autosomal recessive NR2E3 mutations, an autosomal dominant NR2E3 mutation, or an autosomal dominant RHO mutation. The first participant dosed in each cohort is required to have a best-corrected visual acuity (BCVA) of no greater than 20/160 in the study eye or a visual field less than 20° in any meridian. Other participants must have a BCVA no greater than 20/50 or a visual field less than 20° in any meridian. All participants must be able to perform multi-luminance mobility testing (MLMT) using the study eye but must be unable to pass at 1 lux. Patients for whom no evidence of outer nuclear layer containing the nuclei of the retinal photoreceptors is detectable via spectral-domain optical coherence tomography (SD-OCT), and patients who have had cataract surgery within 3 months, YAG capsulotomy in within a month, or any other intraocular surgery within 6 months will be excluded from the study. Additional exclusion criteria relate to patient treatment history and health status, with inability to fixate, high myopia, glaucoma, medium haze, more than 3-fold elevation of liver enzymes, or more than 2-fold elevation of serum creatinine potentially being exclusion criteria based on the investigator’s opinion.

The trial has 3 planned dose-level cohorts. Patients in the low dose cohort received a dose of up to 1.66×1010 vg/mL, patients in the mid-dose cohort received up to 3.33×1010 vg/mL, and the patients in the high-dose cohort will receive up to 1.66x1011 vg/mL. Doses will be administered via subretinal injection. The study’s primary end points are the counts, frequencies, and percentages of adverse events (AEs) related to OCU400, treatment-emergent AEs, and serious AEs. Secondary end points include the changes from baseline in BCVA, low-luminance visual acuity, slit-lamp biomicroscopy, intraocular pressure, indirect ophthalmoscopy, and analyses of blood samples for anti-AAV5, anti-hNR2E3 antibodies, and T-cell response. Other end points include changes from baseline in MLMT, ellipsoid zone width and length on wide-field 45° SD-OCT, contrast sensitivity, full field light stimulation threshold, static visual fields, responses to quality-of-life questionnaires, full field electroretinogram, and wide-field fundus autofluorescence. Enrollment in the third cohort is expected to be completed before the end of the year.

“As principal investigator of numerous major clinical trials developing new medical and surgical treatments for retinal disorders, I have been on the cutting-edge of many new ophthalmology treatments,” Carl D. Regillo, MD, FACS, member of Ocugen’s Retina Scientific Advisory Board and Professor of Ophthalmology at the Sidney Kimmel Medical College at Thomas Jefferson University, Chief of the Retina Service at Wills Eye Hospital, and founder and former director of the Wills Eye Clinical Retina Research Unit in Philadelphia, said in an August 2020 statement.2 “I am very encouraged by the potential for OCU400 given the uniqueness of Ocugen’s Modifier Gene Therapy Platform and the fact that FDA has issued four ODDs for this product.”

1. Ocugen announces completion of dosing in OCU400 phase 1/2 cohort 2. News release. Ocugen, Inc. October 12, 2022. 
2. Ocugen receives fourth FDA orphan drug designation for the same product, OCU400 (AAV-NR2E3) gene therapy, for the treatment of another key inherited retinal disease (IRD), PDE6B gene mutation-associated retinal diseases. News release. Ocugen, Inc. August 10, 2022. 
3. European Commission grants Ocugen orphan medicinal product designation for gene therapy product candidate, OCU400, for the treatment of both retinitis pigmentosa and leber congenital amaurosis. News release. Ocugen, Inc.February 23, 2021. 
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