Ocugen’s Gene-Agnostic Gene Therapy OCU400 Demonstrates Improvement or Stabilization in Retinitis Pigmentosa, Leber Congenital Amaurosis

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Among 12 patients evaluable for efficacy, 10 patients experienced stabilization or improvement from baseline in BCVA in their treated eyes.

Ocugen’s OCU400, an investigational modifier gene therapy intended to treat inherited retinal diseases, has demonstrated improvement or stabilization of vision among patients with retinitis pigmentosa (RP) and leber congenital amaurosis (LCA) treated in a phase 1/2 clinical trial (NCT05203939).1

The data, reported by Ocugen on September 13, 2023, is an update on results previously reported in April of this year. The updated data includes results from 12 patients who were evaluable for efficacy in cohort 1 (low dose, adults with RP), cohort 2 (medium dose, adults with RP), cohort 3 (high dose, adults with RP and adults with LCA), and the phase 2 open enrollment cohort (medium dose, adults with LCA). The patients’ follow-up ranged from 6 months to 12 months, with 2 patients from cohort 1 having 12 months of follow-up; 2 patients from cohort 1 and 3 patients from cohort 2 having 9 months of follow-up; and 2 patients from cohort 3 and 3 patients from the phase 2 open enrollment cohort having 6 months of follow-up.

Among the 12 patients, 10 patients (83%) experienced stabilization or improvement from baseline in best-corrected visual acuity (BCVA) in their treated eyes, 5 patients (42%) showed a 4-letter improvement in BCVA in treated eyes from baseline, and 4 patients (33%) showed a 7-letter improvement in BCVA in treated eyes from baseline. Among a subset of 7 patients who had disease associated with mutations in the RHO gene, 4 patients (57%) showed a 4-letter improvement in BCVA in treated eyes from baseline and 3 patients (43%) showed a 7-letter improvement in BCVA in treated eyes from baseline.

In terms of low-luminance visual acuity (LLVA), 10 of 12 patients (83%) likewise experienced stabilization or improvement from baseline in their treated eyes, 5 patients (42%) showed a 5-letter improvement in LLVA in treated eyes from baseline, and 3 patients (25%) showed a 10-letter improvement in LLVA in treated eyes from baseline. Among the patients with RHO mutations, 3 patients (57%) showed a 5-letter improvement in LLVA in treated eyes from baseline and 2 patients (29%) showed a 10-letter improvement in LLVA in treated eyes from baseline.

The study also measured multiluminance mobility testing (MLMT) scores; on this test, stabilization or improvement from baseline in the treated eyes was observed in 9 of 12 patients (75%). Four patients (33%) achieved at least 1 lux luminance level of improvement in treated eyes from baseline; 2 of these patients (17%) achieved a 3 lux luminance level of improvement. For the patients with RHO mutations, 6 (86%) showed stabilization or improvement from baseline in the treated eyes in MLMT score. Three of the patients with RHO mutations achieved a 3 lux luminance level improvement from baseline in the treated eyes.

“The RHO mutation affects more than 10,000 people in the US,” principal investigator David Birch, PhD, the scientific director of the Retina Foundation of the Southwest, said in a statement.1 “In my view, the clinical study update supports the gene-agnostic mechanism of action of OCU400 in RHO patients. The improvements in BCVA, LLVA, and MLMT in this patient population are very exciting and encouraging because stabilization alone could be considered as a treatment benefit.”

OCU400 was administered via subretinal injection to 1 eye. The trial includes patients with RP related to mutations in the RHO and NR2E3 genes, patients with LCA related to mutations in the CEP290 gene, and pediatric patients with either RP or LCA related to mutations in these genes. Patients were treated at low, medium, and high dose levels corresponding to 1.66x1010 vg/mL, 3.33x1010 vg/mL, and 1.66x1011 vg/mL respectively. In terms of safety, OCU400 was deemed generally safe and well-tolerated across the spectrum of disease-related mutations and dose levels included in the study. No serious adverse events (SAEs) have been reported among the patients who received the low and medium doses of OCU400, although 1 patient who received the high dose and 1 patient included in the open enrollment cohort experienced SAEs. Ocugen stated that the surgical procedure accounted for most AEs and that in the span of a few days to weeks resolution of most was reached.

The study has treated a total of 18 adult patients with RP so far. The ages of these patients range from 18 to 77 years and Ocugen noted that disease stage, racial and ethnic profiles, medical histories, and mutation subgroups are diverse in this group. The patients with LCA and the pediatric patients were enrolled later on. The enrollment of the pediatric patients was specifically cleared by the FDA in March 2023.2 At the time, the company noted that the trial had reached full enrollment for adult patients with RP, but enrollment of adult patients with LCA remained ongoing. Plans to begin a phase 3 trial for OCU400 at the tail end of 2023 were also announced.

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 vector with the intention of resetting retinal homeostasis.3,4 The gene therapy has received orphan drug designation (ODD) from the FDA for both RP and LCA indications.5 The therapy has also received 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.4

REFERENCES
1. Ocugen announces positive clinical study update from the phase 1/2 trial of OCU400, a modifier gene therapy product candidate, for the treatment of retinitis pigmentosa (R) and leber congenital amaurosis (LCA). News release. September 13, 2023. Accessed September 19, 2023. https://ir.ocugen.com/news-releases/news-release-details/ocugen-announces-positive-clinical-study-update-phase-12-trial
2. Ocugen announces FDA approval for enrollment of pediatric patients in ongoing OCU400 phase 1/2 clinical trial for the treatment of retinitis pigmentosa (RP) and Leber Congenital Amaurosis (LCA). March 27, 2023. Accessed September 19, 2023. https://www.globenewswire.com/news-release/2023/03/27/2634720/0/en/Ocugen-Announces-FDA-Approval-for-Enrollment-of-Pediatric-Patients-in-Ongoing-OCU400-Phase-1-2-Clinical-Trial-for-the-Treatment-of-Retinitis-Pigmentosa-RP-and-Leber-Congenital-Amau.html
3. Ocugen announces completion of dosing in OCU400 phase 1/2 cohort 2. News release. Ocugen, Inc. October 12, 2022. Accessed September 19, 2023. https://ir.ocugen.com/news-releases/news-release-details/ocugen-announces-completion-dosing-ocu400-phase-12-cohort-2
4. 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. Accessed September 19, 2023. https://ir.ocugen.com/news-releases/news-release-details/ocugen-receives-fourth-fda-orphan-drug-designation-same-product
5. Ocugen announces OCU400 receives orphan drug designations for retinitis pigmentosa and leber congenital amaurosis. News release. Ocugen, Inc. December 15, 2022. Accessed September 19, 2023. https://ir.ocugen.com/news-releases/news-release-details/ocugen-announces-ocu400-receives-orphan-drug-designations
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