Rod-Cone Dystrophy Gene Therapy Demonstrates Acceptable Safety, Study to Continue

SPVN06 (SparingVision) gene therapy had a manageable safety profile in patients with rod-cone dystrophy (RCD). A data safety monitoring board (DSMB) has provided a positive recommendation to proceed dosing in the trial based off the positive preliminary data.

Data from the phase 1/2 PRODYGY study (NCT05748873) were presented at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, Maryland, by James A. Gow, MD, Vice President, Clinical Development, SparingVision.

“RCD is a rare inherited retinal disorder leading to significant vision loss. No treatment is currently available to most patients,” Gow and colleagues wrote in their poster. “SPVN06 investigational gene therapy is independent from the pathogenic gene causing vision loss and promotes cone function and survival to prolong useful daylight vision.”

SPVN06 is a gene-independent investigational gene therapy expressing the neurotrophic rod-derived cone viability factor (RdCVF) and the thioredoxin RdCVF-Long (RdCVFL). PRODYGY is a first-in-human trial of SPVN06 enrolling participants with advanced RCD due to a mutation in the RHO, PDE6A, or PDE6B gene. The study is evaluating a single unilateral subretinal injection of SPVN06 in participants’ worse-seeing eye. The primary endpoint is safety and tolerability at 1 year after administration and the secondary endpoints are evaluating preliminary efficacy. The study has treated its first 2 cohorts at the low and medium doses. The first, dose-escalation part of the study will be proceeded by a controlled, double-blind, randomized extension phase of 3 cohorts of 33 planned participants total.

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As of the January 3, 2024, cutoff date, cohort 1 was 6 months post-treatment and cohort 2 was 1-3 months post treatment. There were 8 ocular adverse events (AEs) in cohort 1 in 7/8 treated eyes. These AEs were unrelated to SPVN06, with the exception of 1, “possibly related” ongoing moderate cataract progression. Participants in cohort 1 experienced AEs including mild subconjunctival hemorrhage (n = 3) on the day of surgery, all cases of which spontaneously resolved; mild transient increases in intraocular pressure (IOP; n = 1) 1 week after injection which spontaneously resolved 2 weeks after injection; and mild macular edema (n = 1) 6 months after injection which is ongoing without treatment.

Participants in cohort 2 had 15 ocular AEs in all treated eyes. Two AEs, mild-to-moderate increased IOP, were deemed possibly related to SPVN06 and resolved with standard treatment. Other AEs included mild-to-moderate subconjunctival hemorrhage (n = 3) on the day of surgery which spontaneously resolved and a mild macular hole caused by the injection procedure (n = 1). This participant had 250 uL injected instead of 300 uL (82% of planned dose).

The investigators detected total antibodies (Tab) against SPVN06 capsid in serum, which increased with each dose, in 1 participant each in the low and medium dose cohorts who had positive titers prior to injection. No T-cell response was observed against the capsid or RdCVF/ RdCVFL peptides and Tab peaked at week 2 after administration.

“First administration of SPVN06 to patients showed a favorable safety profile at low and medium doses, with no significant immune response,” Gow and colleagues concluded.

The DSMB has recommended continuing the trial without modifications, and to proceed with treatment administration at the highest dose in the third cohort.

REFERENCE

Gow JA, Martel J, Biouin L, et al. PRODYGY: A first-in-human trial of rod-derived cone viability factor (RdCVF) gene therapy in subjects with rod-cone dystrophy. Presented at: ASGCT 27th Annual Meeting, May 7-10; Baltimore, Maryland. Poster #916