Optogenetic Therapy With UGX-201 in Advanced Nonsyndromic Retinitis Pigmentosa: Safety and Efficacy From an Exploratory Clinical Trial

OBJECTIVE: To evaluate the safety, tolerability, and preliminary efficacy of a single intravitreal injection of UGX-201, an optogenetic therapy utilizing an adeno-associated virus 2 type 7m8 variant to deliver a recombinant chimeric opsin to retinal ganglion cells, in advanced nonsyndromic retinitis pigmentosa (RP) patients. DESIGN: An investigator-initiated, open-label, nonrandomized, single-center trial (ChiCTR2200062174). PARTICIPANTS: Nine patients with advanced nonsyndromic RP were enrolled and stratified into two cohorts by visual function: six with light perception (LP) cohort and three with no LP (NLP) cohort. METHODS: vg/eye was administered in one eye per participant. All participants were followed up for at least 52 weeks and underwent comprehensive ophthalmic and systemic safety assessments along with visual structure and function examinations. MAIN OUTCOME MEASURES: The primary endpoint was safety, including adverse events (AEs), serious AEs, and treatment-related AEs over 52 weeks. Secondary endpoints included changes from baseline in best-corrected visual acuity, full-field stimulus threshold testing, and National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) scores through 52-week follow-up period. RESULTS: No serious ocular or systemic AEs occurred during the 52-week follow-up period. In the LP cohort, mean best-corrected visual acuity in the treated eyes assessed by Freiburg Visual Acuity and Contrast Test showed an improvement of 0.30 logMAR at Week 52. One participant exhibited substantial improvement in full-field stimulus threshold testing. The total composite score of the NEI VFQ-25 in LP cohort increased by 3.72 points at Week 52 from that at baseline. In the NLP cohort, all three participants restored LP in the treated eyes at Week 2, Week 4, and Week 24, respectively. Among them, two still maintained LP at Week 52 (end of study). CONCLUSIONS: UGX-201 exhibited a favorable safety profile and was well-tolerated in patients with advanced nonsyndromic RP. Sustained, meaningful visual acuity gains were observed in both LP and NLP cohorts, irrespective of baseline visual function status. These findings underscore the potential of UGX-201 as a first-in-class mutation-independent treatment option for advanced nonsyndromic RP.