Subretinal Gene Therapy Drug AGTC-501 for XLRP Phase 1/2 Multicenter Study (HORIZON): 24-Month Safety and Efficacy Results

Purpose: To evaluate the safety and efficacy of subretinal gene therapy using AGTC-501 (rAAV2tYF-GRK1-RPGR) in male participants with X-linked retinitis pigmentosa (XLRP). Design: Phase 1/2, open-label, dose-escalation study. Methods: Setting: Four centers in the United States. Patient or Study Population: Twenty-nine males with XLRP and confirmed pathogenic RPGR variants. Mean age was 31.6 years (range 15-55). Intervention: Subretinal injection of AGTC-501 at doses ranging from 2.48 × 10¹⁰ to 1.99 × 10¹² vg/eye administered in one eye per participant. Subretinal injection sites initially targeted the peripheral retina and then transitioned to the macula with successive cohorts. Main Outcome Measures: Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), laboratory parameters, and immunological responses. Efficacy was evaluated by mesopic microperimetry mean sensitivity. Results: All 29 participants experienced ≥1 TEAE. Eleven (38%) experienced ≥1 grade 3 TEAE. Six (21%) experienced ≥1 ocular SAE related to AGTC-501, including retinal detachment (n = 4), subcapsular cataract (n = 1), and glaucoma (n = 1). Two (6.9%) experienced non-ocular treatment-emergent SAEs. Immunological findings did not indicate safety concerns. Three of 4 participants at the highest dose exhibited concerning retinal pigment epithelial changes. Half the participants at the highest tolerated dose (6.8 × 10¹¹vg/eye) maintained ≥7 dB improvement in ≥5 loci at 24 months. Conclusions: Subretinal AGTC-501 was generally well-tolerated. Despite all participants experiencing at least one TEAE, most of these events were mild in nature, exhibited complete resolution, and were associated with the subretinal injection procedure itself rather than the study agent. The highest dose exhibited an unfavorable risk-benefit profile due to the development of RPE changes. Although this group had the highest improvement in retinal sensitivity, our team has decided not to continue this dose in future clinical trials. Preliminary efficacy was observed at the maximum tolerated dose. Further studies are warranted to assess long-term safety and efficacy of AGTC-501 for XLRP treatment.