Phase 1/2 AAV5-hRKp.RPGR RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-Associated X-Linked Retinitis Pigmentosa

center dot PURPOSE: To assess the safety and efficacy of AAV5hRKp.RPGR RPGR in participants with retinitis pigmentosa GTPase regulator (RPGR)-associated RPGR )-associated X-linked retinitis pigmentosa (XLRP). center dot DESIGN: Open-label, phase 1/2 dose escalation/expansion study (ClinicalTrials.gov Identifier: NCT03252847). . center dot METHODS: Males ( > 5 years old) with XLRP-RPGR RPGR were evaluated. In the dose escalation phase, subretinal AAV5-hRKp.RPGR RPGR (low: 1.0 x 1011 11 vg/ml; intermediate: 2.0 x 1011 11 vg/ml; high: 4.0 x 1011 11 vg/ml) was administered to the poorer-seeing eye (n = 10). Dose confirmation (intermediate dose) was carried out in 3 pediatric participants. In the dose expansion phase, 36 participants were randomized 1:1:1 to immediate (low or intermediate dose) or deferred (control) treatment. The primary outcome was safety. Secondary efficacy outcomes included static perimetry, microperimetry, vision-guided mobility, best corrected visual acuity, and contrast sensitivity. Safety and efficacy outcomes were assessed for 52 weeks for immediate treatment participants and 26 weeks for control participants. center dot RESULTS: AAV5-hRKp.RPGR RPGR was safe and well tolerated, with no reported dose-limiting events. Most adverse events (AEs) were transient and related to the surgical procedure, resolving without intervention. Two serious AEs were reported with immediate treatment (retinal detachment, uveitis). A third serious AE (increased intraocular pressure) was reported outside the reporting period. All ocular inflammation-related AEs responded to corticosteroids. Treatment with AAV5-hRKp.RPGR RPGR resulted in improvements in retinal sensitivity and functional vision compared with the deferred group at Week 26; similar trends were observed at Week 52. center dot CONCLUSIONS: AAV5-hRKp.RPGR RPGR demonstrated an anticipated and manageable AE profile through 52 weeks. Safety and efficacy findings support investigation in a phase 3 trial. (Am J Ophthalmol 2024;267: 122134.