Microperimetry as an Outcome Measure Improves Patient Eligibility and Efficacy Detection in RPGR Gene Therapy Trials

Abstract

Purpose: To evaluate how primary endpoint selection influences patient eligibility, enrolment, and detection of treatment efficacy in RPGR gene therapy trials, comparing low luminance visual acuity (LLVA) with microperimetry-based outcome measures. Design: Retrospective analysis of a phase 1/2-3 interventional clinical trial. Subjects: Fifteen patients were included in this study. Each was administered with gene therapy in one eye with the other eye serving as control. Methods: Month 12 data from patients with RPGR-associated retinopathy enrolled at a single centre in the XIRIUS trial (NCT03116113) were retrospectively analysed. FDA-aligned low-luminance visual acuity responder criteria and EMA-aligned significant change from baseline in microperimetry mean sensitivity were applied. Microperimetry outcomes were evaluated across the full 68-point MAIA grid and within a central 16-point subset. Results: At baseline, LLVA excluded more patients from study inclusion due to floor effects than microperimetry. At month 12, 2 of 10 patients met LLVA responder criteria. In contrast, 5 of 11 patients met EMA-aligned whole-grid microperimetry responder criteria, including all LLVA responders and three additional patients with clear functional improvement not captured by LLVA. Restricting analysis to the central 16 microperimetry points identified 7 of 11 patients. No responders were identified for any endpoint in untreated fellow eyes. Conclusions: Primary endpoint choice substantially affects efficacy detection and patient inclusion in RPGR gene therapy trials. Microperimetry mean sensitivity, particularly when spatially aligned with the treated retinal area, detected functional improvement in a substantially larger proportion of patients and supports broader enrolment.