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

Abstract

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. Retrospective analysis of a phase 1/2 to 3 interventional clinical trial. Fifteen patients were included in this study. Each was administered with gene therapy in one with the other eye serving as control. Month 12 data from patients with RPGR-associated retinopathy enrolled at a single center in the XIRIUS trial (NCT03116113) were retrospectively analyzed. FDA-aligned low-luminance visual acuity (LLVA) responder criteria (≥15-letter gain) 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. Minimal baseline inclusion thresholds were used. The proportion of gene therapy-treated patients meeting FDA- and EMA-aligned (≥2.5 dB improvement in mean sensitivity) responder criteria was determined. Proportion of patients meeting the responder criteria in either microperimetry or LLVA. At baseline, LLVA excluded more patients from study inclusion due to floor effects than microperimetry. At month 12, 2 of 10 patients (20%) met LLVA responder criteria. In contrast, 5 of 11 patients (45%) met EMA-aligned whole-grid microperimetry responder criteria, including all LLVA responders and 3 additional patients with clear functional improvement not captured by LLVA. Restricting analysis to the central 16 microperimetry points further increased responder detection, identifying 7 of 11 patients (64%). Improvements in microperimetry mean sensitivity of at least 2.5 dB, exceeding expected test-retest variability. No responders were identified for any endpoint in untreated fellow eyes. Primary endpoint choice substantially affects efficacy detection and patient inclusion in RPGR gene therapy trials. LLVA demonstrated limited sensitivity and restricted eligibility to a narrow disease window, risking underestimation of treatment benefit. 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. Microperimetry-based endpoints provide a more sensitive and inclusive primary outcome measure for RPGR gene therapy trials.