To compare the bilateral treatment effect on best-corrected visual acuity (BCVA) of gene therapy for Leber Hereditary Optic Neuropathy (LHON) to an external control group of untreated patients.

The two Phase-3 multi-center clinical trials RESCUE (NCT02652767) and REVERSE (NCT02652780) showed unexpected sustained bilateral improvement of BCVA following unilateral injection of rAAV2/2-ND4 gene therapy for LHON.

The treated population consisted of 76 ND4-LHON subjects injected unilaterally with rAAV2/2-ND4 in the RESCUE and REVERSE trials, of which 62 subjects enrolled in a long-term follow-up study (NCT03406104). The untreated population included a total of 208 subjects: 23 ND4-LHON subjects enrolled in the REALITY LHON Registry (NCT03295071) and 185 ND4-LHON subjects with individual patient-level data collected from 10 natural history studies in the literature. To allow for comparison with the treated population, the untreated population included only patients who were at least 15 years old at onset of vision loss. A Locally Estimated Scatterplot Smoothing (LOESS), non-parametric, local regression model was used to represent the evolution of BCVA over time. Comparison of BCVA between treated and untreated patients was performed at 12, 18, 24, 36 and 48 months after onset of vision loss.

BCVA evolution in the treated patients showed gradual, progressive, and sustained improvement from Month 12 to the last available observation (on average 51.5 months), whereas no recovery was observed in the untreated patients. At Month 48, mean BCVA was 1.26 LogMAR for treated patients and 1.59 LogMAR for untreated patients (a difference of 0.33 LogMAR or 16.5 ETDRS letters equivalent; p<0.01 for Kruskal -Wallis and repeated measures tests).

This indirect comparison of 76 treated patients with an external control group of 208 untreated patients showed a clinically meaningful effect of gene therapy on visual outcomes in ND4-LHON patients.