Meta‐analysis of treatment outcomes for patients with m.117 | 8G>A MT‐ND4 leber hereditary optic neuropathy

Aims/Purpose: To assess the visual outcomes of patients with Leber hereditary optic neuropathy (LHON) harboring the m.11778G>A MT‐ND4 mutation treated with no treatment (natural history), idebenone or lenadogene nolparvovec gene therapy.

Methods: Efficacy outcomes were clinically relevant recovery (CRR) from nadir and final best‐corrected visual acuity (BCVA). For the natural history and idebenone groups, a systematic review of the literature and available clinical/regulatory reports was performed. A total of 5 and 13 natural history studies were selected for the meta‐analyses of CRR from nadir and final BCVA, while 7 and 3 idebenone studies were selected, respectively. For the lenadogene nolparvovec group, all phase 3 studies were included (RESCUE, REVERSE, RESTORE and REFLECT). The overall effect and its 95% confidence interval (CI) were estimated using a random effects model.

Results: For each meta‐analysis, patients had a mean age of approximately 30 years at the time of vision loss and were mostly (≥78%) men. The CRR from nadir [95% CI] at eye level was estimated at 17% [7%; 30%] (n = 316 eyes), 31% [24%; 40%] (n = 313) and 59% [54%; 64%] (n = 348) in untreated, idebenone‐treated and lenadogene nolparvovec‐treated eyes, respectively. This gradient of efficacy was also observed with CRR at the patient level and final BCVA.

Conclusions: There was a gradient of efficacy in all assessed visual outcomes, more marked for CRR than for final BCVA, with lenadogene nolparvovec gene therapy superior to idebenone treatment, and both superior to the natural history of the disease.