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Objective REFLECT is the first randomised, double-masked, placebo-controlled multicentre phase 3 clinical trial that evaluated the efficacy and safety of bilateral intravitreal (IVT) injection of lenadogene nolparvovec in subjects with Leber hereditary optic neuropathy carrying the m.11778G>A mutation.Methods and analysis A total of 98 subjects were enrolled with vision loss of ≤12 months. The subjects were randomised to one of two treatment arms with all subjects receiving an intravitreal (IVT) injection of lenadogene nolparvovec in their first affected eye and the second-affected eye randomised to receive IVT of either lenadogene nolparvovec or placebo.Results The majority of subjects were male with a mean duration of vision loss of 8.3 months. All but one subject experienced bilateral loss of vision at the time of injection. The mean best-corrected visual acuity of first-affected eyes was worse compared with second/not-yet-affected eyes. Analysis of retinal anatomical parameters showed increased thinning in the first-affected eyes when compared with the second/not-yet-affected eyes with both treatment arms showing significant changes compared with unaffected individuals.Conclusion The REFLECT trial is the third and the largest phase 3 clinical study evaluating lenadogene nolparvovec in m.11778G>A Leber hereditary optic neuropathy (LHON) subjects. The observed demographics in REFLECT are consistent with previous reports in LHON subjects in the acute and dynamic phases of LHON disease. Combined with the visual function and anatomical parameters obtained in the previous RESCUE and REVERSE trials, REFLECT has provided a uniformly collected data set that should help direct future LHON clinical trials.

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON., Competing Interests: Declaration of interests P.Y.-W.-M., V.C., N.J.N., B.P., L.C., and T.K. received research support and/or personal compensation from Santhera Pharmaceuticals, Chiesi, and GenSight Biologics. P.Y.-W.-M. is also a consultant for Neurophth and Stoke Therapeutics. N.J.N. is also a consultant for Santhera Pharmaceutical, Chiesi, GenSight Biologics, Stoke Therapeutics, Avidity Biosciences, and Neurophoenix SAS, and has been a speaker and contributing writer for educational activities under the auspices of WebMD and First Class. P.S.S. is a consultant to GenSight Biologics and received research support from GenSight Biologics and Santhera Pharmaceuticals. M.H.L. received personal compensation from Santhera Pharmaceuticals. C.L.M. has acted as a consultant for Chiesi Farmaceutici, Regulatory PharmaNet, and Thenewway srl, and has also received speaker honoraria and/or financial support for meetings from these companies, as well as from First Class srl and Biologix. C.L.M. has also acted as a principal or study investigator for clinical trials sponsored by GenSight Biologics, Santhera Pharmaceuticals, Stoke Therapeutics, and Reneo Pharmaceuticals. C.P. received personal compensation from Novartis and has acted as an investigator in clinical trials for Santhera Pharmaceuticals, GenSight Biologics, and Iveric Bio. X.L. and L.T. are employees of Chiesi Farmaceutici S.p.A., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)