Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy
Authors: Yu-Wai-Man Patrick , Newman Nancy J. , Biousse Valérie , Carelli Valerio , Moster Mark L. , Vignal-Clermont Catherine , Klopstock Thomas , Sadun Alfredo A. , Sergott Robert C. , Hage Rabih , Degli Esposti Simona , La Morgia Chiara , Priglinger Claudia , Karanja Rustum , Taiel Magali , Sahel José-Alain ,   LHON Study Group, Barboni Piero , Carbonelli Michele , Di Vito Lidia , Amore Giulia , Contin Manuela , Mohamed Susan , Silvestri Sara , Baker Hubbard George , Hendrick Andrew M. , Dattilo Michael , Peragallo Jason H. , Hawy Eman , DuBois Lindreth , Gibbs Deborah , Fernandes Filho Alcides , Dobbs Jannah , Aung Andre , Acheson James , Boston Hayley , Eleftheriadou Maria , Gemenetzi Maria , Leitch-Devlin Lauren , Tucker William R. , Jurkute Neringa , Burale Asma , DeBusk Adam A. , Haller Julia A. , Massini Maria , SantaMaria Melissa , Tollis Heather , Girmens Jean-François , Plaine Lise , Khemliche Wahiba , Catarino Claudia B. , Priglinger Siegfried , Rudolph Günther , Thurau Stephan , von Livonius Bettina , Muth Daniel , Wolf Armin , Al-Tamami Jasmina , Pressler Angelika , Schertler Cosima , Hildebrandt Martin , Neuenhahn Michael , Heilweil Gad , Tsui Irena 
Published: December 2024

ImportanceLimited studies have assessed the long-term benefit/risk of gene therapy for Leber hereditary optic neuropathy (LHON).ObjectiveTo determine the safety and efficacy of lenadogene nolparvovec in patients with LHON due to the MT-ND4 gene variant for up to 5 years after administration.Design, Setting, and ParticipantsThe RESCUE and REVERSE Long-Term Follow-up Study (RESTORE), conducted from 2018 to 2022, is the 5-year follow-up study of the 2 phase 3 clinical studies RESCUE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss Up to 6 Months From Onset in LHON Due to the MT-ND4 Mutation) and REVERSE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the MT-ND4 Mutation). At the end of each study, ie, 2 years after gene therapy administration, patients were offered enrollment in the RESTORE trial, a multinational, multicenter, prospective study, for an additional 3 years of follow-up. Patients with LHON due to the MT-ND4 gene variant received lenadogene nolparvovec in 1 eye and a sham injection in the other eye.InterventionLenadogene nolparvovec was administered as a single intravitreal injection in the RESCUE/REVERSE studies.Main Outcomes and MeasuresMeasures included best-corrected visual acuity (BCVA), quality of life using the National Eye Institute visual functioning questionnaire 25 (NEI VFQ-25), and adverse events.ResultsAmong the 76 patients who received gene therapy in the RESCUE (n = 39) and REVERSE (n = 37) studies, 72 (94.7%) completed these studies; 62 patients (81.6%) participated in the RESTORE trial, and 55 patients (72.4%) completed the 5-year follow-up. Participants were mostly male (49 [79.0%]) with a mean (SD) age of 35.9 (15.3) years at treatment. At baseline, the mean (SD) BCVA was 1.5 (0.5) logMAR (20/600 Snellen) in eyes to be treated with lenadogene nolparvovec and 1.4 (0.5) logMAR (20/500) in sham eyes. At the end of the RESCUE/REVERSE trials, ie, 2 years after treatment, eyes treated with lenadogene nolparvovec and eyes treated with sham reached a mean BCVA value of 1.4 (0.6) logMAR (20/500). The mean (SD) change from baseline to year 2 was −0.05 (0.6) logMAR (+1 line) and 0.01 (0.6) logMAR (−0 line) in gene therapy–treated and sham eyes, respectively (difference, −0.03; 95% CI, −0.16 to 0.09; P = .60). Five years after treatment, the bilateral improvement from nadir was similar to that observed at 2 years, with a mean (SD) change in BCVA of −0.4 (0.5) logMAR (more than +4 lines) for eyes treated with lenadogene nolparvovec and −0.4 (0.4) logMAR (+4 lines) for eyes treated with sham (difference, −0.05; 95% CI, −0.15 to 0.04; P = .27). An improvement of at least −0.3 logMAR (+3 lines) from the nadir in at least 1 eye was observed in 66.1% of participants (41 of 62). Between 2 and 5 years, intraocular inflammation was noted in 4 participants with 8 events in eyes treated with lenadogene nolparvovec and 1 event in an eye treated with sham.Conclusions and RelevanceIn this analysis of the RESTORE trial, follow-up of patients with LHON due to the MT-ND4 gene variant unilaterally treated with lenadogene nolparvovec demonstrated a sustained bilateral improvement in BCVA and a good safety profile up to 5 years after treatment. This evidence of persistent benefit over time is promising for the use of gene therapy in these patients.Trial RegistrationClinicalTrials.gov Identifier: NCT03406104