Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation.

• Type of Material: Article
• Authors: Valerio Carelli, Istituto delle Scienze Neurologiche di Bologna; Nancy J. Newman, Emory University; Patrick Yu-Wai-Man, University of Cambridge; Valerie Biousse, Emory University; Mark L. Moster, Thomas Jefferson University; Prem S. Subramanian, University of Colorado Aurora; Catherine Vignal-Clermont, Rothschild Foundation Hospital; An-Guor Wang, National Yang Ming Chiao Tung University; Sean P. Donahue, Vanderbilt University; Bart P. Leroy, Ghent University; Robert C. Sergott, Thomas Jefferson University; Thomas Klopstock, Ludwig-Maximilians-University Munich; Alfredo A. Sadun, University of California Los Angeles; Gema Rebolleda Fernández, Alcala University; Bart K. Chwalisz, Harvard University; Rudrani Banik, Icahn School of Medicine at Mount Sinai; Jean Francois Girmens, Centre Hospitalier National d’Ophtalmologie des Quinze Vingts; Chiara La Morgia, Istituto delle Scienze Neurologiche di Bologna; Adam A. DeBusk, Thomas Jefferson University; Neringa Jurkute, NHS Foundation Trust; Claudia Priglinger, Ludwig-Maximilians-University Munich; Rustum Karanjia, University of California Los Angeles; Constant Josse, eXYSTAT; Julie Salzmann, Medical and Regulatory Consulting; Francois Montestruc, eXYSTAT; Michel Roux, GenSight Biologics; Magali Taiel, GenSight Biologics; Jose-Alain Sahel, Sorbonne Université
• Language: English
• Date: 2023-02
• Publisher: Adis
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s40123-022-00611-x
• Title of Journal or Parent Work: Ophthalmol Ther
• Volume: 12
• Issue: 1
• Start Page: 401
• End Page: 429
• Grant/Funding Information: GenSight Biologics fully funded the interventional studies RESCUE, REVERSE, RESTORE and REFLECT and the registry study REALITY. GenSight Biologics participated in the design and conduct of this study, the collection, management, analysis and interpretation of the data, and in the preparation, review, and approval of this manuscript. The journal’s Rapid Service Fees were funded by GenSight Biologics.
• Keywords: Natural history; MT-ND4; Visual acuity; LHON; Leber hereditary optic neuropathy; Gene therapy
• Research Categories: Biology, Genetics; Physics, Optics

Abstract

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. CONCLUSION: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. TRIAL REGISTRATION NUMBERS: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).