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
Valério Carelli, Nancy J. Newman, Patrick Yu‐Wai‐Man, Valérie Biousse, Mark L. Moster, Prem S. Subramanian, Catherine Vignal, An-Guor Wang, Sean P. Donahue, Bart P. Leroy, Robert C. Sergott, Thomas Klopstock, Alfredo A. Sadun, Gema Rebolleda Fernández, Bart K. Chwalisz, Rudrani Banik, Jean‐François Girmens, Chiara La Morgia, Adam A. DeBusk, Neringa Jurkutė, Claudia Priglinger, Rustum Karanjia, Constant Josse, Julie Salzmann, François Montestruc, Michel J. Roux, Magali Taiel, José‐Alain Sahel, on behalf of the LHON Study Group, Valério Carelli, Piero Barboni, Michele Carbonelli, Lidia Di Vito, Giulia Amore, Manuela Contin, Susan Mohamed, Chiara La Morgia, Sara Silvestri, Pietro D’Agati, Nancy J. Newman, Valérie Biousse, George Baker Hubbard, O’Keefe Ghazala, Andrew Hendrick, Michael Dattilo, Jason H. Peragallo, Eman Hawy, Lindreth DuBois, Deborah Gibbs, Alcides Fernandes Filho, Jannah Dobbs, Patrick Yu‐Wai‐Man, James Acheson, Hayley Boston, Maria Eleftheriadou, Simona Esposti, Maria Gemenetzi, Lauren Leitch-Devlin, William Tucker, Neringa Jurkutė, Asma Burale, Shweta Anand, Muhammad Ali Memon, Rima Hussain, Rasha Jorany, Priyansha Sheel, Mark L. Moster, Robert C. Sergott, Melissa SantaMaria, Heather Tollis, Adam A. DeBusk, Julia A. Haller, Maria Massini, Prem S. Subramanian, Pecen Paula, Mathias Marc, Mary Preston, Steve Cho, José‐Alain Sahel, Catherine Vignal, Jean François Girmens, Rabih Hage, Lise Plaine, Wahiba Khemliche, An-Guor Wang, Hui‐Chen Cheng, Chen Celia, Jeong‐Min Hwang, Sun Chuanbin, Sean P. Donahue, Shriji Patel, Sapna Gangaputra, Megan Barrett, Scott T. Ruark, Wilkins Saige, Bart P. Leroy, Julie De Zaeytijd, Caroline Van Cauwenbergh, Hilde Verhauwen, Thomas Klopstock
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).