Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

• Type of Material: Article
• Authors: Nancy Newman, Emory University; Patrick Yu-Wai-Man, University of Cambridge; Valerio Carelli, Istituto di Ricovero e Cura a Carattere Scientifico Istituto delle Scienze Neurologiche di Bologn; Valerie Biousse, Emory University; Mark L Moster, Wills Eye Hospital and Thomas Jefferson University; Catherine Vignal-Clermont, A. de Rothschild Foundation Hospital; Robert C Sergott, Wills Eye Hospital and Thomas Jefferson University; Thomas Klopstock, Ludwig-Maximilians-University Munich; Alfredo A Sadun, University of California Los Angeles; Jean-François Girmens, Ctr Hosp Natl Ophtalmol Quinze Vingts; Chiara La Morgia, Istituto di Ricovero e Cura a Carattere Scientifico Istituto delle Scienze Neurologiche di Bologna; Adam A DeBusk, Wills Eye Hospital and Thomas Jefferson University; Neringa Jurkute, Moorfields Eye Hospital National Health Service Foundation Trust; Claudia Priglinger, Ludwig-Maximilians-University Munich; Rustum Karanjia, University of California Los Angeles; Constant Josse, eXYSTAT; Julie Salzmann, Medical and Regulatory Consulting; François Montestruc, eXYSTAT; Michel Roux, GenSight Biol; Magali Taiel, GenSight Biol; José-Alain Sahel, Sorbonne Universite
• Language: English
• Date: 2021-05-24
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Newman, Yu-Wai-Man, Carelli, Biousse, Moster, Vignal-Clermont, Sergott, Klopstock, Sadun, Girmens, La Morgia, DeBusk, Jurkute, Priglinger, Karanjia, Josse, Salzmann, Montestruc, Roux, Taiel and Sahel.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fneur.2021.662838
• Title of Journal or Parent Work: FRONTIERS IN NEUROLOGY
• Volume: 12
• Start Page: 662838
• End Page: 662838
• Grant/Funding Information: GenSight fully funded RESCUE, REVERSE, CLIN06, and REALITY Registry studies. GenSight participated in the design and conduct of this study, in the collection, management, analysis, and interpretation of the data, and in the preparation, review, and approval of this manuscript. NN was supported in part by an ophthalmology department core grant from the NIH/NEI (P30 EY006360). PY-W-M was supported by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK) and also receives funding from Fight for Sight (UK), the Isaac Newton Trust (UK), Moorfields Eye Charity, the Addenbrooke's Charitable Trust, the National Eye Research Centre (UK), the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration, and the NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology.; VC was supported by grants from the Italian Ministry of Health (RF-2018-12366703), the Italian Ministry of Research (20172T2MHH), and Telethon-Italy (GUP15016). VC was also supported by patients' organizations MITOCON and IFOND and patients' donations. TK was supported by the German Federal Ministry of Education and Research (BMBF, Bonn, Germany) through grants to the German Network for Mitochondrial Disorders (mitoNET, 01GM1906A) and to the E-Rare project GENOMIT (01GM1920B). VB was supported in part by an ophthalmology department core grant from the NIH/NEI (P30 EY006360). J-AS was supported by the Agence Nationale de la Recherche within the Programme Investissements d'Avenir, Institut Hospitalo Universitaire FOReSIGHT (ANR-18-IAHU-0001) and LabEx LIFESENSES (ANR-10-LABX-65).
• Keywords: TRIAL; ND4; Science & Technology; Life Sciences & Biomedicine; Clinical Neurology; Neurosciences; CLINICAL-FEATURES; PEDIGREES; END-POINTS; natural history; Neurosciences & Neurology; gene therapy; IDEBENONE; Leber hereditary optic neuropathy; visual acuity
• Research Categories: Health Sciences, Opthamology; Health Sciences, Medicine and Surgery

Abstract

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p < 0.0001). Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.