Treatment Options for Acute/Subacute Patients With m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy: A Meta-Analysis

We assessed the visual outcomes of patients with Leber hereditary optic neuropathy (LHON) harboring the m.11778G>A MTND4 mutation with no treatment (natural history), idebenone therapy, and lenadogene nolparvovec gene therapy intravitreal injection.

396 Treatment Options For Acute/Subacute Patients With m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy: A MetaAnalysis. Nancy J Newman 1, Patrick Yu-Wai-Man 2, Valerio Carelli 3, Valérie Biousse 1, Catherine Vignal-Clermont 4, François Montestruc 5, Magali Taiel 6, José-Alain Sahel 7 Emory University School of Medicine, 2 John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, United Kingdom; Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom, 3 IRCCS Istituto di Scienze Neurologiche di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy, 4 Department of Neuro Ophthalmology and Emergencies, Rothschild Foundation Hospital, Paris, France, 5 EXYSTAT, Malakoff, France, 6 GenSight Biologics, Paris, France, 7 Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France 1 Introduction: We assessed the visual outcomes of patients with Leber hereditary optic neuropathy (LHON) harboring the m.11778G>A MTND4 mutation with no treatment (natural history), idebenone therapy, and lenadogene nolparvovec gene therapy intravitreal injection. Methods: Based on a pre-defined statistical analysis plan, three independent meta-analyses were performed on these three groups of patients, with efficacy outcome being the clinically relevant recovery (CRR; on-chart best-corrected visual acuity [BCVA] gain of at least 10 ETDRS letters, or conversion from off-chart to on-chart BCVA) from nadir. For the natural history and idebenone groups, a systematic review of all available individual and aggregate data was performed, resulting in the inclusion of 173 untreated patients (from 5 studies) and 201 idebenone-treated patients (from 6 studies). For the lenadogene nolparvovec group, 174 patients were included from all phase 3 studies: RESCUE, REVERSE, RESTORE and REFLECT. An inverse-varianceweighted method was used to estimate an overall effect and its 95% confidence interval (CI). Results: For each meta-analysis, patients were mostly (≥80%) men, aged around 30 years at the time of vision loss. With the randomeffects model, the CRR from nadir [95% CI] at eye level was estimated at 19% [9%; 32%], 30% [20%; 41%] and 58% [52%; 63%] in untreated, idebenone-treated and lenadogene nolparvovec-treated patients, respectively. This gradient of recovery was also observed with CRR at the patient level (response in one or both eyes). There was no overlap in CRR 95% CIs when comparing lenadogene nolparvovec versus natural history and idebenone. Conclusions: There was a gradient of efficacy of visual recovery with lenadogene nolparvovec intravitreal gene therapy superior to idebenone treatment, and both superior to the natural history of the disease. References: None provided. Keywords: Optic neuropathy, Neuro-ophth & systemic disease ( eg. MS, MG, thyroid), Retina Financial Disclosures: Nancy J Newman; Patrick Yu-Wai-Man: Received research support and/or personal compensation from Santhera Pharmaceuticals, Chiesi, and GenSight Biologics.; Valerio Carelli: Received research support and/or personal compensation from Santhera Pharmaceuticals, Chiesi, and GenSight Biologics; Valérie Biousse; Catherine Vignal-Clermont; François Montestruc: Co-founder of eXYSTAT and consultant for GenSight Biologics.; Magali Taiel: Employee of GenSight Biologics (Paris, France).; José-Alain Sahel: Cofounder and shareholder of GenSight Biologics (Paris, France) and a patent coauthor on allotopic transport. Grant Support: None. Contact Information: None provided. 550 | North American Neuro-Ophthalmology Society