FREE PAPER PRESENTATIONS FP02-4 FP02-5 Treatment with lenadogene nolparvovec gene therapy results in sustained visual improvement in m.11778G>A MT-ND4-LHON patients: the RESTORE study V. Biousse1, P. Yu-Wai-Man2, N.J. Newman1, V. Carelli3, M.L. Moster4, C. Vignal-Clermont5, T. Klopstock6, A.A. Sadun7, R.C. Sergott4, M. Taiel8, J.-A. Sahel9 1Emory University School of Medicine, Departments of Ophthalmology, Neurology and Neurological Surgery, Atlanta, United States, 2Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, University of Cambridge, Department of Clinical Neurosciences, Cambridge, United Kingdom, 3IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy, 4Wills Eye Hospital and Thomas Jefferson University, Departments of Neurology and Ophthalmology, Philadelphia, United States, 5Rothschild Foundation Hospital, Department of Neuro Ophthalmology and Emergencies, Paris, France, 6Friedrich Baur Institut, Munich, Germany, 7Doheny Eye Institute, UCLA School of Medicine, Los Angeles, United States, 8GenSight Biologics, Paris, France, 9Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France Purpose: Two phase 3 clinical studies, RESCUE and REVERSE, assessed the efficacy and safety of an intravitreal injection of lenadogene nolparvovec gene therapy in patients with Leber hereditary optic neuropathy (LHON) due to the m.11778G>A mitochondrial DNA mutation in MT-ND4. Recruited patients were followed up for a period of 5 years post-treatment as part of the long- term RESTORE study. Methods: In RESCUE and REVERSE, all patients were treated with lenado- gene nolparvovec in one eye with a sham injection in the other eye. After 96 weeks, patients were invited to participate in RESTORE for another 3 years, corresponding to 5 years post-treatment administration. Quality of life was monitored using the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25). Results: Of the 72 patients who completed RESCUE or REVERSE, 62 par- ticipated in RESTORE. Patients were mostly male (79.0%) with a mean (stan- dard deviation [SD]) age of 37.1 (15.3) years. Five years after treatment, the bilateral improvement from nadir observed at 2 years was maintained with an absolute mean change (SD) in BCVA from nadir of -0.44 (0.46) LogMAR (+22.0 EDTRS letters equivalent) for lenadogene nolparvovectreated eyes and -0.39 (0.36) LogMAR (+19.5 EDTRS letters equivalent) for shamtreated eyes. At 5 years, BCVA for most patients (80.7%) were on chart (i.e., ≤1.6 LogMAR). A clinically relevant response from nadir was observed in 71.0% of patients. Overall, quality of life improved in a clinically meaningful way with a mean gain of 7 points from baseline for the VFQ-25 composite score. The safety profile was favorable, similar to that observed in the first 2 years after treat- ment. Conclusion: Long-term follow-up of MT-ND4-LHON patients who were uni- laterally treated with lenadogene nolparvovec demonstrated a sustained im- provement of BCVA in both eyes with an improvement of quality of life up to 5 years after treatment. Indirect comparison of lenadogene nolparvovec gene therapy versus natural history in m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy patients N.J. Newman1, M.L. Moster2, V. Carelli3, P. Yu-Wai-Man4, V. Biousse1, P.S. Subramanian5, C. Vignal-Clermont6, A.-G. Wang7, S.P. Donahue8, B.P. Leroy9, R.C. Sergott2, T. Klopstock10, A.A. Sadun11, G. Rebolleda Fernández12, B.K. Chwalisz13, R. Banik14, M. Taiel15, J.-A. Sahel16 1Emory University School of Medicine, Departments of Ophthalmology, Neurology and Neurological Surgery, Atlanta, United States, 2Wills Eye Hospital and Thomas Jefferson University, Department of Neurology and Ophthalmology, Philadelphia, United States, 3IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy, 4Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, University of Cambridge, Department of Clinical Neurosciences, Cambridge, United Kingdom, 5Sue Anschutz- Rodgers University of Colorado Eye Center, University of Colorado School of Medicine, Aurora, United States, 6Rothschild Foundation Hospital, Department of Neuro Ophthalmology and Emergencies, Paris, France, 7Taipei Veterans General Hospital, National Yang Ming Chiao Tung University, Department of Ophthalmology, Taipei, Taiwan, 8Vanderbilt University, and Vanderbilt Eye Institute, Vanderbilt University Medical Center, Department of Ophthalmology, Neurology, and Pediatrics, Nashville, United States, 9Department of Ophthalmology and Center for Medical Genetics, Ghent University Hospital, and Department of Head & Skin, Ghent University, Ghent, Belgium, 10Friedrich Baur Institut, Munich, Germany, 11Doheny Eye Institute, UCLA School of Medicine, Los Angeles, United States, 12Alcala University, Department of Ophthalmology, Madrid, Spain, 13Massachusetts Eye & Ear, Harvard Medical School, Department of Ophthalmology, Boston, United States, 14Icahn School of Medicine at Mount Sinai, Department of Ophthalmology, New York, United States, 15GenSight Biologics, Paris, France, 16Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France Purpose: To compare the visual acuity of MT-ND4 Leber hereditary optic neuropathy (LHON) patients treated with lenadogene nolparvovec in clinical trials to the spontaneous evolution of visual acuity in an external control group of untreated MTND4 LHON patients. A previous analysis was performed on treated patients from three phase 3 stud- ies. This updated analysis incorporates a fourth trial, REFLECT, in which pa- tients received lenadogene nolparvovec unilaterally or bilaterally. Methods: Visual acuity data of 174 MT-ND4 LHON patients intravitreally injected in one or both eyes were pooled from four phase 3 trials: REVERSE, RESCUE, RESTORE and REFLECT. The external control group included 208 age-comparable (≥ 15 years old) untreated m.11778G>A MT-ND4 LHON patients from 11 natural history studies. Results: Both cohorts were predominantly male patients (81.2%) with a me- dian age at onset of vision loss of 26.0 years. Eyes treated with lenadogene nolparvovec had better visual acuity at all timepoints when compared to natu- ral history eyes. Mean [95% confidence interval (CI)] difference versus natural history was 0.30 [0.39; 0.22] LogMAR (+15 EDTRS letters) at last observation (p<0.01) with a maximal follow-up of 3.9 years after treatment. When adjusting for covariates, the estimated mean [95% CI] difference was 0.43 [0.53; 0.33] LogMAR (+21.5 EDTRS letters) versus natural history at last observation (p<0.0001). 8 Congress of the European Society of Ophthalmology (SOE) 15 - 17 June, 2023, Prague, Czech Republic - Abstract Book