Treatment Options for Acute/Subacute Patients with m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy: A Meta-analysis (P10-10.006)

Objective: To assess the visual outcomes of patients with Leber hereditary optic neuropathy (LHON) harboring the m.11778G>A MT-ND4 mutation with no treatment (natural history), idebenone therapy, and lenadogene nolparvovec intravitreal injection. Background: Current treatment options for LHON are limited to idebenone, a therapy not approved in all countries. Lenadogene nolparvovec is a novel gene therapy for MT-ND4 LHON patients, not yet approved except for compassionate use. Design/Methods: Based on a pre-defined statistical analysis plan, three independent meta-analyses were performed on 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 untreated patients from 5 studies and idebenone-treated patients from 6 studies. For the lenadogene nolparvovec group, patients were included from all phase 3 studies: RESCUE, REVERSE, RESTORE and REFLECT. An inverse-variance-weighted method was used to estimate an overall effect and its 95% confidence interval (CI) using random effects model. Results: For each meta-analysis, patients were mostly (≥80%) men, aged around 30 years at the time of vision loss. The CRR from nadir [95% CI] at eye level was estimated at 19% [9%; 32%] (n=173), 30% [20%; 41%] (n=201) and 58% [52%; 63%] (n=174) 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. Disclosure: Dr. Newman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for GenSight. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Chiesi. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurophoenix. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avidity. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurophth. The institution of Dr. Newman has received research support from GenSight. The institution of Dr. Newman has received research support from Chiesi/Santhera. The institution of Dr. Newman has received research support from NINDS/NIH. Dr. Newman has received publishing royalties from a publication relating to health care. Dr. Newman has received publishing royalties from a publication relating to health care. Dr. Newman has received publishing royalties from a publication relating to health care. Patrick Yu-Wai-Man has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GenSight Biologics. Dr. Carelli has received personal compensation in the range of $0-$499 for serving as a Consultant for Chiesi Farmaceutici. Dr. Carelli has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Chiesi Farmaceutici. Dr. Biousse has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gensights Biologic. Dr. Biousse has received personal compensation in the range of $0-$499 for serving as a Consultant for Neurophoenix. The institution of Dr. Biousse has received research support from NIH. Dr. Biousse has received publishing royalties from a publication relating to health care. Dr. Biousse has received publishing royalties from a publication relating to health care. Mrs. Vignal-Clermont has received personal compensation in the range of $0-$499 for serving as a Consultant for Gensight Biologics. Mr. Montestruc has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for eXYSTAT SAS. The institution of Mr. Montestruc has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AFM Telethon. Magali Taiel has nothing to disclose. The institution of Jose-Alain Sahel has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Avista. The institution of Jose-Alain Sahel has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Tenpoint . The institution of Jose-Alain Sahel has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for THE BOARD OF GENSIGHT. The institution of Jose-Alain Sahel has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for THE BOARD OF SPARINGVISION. Jose-Alain Sahel has stock in Prophesee. Jose-Alain Sahel has stock in Tilak Healthcare. Jose-Alain Sahel has stock in Sparing Vision. Jose-Alain Sahel has stock in Chronolife. Jose-Alain Sahel has stock in VegaVect Inc. Jose-Alain Sahel has stock in Avista. Jose-Alain Sahel has stock in Tenpoint. Jose-Alain Sahel has stock in SharpEye. Jose-Alain Sahel has stock in GenSight. The institution of Jose-Alain Sahel has received research support from LabEx LIFESENSES (ANR-10-LABX-65). The institution of Jose-Alain Sahel has received research support from IHU FOReSIGHT (ANR-18-IAHU-01). The institution of Jose-Alain Sahel has received research support from ERC Synergy "HELMHOLTZ". Jose-Alain Sahel has received intellectual property interests from a discovery or technology relating to health care.