Treatment Options for Acute/Subacute Patients with m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy: A Meta-analysis
Nancy Newman1, Patrick Yu-Wai-Man2, Valerio Carelli3, Valerie Biousse1, Catherine Vignal-Clermont4, François Montestruc5, Magali Taiel6, José-Alain Sahel7
1Emory University School of Medicine, Atlanta, GA, USA, 2Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK, 3University of Bologna, Bologna, Italy, 4Department of Neuro Ophthalmology and Emergencies, Rothschild Foundation Hospital, Paris, France, 5eXYSTAT, Malakoff, France, 6GenSight Biologics, Paris, France, 7Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
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.