Efficacy of Lenadogene Nolparvovec Gene Therapy Versus Idebenone: A Matched Adjusted Indirect Comparison
Valerie Biousse1, Patrick Yu-Wai-Man2, Nancy Newman1, Valerio Carelli3, Adeline Pierache4, Francois Montestruc4, Magali Taiel5, Jose-Alain Sahel6
1Emory University School of Medicine, 2John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, 3University of Bologna, 4EXYSTAT, 5GenSight Biologics, 6Sorbonne Université, INSERM, CNRS, Institut de la Vision
Objective:
To estimate the relative treatment effects of lenadogene nolparvovec gene therapy (LNGT) versus idebenone, we performed two matched adjusted indirect comparisons (MAICs) between idebenone aggregated data from the LEROS study and EAP program, and LNGT individual data from the REFLECT study (bilateral treatment).
Background:
Lenadogene nolparvovec is a not yet approved intravitreal gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 variant. Idebenone, a synthetic analog of coenzyme Q10, is the only approved treatment for LHON.
Design/Methods:
Matching covariates included age at disease onset, sex, baseline best-corrected visual acuity (BCVA), and time from vision loss to treatment. The outcomes of interest were clinically relevant recovery (CRR) from nadir at 24 months, time to initial CRR, and change from baseline of BCVA at 24 months.
Results:
For the MAIC LEROS vs REFLECT (effective sample size [ESS]: 77), a statistically higher CRR at 24 months was observed with LNGT compared with idebenone (60.4% vs 35.4%; OR=2.78, 95% CI [1.53; 5.06]; p=0.001). No statistically significant difference was observed between LNGT and idebenone for time to initial CRR and change from baseline BCVA at 24 months. For the MAIC EAP vs REFLECT, there was a low overlap between the two populations related to a difference in the time from vision loss to treatment (4.3 [2.7] vs 8.4 [3.4] months; p< 0.001). In a post-hoc sensitivity analysis comparing EAP to RESCUE (ESS: 33), CRR was 39.0% for idebenone vs 69.5% for LNGT (OR=3.59, [1.42; 9.06]; p=0.011).
Conclusions:
The two MAICs demonstrated a clinically meaningful higher visual recovery at 24 months with LNGT than with idebenone in ND4 patients.
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