Indirect Comparison of Lenadogene Nolparvovec Gene Therapy versus Natural History in m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy Patients
Nancy Newman1, Valerio Carelli2, Patrick Yu-Wai-Man3, Valerie Biousse1, Mark Moster4, Prem Subramanian5, Catherine Vignal-Clermont6, An-Guor Wang7, Sean Donahue8, Bart Leroy9, Robert Sergott10, Thomas Klopstock11, Alfredo Sadun12, Gema Rebolleda13, Bart Chwalisz14, Rudrani Banik15, Magali Taiel16, Jose-Alain Sahel17
1Emory University School of Medicine, 2University of Bologna, 3Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, 4Neuro-Ophthalmology -Wills Eye Hospital, 56. Sue Anschutz-Rodgers University of Colorado Eye Center, 6Foundation Ophtalmologique A De Rothschild, 7Taipei Veterans General Hospital, 8Vanderbilt University and Vanderbilt Eye Institute, 9Ghent University Hospital, 10Wills Eye Hospital, 11University of Munich, Dept. of Neurology, 12Doheny Eye Institute USC Sch., 13Ramon y Cajal hospital, 14Massachusetts General Hospital, Department of Neurology, 15Icahn School of Medicine at Mount Sinai, 16GenSight Biologics, 17Institut de la Vision
Objective:
To compare the visual acuity of m.11778G>A MT-ND4 Leber hereditary optic neuropathy (LHON) patients treated with lenadogene nolparvovec in clinical studies to the spontaneous evolution of visual acuity in an external control group of m.11778G>A MT-ND4 LHON patients.
Background:
A previous analysis was performed on treated patients from three phase 3 studies. This updated analysis incorporates a fourth study, REFLECT, in which patients received lenadogene nolparvovec unilaterally or bilaterally.
Design/Methods:
Data of 174 MT-ND4 LHON patients intravitreally injected in one or both eyes were pooled from four phase 3 studies: 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:
Eyes treated with lenadogene nolparvovec had better visual acuity at all timepoints when compared to natural history eyes. Mean improvement versus natural history was -0.30 LogMAR (+15 letters) at last observation (p<0.01) with a maximal follow-up of 3.9 years after injection. When adjusting for covariates, the mean gain was -0.43 LogMAR (+21.5 letters) (p<0.0001). The size of the treatment effect was larger in patients who received bilateral treatment than in patients who received unilateral treatment.
Conclusions:
This comparison of treated patients with natural history patients confirmed a clinically meaningful and sustained improvement in visual acuity induced by lenadogene nolparvovec intravitreal injection in m.11778G>A MT-ND4 LHON patients.