Treatment with lenadogene nolparvovec gene therapy results in sustained visual improvement in m.11778G>A MT-ND4-LHON patients: the RESTORE study

Abstract

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 lenadogene 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 participated in RESTORE. Patients were mostly male (79.0%) with a mean (standard 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 nolparvovec-treated eyes and -0.39 (0.36) LogMAR (+19.5 EDTRS letters equivalent) for sham-treated 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 treatment.

Conclusions : Long-term follow-up of MT-ND4-LHON patients who were unilaterally treated with lenadogene nolparvovec demonstrated a sustained improvement of BCVA in both eyes with an improvement of quality of life up to 5 years after treatment.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.