MT-ND4 LHON Gene Therapy Continues to Yield Vision Improvements

The safety profile of lenadogene nolparvovec at 5-years post treatment was similar to 2-year data.

Patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4) had sustained improvements in best corrected visual acuity (BCVA) in both eyes and quality of life 5 years after treatment with lenadogene nolparvovec (Gensight Biologics; Lumevoq) gene therapy.

These findings were presented in long-term follow-up data from the phase 3 RESTORE study (NCT03406104) atthe Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting, held April 23-27, 2023, in New Orleans, Louisiana, by Patrick Yu Wai Man, PhD, FRCPath, FRCOphth, professor, ophthalmology, Unviersity of Cambridge.

“Two phase 3 clinical studies, RESCUE and REVERSE, assessed the efficacy and safety of an intravitreal injection of lenadogene nolparvovec gene therapy in patients MT-ND4 LHON. Recruited patients were followed up for a period of 5 years post-treatment as part of the long-term RESTORE study,” Yu Wai Man and colleagues wrote.

The investigators evaluated data from 62 out of 72 total participants from RESCUE and REVERSE enrolled in RESTORE 96 weeks after treatment to be followed up for another 3 years (for a total of 5 years post treatment).These participants had a mean age of 37,1 years (standard deviation [SD], 15.3) and 79% were male. Both trials administered lenadogene nolparvovec in 1 eye of each patient.

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Yu Wai Man and colleagues found that participants had a bilateral improvement from nadir to 2 years of +22.0 EDTRS letters in the treated eyes and +19.5 EDTRS letters in the sham-treated eyes. Most patients (80.7%) had BCVA on chart (at most 1.6 LogMAR) and had a clinically relevant response from nadir (71.0%). The investigators also assessed quality of life using the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) and found that patients had a mean gain of 7 points from baseline on VFQ-25 composite score.

“Long-term follow-up of MT-ND4-LHON patients who were unilaterally treated with lenadogenenolparvovec demonstrated a sustained improvement of BCVA in both eyes with an improvement of quality of life up to 5 years after treatment,” Yu Wai Man and colleagues concluded.

No notable new safety data were observed, and the safety profile was similar tothat observed in the first 2 years after treatment. Recently reported 3-year data from the phase 3 REFLECT study (NCT03293524) also assessing lenadogene nolparvovec that align with the 5-year data.2

"The REFLECT trial has delivered a further set of results demonstrating the sustained benefit of lenadogenenolparvovec, while reconfirming its safety profile" Nancy J. Newman, MD, a professor of ophthalmology and neurology at Emory University School of Medicine and the international principal investigator of REFLECT, said in an earlier statement.2 "In addition, the additional benefit among bilaterally treated patients suggests that injection of both eyes may be the best option for LHON patients with the ND4 mutation."

1. Yu Wai Man P, Newman NJ, Valérie B, et al. Treatment with lenadogenenolparvovec gene therapy results in sustained visual improvement in m.11778G>A MT-ND4-LHON patients: the RESTORE study. Presented at: ARVO 2023 Annual Meeting; April 23-27; New Orleans, Louisiana. Abstract 1955
2.GenSight Biologics confirms sustained efficacy and safety of bilateral Lumevoq® injections at 3-year follow-up of REFLECT phase III trial. News release. GenSight Biologics. March 13, 2023. Accessed March 13, 2023.
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