Gene Therapy Improves Vision Recovery in LHON Over Idebenone, Natural History


Data from a meta-analysis of 3 groups of patients were presented at AAN 2024.

Nancy J. Newman, MD, professor, department of ophthalmology, Emory University School of Medicine

Nancy J. Newman, MD

Credit: Emory University

Patients with Leber hereditary optic neuropathy with a m.11778G>A MT-ND4 mutation (m.11778G>A MT-ND4 LHON) treated with lenadogene nolparvovec (Lumevoq; GenSIght Biologics) gene therapy had greater improvements in visual recovery than those treated with idebenone, and patients treated with either therapy had improvements over natural history.1

These data, from a retrospective analysis, were presented at the 2024 annual meeting of the North American Neuro-Ophthalmology Society (NANOS), held March 2-7, in Honolulu, Hawaii, by Nancy J. Newman, MD, professor, department of ophthalmology, Emory University School of Medicine.

“This study is very important in order to compare these therapies’ abilities to achieve equivalent end-point metrics. It is clear that the degree of efficacy of the gene therapy was greater than the other currently available options of no treatment and idebenone use as previously administered in studies,” Newman said in a statement.2

Newman and colleagues conducted 3 independent meta-analyses on 3 groups of patients with m.11778G>A MT-ND4 LHON that received no treatment (natural history), idebenone therapy, or lenadogenenolparvovec gene therapy intravitreal injection.The gene therapy group was derived from 174 patients from the phase 3 trials of lenadogenenolparvovec (NCT02652767, NCT03406104, NCT02652780, NCT03293524). The idebenone group was derived from 201 patients from 6 studies, and the natural history group was derived from 173 untreated patients from 5 studies.1

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The analysis’ primary outcome of CRR from nadir was a composite endpoint comprising on-chart best-corrected visual acuity (BCVA), gain of at least 10 ETDRS letters, and conversion from off-chart to on-chart BCVA. The investigators used an inverse-variance-weighted method to estimate an overall effect with a 95% CI.1

“The meta-analyses formalize the patient testimonies we have received that attest to the difference LUMEVOQ can make in patients’ lives: this treatment transforms the natural history of the disease,” Laurence Rodriguez, Chief Executive Officer, GenSight, added.2 “The team is working hard to make sure that patients and clinicians facing the visual emergency that is LHON have access to an efficacious treatment.”

Patients included in the meta-analysis were mostly (≥80%) men with around 30 years of age at the time of vision loss. Using the random-effects model, the investigators calculated CRR from nadir at eye level estimated at 19% [95% CI, 9-32] in the natural history group, 30% [95% CI, 20-41] in the idebenone-treated group, and 58% [95% CI, 52-63] in the lenadogene nolparvovec-treated group.1

Newman and colleagues also observed a trend of gradient of recovery with CRR at the patient level, with a response in one or both eyes, and no overlap in CRR 95% CIs when comparing lenadogene nolparvovec with natural history or idebenone.1

“Absence of a true placebo group in nearly all LHON clinical trials precludes drawing definitive conclusions on efficacy,” Newman and colleagues wrote, noting a limitation of the analysis.1

Other limitations that the authors noted included high heterogeneity across natural history studies and a lack of uniformity in standardized assessments of visual acuity and their frequency, with BCVA LogMAR assessment and prospective study design in 2/5 studies, and the inclusion of idebenone-treated patients in 2 natural history studies. Additionally, some natural history studies and idebenone studies included patients under the age of 15 years old at onset.1

“Lenadogene nolparvovec gene therapy improves visual recovery more than idebenone in m.11778G>A MT-ND4 LHON, and both treatments exceed the natural course of the disease,” Newman and colleagues concluded.1

1. Newman NJ, Yu-Wai-Man P, Carelli V, et al. Treatment Options For Acute/Subacute Patients with m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy: A Meta-analysis.Presented at: 2024NANOS Annual Meeting; March 2-7; Honolulu, Hawaii.
2. GenSight Biologics Announces Initial Results from New Meta-Analyses on Visual Outcomes with LUMEVOQ® Gene Therapy at NANOS 2024. News release. GenSightBIologies. March 12, 2024.
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