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Clinical Trial
. 2025 Feb 1;143(2):99-108.
doi: 10.1001/jamaophthalmol.2024.5375.

Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy

Patrick Yu-Wai-Man  1   2   3   4 , Nancy J Newman  5   6 , Valérie Biousse  5   6 , Valerio Carelli  7   8 , Mark L Moster  9   10 , Catherine Vignal-Clermont  11   12 , Thomas Klopstock  13   14   15 , Alfredo A Sadun  16 , Robert C Sergott  9   10 , Rabih Hage  12 , Simona Degli Esposti  3   4 , Chiara La Morgia  7   8   17 , Claudia Priglinger  18 , Rustum Karanja  19 , Magali Taiel  20 , José-Alain Sahel  12   21   22   23 ; LHON Study Group
Collaborators, Affiliations
Clinical Trial

Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy

Patrick Yu-Wai-Man et al. JAMA Ophthalmol. .

Abstract

Importance: Limited studies have assessed the long-term benefit/risk of gene therapy for Leber hereditary optic neuropathy (LHON).

Objective: To determine the safety and efficacy of lenadogene nolparvovec in patients with LHON due to the MT-ND4 gene variant for up to 5 years after administration.

Design, setting, and participants: The RESCUE and REVERSE Long-Term Follow-up Study (RESTORE), conducted from 2018 to 2022, is the 5-year follow-up study of the 2 phase 3 clinical studies RESCUE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss Up to 6 Months From Onset in LHON Due to the MT-ND4 Mutation) and REVERSE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the MT-ND4 Mutation). At the end of each study, ie, 2 years after gene therapy administration, patients were offered enrollment in the RESTORE trial, a multinational, multicenter, prospective study, for an additional 3 years of follow-up. Patients with LHON due to the MT-ND4 gene variant received lenadogene nolparvovec in 1 eye and a sham injection in the other eye.

Intervention: Lenadogene nolparvovec was administered as a single intravitreal injection in the RESCUE/REVERSE studies.

Main outcomes and measures: Measures included best-corrected visual acuity (BCVA), quality of life using the National Eye Institute visual functioning questionnaire 25 (NEI VFQ-25), and adverse events.

Results: Among the 76 patients who received gene therapy in the RESCUE (n = 39) and REVERSE (n = 37) studies, 72 (94.7%) completed these studies; 62 patients (81.6%) participated in the RESTORE trial, and 55 patients (72.4%) completed the 5-year follow-up. Participants were mostly male (49 [79.0%]) with a mean (SD) age of 35.9 (15.3) years at treatment. At baseline, the mean (SD) BCVA was 1.5 (0.5) logMAR (20/600 Snellen) in eyes to be treated with lenadogene nolparvovec and 1.4 (0.5) logMAR (20/500) in sham eyes. At the end of the RESCUE/REVERSE trials, ie, 2 years after treatment, eyes treated with lenadogene nolparvovec and eyes treated with sham reached a mean BCVA value of 1.4 (0.6) logMAR (20/500). The mean (SD) change from baseline to year 2 was -0.05 (0.6) logMAR (+1 line) and 0.01 (0.6) logMAR (-0 line) in gene therapy-treated and sham eyes, respectively (difference, -0.03; 95% CI, -0.16 to 0.09; P = .60). Five years after treatment, the bilateral improvement from nadir was similar to that observed at 2 years, with a mean (SD) change in BCVA of -0.4 (0.5) logMAR (more than +4 lines) for eyes treated with lenadogene nolparvovec and -0.4 (0.4) logMAR (+4 lines) for eyes treated with sham (difference, -0.05; 95% CI, -0.15 to 0.04; P = .27). An improvement of at least -0.3 logMAR (+3 lines) from the nadir in at least 1 eye was observed in 66.1% of participants (41 of 62). Between 2 and 5 years, intraocular inflammation was noted in 4 participants with 8 events in eyes treated with lenadogene nolparvovec and 1 event in an eye treated with sham.

Conclusions and relevance: In this analysis of the RESTORE trial, follow-up of patients with LHON due to the MT-ND4 gene variant unilaterally treated with lenadogene nolparvovec demonstrated a sustained bilateral improvement in BCVA and a good safety profile up to 5 years after treatment. This evidence of persistent benefit over time is promising for the use of gene therapy in these patients.

Trial registration: ClinicalTrials.gov Identifier: NCT03406104.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Yu-Wai-Man reported receiving consultant fees from GenSight Biologics, Chiesi, and Neurophth and research support from GenSight Biologics and Santhera outside the submitted work. Dr Newman reported receiving consultant fees from GenSight, Santhera, Chiesi, Neurophoenix, Stoke, Neurophth Therapeutics, and Avidity Bioscience, and research support from GenSight Biologics and Santhera outside the submitted work. Dr Biousse reported receiving consultant fees from GenSight Biologics and Neurophoenix during the conduct of the study. Dr Carelli reported receiving consultant fees from GenSight Biologics, Santhera, Stealth BioTherapeutics, Chiesi, and Pretzel Therapeutics and research support from Santhera and Stealth BioTherapeutics outside the submitted work. Dr Moster reported receiving grants from Genworth and consultant fees/research support from GenSight Biologics during the conduct of the study. Dr Vignal-Clermont reported receiving grants and consultant fees from GenSight Biologics and research support from Santhera during the conduct of the study. Dr Klopstock reported receiving grants and consultant fees from GenSight Biologics and consultant fees from Chiesi Farmaceutici during the conduct of the study. Dr Sadun reported receiving consultant fees from GenSight and Stealth BioTherapeutics during the conduct of the study. Dr Sergott reported consultant fees from Wills Eye Hospital and GenSight Biologics during the conduct of the study. Dr Hage reported personal fees from GenSight Biologics during the conduct of the study. Dr Degli Esposti reported personal fees from GenSight Biologics and other from GenSight Biologics during the conduct of the study; personal fees from GlaxoSmithKline, personal fees from Roche, personal fees from GlaxoSmithKline, personal fees from Bayer UK, personal fees from AbbVie, other from Bayer UK, other from Roche, and other from GlaxoSmithKline outside the submitted work. Dr La Morgia reported receiving consultant fees from Chiesi Farmaceutici, GenSight Biologics, Regulatory PharmaNet, and Thenewway srl and speaker honoraria and/or financial support for meetings from Santhera Pharmaceuticals, Chiesi Farmaceutici, GenSight Biologics, Regulatory PharmaNet, Thenewway srl, First Class srl, and Biologix outside the submitted work. Dr Priglinger reported receiving consultant fees/research support from GenSight and Novartis outside the submitted work. Dr Karanjia reported receiving consultant fees from Chiesi outside the submitted work. Dr Taiel reported being employed by and receiving a salary from GenSight Biologics outside the submitted work. Dr Sahel reported being a cofounder and shareholder of GenSight Biologics; receiving grants from Laboratoire d’Excellence (LabEx) LIFESENSES (ANR-10-LABX-0065), Institut Hospitalo-Universitaire FOReSIGHT (ANR-18-IAHU-0001), National Institutes of HealthCORE Grant (P30 EY08098), and RPB Research to Prevent Blindness, an unrestricted grant, LIGHT4DEAF (ANR-15-RHUS-000), and European Research Council (ERC) Synergy Helmholtz Grant (#610110) outside the submitted work; having a patent to on allotopic expression relevant to gene therapy of Leber hereditary optic neuropathy; a personal financial interest in Pixium Vision, GenSight Biologics, Sparing Vision, Prophesee, Chronolife, Tilak Healthcare, VegaVect Inc, Avista, Tenpoint, SharpEye; consultant fees from Tenpoint and Avista; and serving (unpaid censor) on the Board of GenSight and Sparing Vision. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flowchart of the Participants in RESCUE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss Up to 6 Months From Onset in LHON Due to the MT-ND4 Mutation), REVERSE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the MT-ND4 Mutation), and the RESCUE and REVERSE Long-Term Follow-up Study (RESTORE) Studies
Figure 2.
Figure 2.. Evolution of Best-Corrected Visual Acuity (BCVA) in Eyes (Treated and Sham) From the REVERSE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the MT-ND4 Mutation), RESCUE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss Up to 6 Months From Onset in LHON Due to the MT-ND4 Mutation), and the RESCUE and REVERSE Long-Term Follow-up Study (RESTORE) studies vs Natural History Eyes
The evolution of BCVA over time for treated eyes (n = 76 [RESCUE n = 39; REVERSE n = 37]) and natural history eyes (n = 408) was estimated by locally estimated scatterplot (LOESS) regression (solid line) with 95% CI around the fitted curve (shaded area). For natural history eyes, BCVA values after 86 months were assigned to the 86-month time point using the next observation carried backward method. Smoothing parameter: 0.302 for treated eyes and 0.413 for natural history eyes. The statistically significant difference between treated eyes (lenadogene nolparvovec and sham) and natural history eyes is illustrated by the nonoverlapping CIs of LOESS curves. Mean difference at last observation was estimated by a mixed-model analysis of covariance with repeated measures: −0.32 (95% CI, −0.44 to −0.21) logMAR (P <.001 vs natural history and Kruskal-Wallis test: P <.001 vs natural history).
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Comment on

References

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