Phase 2 Study of Lenadogene Nolparvovec Gene Therapy for Leber Hereditary Optic Neuropathy: The REVISE Trial

Welcome to NeurologyLive^®'s Clinical Trial in Focus. Every month, an ongoing clinical trial in the landscape of neurology is featured, highlighting the design of the study, the targeted patient population, the enrollment criteria, the primary and secondary end points, and its potential implications for clinical care. This month’s spotlight is the phase 2 REVISE trial (NCT07303296) of lenadogene nolparvovec (Lumevoq; GenSight Biologics), also known as GS010, for patients with Leber hereditary optic neuropathy (LHON), a rare genetic disorder that leads to bilateral vision loss.

Phase 2 REVISE Trial

Lenadogene nolparvovec is an investigational gene therapy being studied in patients with LHON associated with the m.11778G>A MT-ND4 mutation, the most prevalent and severe genetic cause of the disease. The therapy is designed to deliver a functional copy of the MT-ND4 gene to mitochondria to restore complex I activity and address vision loss.¹ REVISE, the currently ongoing study, is a phase 2, dose-ranging, randomized, open-label trial assessing the safety and efficacy of bilateral intravitreal injections at 2 dose levels on visual acuity and retinal mitochondrial activity in 14 patients with ND4-associated LHON.²

Primary and Secondary End Points

REVISE will be led by principal investigator Catherine Vignal-Clermont, MD, an ophthalmologist in the Department of Neuro-Ophthalmology and Emergencies at the Rothschild Foundation Hospital in Paris. The primary end point will be change in best-corrected visual acuity (BCVA) from baseline to 1.5 years post-treatment in the study eyes. Secondary end points include BCVA responder rates over the same period, defined as an improvement of at least −0.2 LogMAR, BCVA change from baseline to 1.5 years post-treatment in both eyes, and comparisons of BCVA change between the high-dose and low-dose treatment arms.

Inclusion Criteria

Eligible participants will be required to be aged 15 years or older at the time of vision loss onset and to have clinically manifest bilateral vision loss because of ND4-associated LHON. Inclusion criteria will include a best-corrected visual acuity of at least logMAR +2.39 in both eyes, as measured by the Freiburg Visual Acuity and Contrast Test, and documented genotyping confirming the presence of pathogenic ND4 mitochondrial mutations in the absence of other pathogenic LHON-associated or optic nerve–related mutations.

Participants will be required to have a duration of vision loss between 6 months and 1.5 years in the first affected eye at the inclusion visit. Additional criteria will include the ability to obtain high-quality optical coherence tomography images in both eyes, clear ocular media with adequate pupillary dilation for examination, and negative serology for human immunodeficiency virus.

Exclusion Criteria

Participants will be excluded if they have a known allergy or hypersensitivity to lenadogene nolparvovec or its components, or if intravitreal treatment is contraindicated in either eye based on investigator judgment and international guidelines. Individuals with clinically relevant prior intraocular surgery, procedures, or intravitreal treatment in 6 months before enrollment, planned intraocular surgery, or optic neuropathy from causes other than LHON will not be eligible.

Additional exclusions will include a history of recurrent uveitis or active intraocular inflammation, indications for unilateral lenadogene nolparvovec treatment, recent idebenone use in 7 days before inclusion, inability to tolerate the required anti-inflammatory regimen, or the presence of ocular or systemic conditions that may compromise safety or interfere with study assessments. Participants will also be excluded if they have used investigational drugs or devices in the specified washout period, have previously received ocular gene therapy, or are pregnant or breastfeeding.

Phase 3 REFLECT Study

Lenadogene nolparvovec was previously studied in the phase 3 REFLECT trial (NCT03293524), a randomized, double-masked, placebo-controlled trial of 98 patients with vision loss because of LHON. All told, patients in that study who received one-time administration of the gene therapy sustained improvement in visual acuity over 5 years.³ Additionally, findings revealed that patients who underwent bilateral injections saw higher rates of visual acuity improvement. Notably, improvement of placebo eyes highlighted the consistent contralateral treatment effect observed in other phase 3 studies, including the REVERSE (NCT02652780) and RESCUE (NCT02652767) trials.

“The latest REFLECT data confirms that the improvement seen with lenadogene nolparvovec is sustained 5 years after treatment has been given, including the additional benefit observed in participants receiving a bilateral intravitreal injection of the gene therapy,” international principal investigator of REFLECT Patrick Yu-Wai-Man, MD, PhD, professor of ophthalmology and Honorary Consultant Neuro-ophthalmologist at the University of Cambridge, Moorfields Eye Hospital, and the UCL Institute of Ophthalmology, United Kingdom, said in a statement at the time of the REFLECT data release.³ “Importantly, REFLECT participants receiving a bilateral injection had a comparable safety profile to those treated unilaterally.”

In REFLECT, all participants received an intravitreal injection of lenadogene nolparvovec in their first affected eye, and the second affected eye was randomly assigned to either a second injection of the therapy or a placebo. Researchers randomly assigned 48 patients to bilateral treatment with lenadogene nolparvovec and 50 participants to unilateral treatment.⁴ The study evaluated treatment effects relative to the observed nadir, defined as the lowest BCVA recorded over the 5-year observation period.

The company noted that the mean visual acuity for eyes treated with lenadogene nolparvovec increased relative to the observed nadir, exceeding the +15-letter threshold (−0.3 LogMAR change) commonly used to define clinically meaningful improvement. Overall, patients who received bilateral treatment demonstrated a higher rate of recovery from the observed nadir. Investigators reported that 79% of bilaterally treated patients achieved on-chart vision compared with 72% of patients who received treatment in only one eye.

In terms of the safety profile, investigators observed that the most common ocular adverse event was intraocular inflammation, which was generally mild. Moreover, no serious ocular adverse events were reported, and no patients discontinued the study because of ocular or systemic adverse effects. These results were consistent with the 4-year post-treatment findings reported by the company in March 2024.⁵

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REFERENCES
1. Sergott RC, Carelli V, Newman NJ, et al. Predictors of Final Visual Outcome in Patients With Leber Hereditary Optic Neuropathy Treated With Lenadogene Nolparvovec Gene Therapy. Invest Ophthalmol Vis Sci. 2025;66(9):42. doi:10.1167/iovs.66.9.42
2. GenSight Biologics Announces Regulatory Approval for GS010/LUMEVOQ® REVISE Dose-Ranging Study in France. News release. GenSight Biologics. December 2, 2025. Accessed January 23, 2026. https://www.gensight-biologics.com/2025/12/02/gensight-biologics-announces-regulatory-approval-for-gs010-lumevoq-revise-dose-ranging-study-in-france/
3. GenSight Biologics Announces Five-Year Efficacy and Safety Results for LUMEVOQ® Gene Therapy at the Conclusion of the REFLECT Study. News release. GenSight Biologics. Published February 12, 2025. Accessed January 23, 2026. https://www.gensight-biologics.com/2025/02/12/gensight-biologics-announces-five-year-efficacy-and-safety-results-for-lumevoq-gene-therapy-at-the-conclusion-of-the-reflect-study/
4. Newman NJ, Yu-Wai-Man P, Subramanian PS, et al. Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy. Brain. 2023;146(4):1328-1341. doi:10.1093/brain/awac421
5. GenSight Biologics Confirms Sustained Efficacy and Safety of Bilateral LUMEVOQ® Injections Four Years After One-Time Administration. News release. GenSight Biologics. March 20, 2024. Accessed January 23, 2026. https://www.gensight-biologics.com/2024/03/20/gensight-biologics-confirms-sustained-efficacy-and-safety-of-bilateral-lumevoq-injections-four-years-after-one-time-administration/