The outcomes of an experimental treatment of “LUMEVOQ” (GS010; lenadogene nolparvovec), for ND4-LHON patients, were presented this month by GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), based in Paris, France. The final efficacy and safety results showed that five years after a one-time administration of the gene therapy, “the visual acuity improvement among patients with LHON (Leber Hereditary Optic Neuropathy) was sustained while maintaining a favourable safety profile.” Following the announcement, Prof. Patrick Yu-Wai-Man, MD, PhD, Professor of Ophthalmology and Honorary Consultant Neuro-ophthalmologist at the University of Cambridge, (and Principal Investigator of the trial), said, “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. Importantly, ‘REFLECT’ participants receiving a bilateral injection had a comparable safety profile to those treated unilaterally.”
Lenadogene nolparvovec was used as a novel gene therapy for LHON, an inherited retinal degeneration with has an estimated prevalence of 1 in 40,000 in Europe. GenSight estimated that 1,100 to 1,200 LHON patients may be seeking therapies for this disorder each year. The connection between LHON and mitochondrial DNA (mtDNA) arose following studies that reported a homoplasmic nucleotide transition from guanosine to adenosine at position 11778, resulting in an arginine-to-histidine substitution in ubiquinone oxidoreductase (NADH) subunit 4 (ND4) of the mitochondrial complex I. It is now known that the majority of LHON cases are associated with mutations in one of three mitochondrial genes that encode subunits of the same complex I of the mitochondrial respiratory chain. This complex I enzyme, containing 7 subunits encoded by mtDNA, is closely associated with the inner mitochondrial membrane, while a further 35 subunits, encoded by nuclear DNA, are imported into the organelle to facilitate specific steps of the respiratory pathway. To evaluate a series of clinical studies, a number of trials were followed with administering lenadogene nolparvovec study as a single intravitreal injection at a dose of 9 × 1010 viral genomes, with the other eye received a sham injection. (Clinical studies were named as RESCUE, REVERSE, RESTORE and REFLECT, distinguished in the duration of the study).
In a recent paper published in JAMA Ophthalmology (2025;143(2):99-108), the funder of the study (GenSight) reported results showing that, at baseline, the mean (SD) BCVA was 1.5 (0.5) logMAR (20/600 Snellen) in eyes treated with the therapy, while BCVA was 1.4 (0.5) logMAR (20/500) in sham eyes. At the end of the trials, 2 years after treatment, the mean (SD) change from baseline (to year 2) was −0.05 (0.6) logMAR (+1 line) for lenadogene nolparvovec, and 0.01 (0.6) logMAR (−0 line) in sham eyes, (difference, −0.03; 95%CI, −0.16 to 0.09; P = .60). In addition, five years after treatment (collated data in their ‘REFLECT’ study), 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, 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). While the outcomes provided improvements between treatment vs sham injections, in terms of BCVA, there were some limitations on the measurement of baselines and controls.
Figure 1: 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. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), entitled: Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy, by Yu-Wai-Man, P et al, JAMA Ophthalmology February 2025 Volume 143, Number 2).
In the collected data over time, the authors reported that for treated eyes (n = 76 [RESCUE n = 39; REVERSE n = 37]) and natural history eyes (n = 408), the data reported by locally estimated scatterplot (LOESS) regression (solid line above) with 95%CI around the fitted curve (shaded area). From their research, 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. According to the researcher, “the statistically significant difference between treated eyes (lenadogene nolparvovec and sham) and natural history eyes is illustrated by the nonoverlapping CIs of LOESS curves (abve). 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).” In conclusion, the report outlined that 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.” Comprehensive details are available at Yu-Wai-Man, P et al, JAMA Ophthalmology, February 2025, Volume 143, Number 2.