Gene Therapy Improves Visual Acuity in MT-ND4 LHON Compared to Natural History


Investigators analyzed data from 3 phase 3 studies and a long-term follow-up study.

Lenadogene nolparvovec improved visual acuity in patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4) compared to what has previously been observed with natural history of the disease as seen in the observational REALITY trial (NCT03295071), according to an indirect comparison including data from the phase 3 REFLECT (NCT03293524), RESCUE (NCT02652767), REVERSE (NCT02652780), and RESTORE (NCT03406104) trials.1

“The results published in this peer-reviewed scientific paper provide more evidence of LUMEVOQ’s potential as an effective treatment for LHON. The results indicate that LUMEVOQ treatment offers a better chance of recovery of vision than the published natural history of this disorder, giving hope to people affected by this debilitating blinding disease,” lead author Valerio Carelli, MD, PhD, Professor, Medical Genetics, and Director, Program in Neurogenetics, Department of Biomedical and NeuroMotor Sciences, University of Bologna School of Medicine, said in a statement.2

Carelli and colleagues analyzed best-corrected visual acuity (BCVA) trends in pooled data from 174 patients with MT-ND4 LHON treated with lenadogene nolparvovec from the 3 interventional studies.1 These patients received 9 × 1010 viral genomes/eye of the gene therapy as a single unilateral or bilateral intravitreal injection. The data were updated as of week 96 after treatment in the REVERSE and RESCUE studies, up to year 1.5 after treatment in REFLECT, and up until the last available obseration in the long-term follow-up RESTORE study for patients from REVERSE and RESCUE.

The investigators found that mean improvement in BCVA was − 0.30 logMAR (+15 ETDRS letters equivalent) compared to natural history (P <.01) with a maximum of 3.9 years after injection of follow-up. Most treated eyes (89.6% [95% CI, 79.7-95.7]) were on-chart as compared to less than half of natural history control eyes (48.1%); at 48 months after vision loss (P <.01) and at last observation (76.1% [95% CI, 71.3-80.5] versus 44.4% [95% CI, 39.5-49.3]; P < .01).

READ MORE: New Leber Hereditary Optic Neuropathy Gene Therapy Trial Doses First Patient

Carelli and colleagues also adjusted for ethnicity, gender, age of onset, and duration of follow-up and determined the estimated mean gain was − 0.43 logMAR (+ 21.5 ETDRS letters) versus natural history at last observation (P <.0001). They found that in the univariate analysis, a later treatment administration (within 1 year after vision loss) was associated with a better response to treatment compared to an earlier treatment, with an effect estimate of −0.0216 logMAR (95% CI [− 0.0398 to − 0.0034]; P = .0201) for each month of delayed treatment. Other factors had no significant impact. Similar results were seen in the multivariate analysis, with an effect estimate of − 0.0217 logMAR (95% CI [− 0.0400 to −0.0035]; P = .0200) for each month of delayed treatment.

BCVA trends were consistent across data from all phase 3 clinical trials, although analyses from the REFLECT trial suggest that bilateral injection of the gene therapy led to a larger treatment effect compared to unilateral injection, with 79% of bilaterally treated patients’ eyes reaching logMAR of at least 1.6 and 67% of unilaterally treated patients’ eyes reaching the same responder level. In comparison, 44.4% of natural history patients’ eyes reached that level of response (P <.0101 for both comparisons by parametric and non-parametric tests).

“These results confirm a clinically relevant improvement of visual acuity in MT-ND4-carrying patients with LHON treated with lenadogene nolparvovec to a degree not demonstrated in natural history studies. The treatment effect of lenadogene nolparvovec was long-lasting up to the last visual acuity value currently documented,” Carelli and colleagues concluded their paper.1MT-ND4 LHON disease remains an area of acute unmet medical need. Lenadogene nolparvovec provides a substantial benefit to MT-ND4-carrying patients with LHON, who face a blinding disease with limited treatment options at this time.”

1. Carelli V, Newman NJ, Yu-Wai-Man P, et al. Indirect comparison of lenadogene nolparvovec gene therapy versus natural history in patients with Leber hereditary optic neuropathy carrying the m.11778G>A MT-ND4 mutation. Ophthalmol Ther 12, 401–429 (2023).
2. GenSight Biologics announces publication of indirect comparison of LUMEVOQ® versus natural history in ND4-LHON patients in peer-reviewed Journal Ophthalmology and Therapy. News release. GenSight Biologics. December 15, 2022.
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