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

Abstract

Introduction: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174.

Methods: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies.

Results: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection.

Conclusion: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection.

Trial registration numbers: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).

Keywords: Gene therapy; LHON; Leber hereditary optic neuropathy; MT-ND4; Natural history; Visual acuity.

Fig. 1

Evolution of visual acuity of treated eyes versus natural history eyes. The evolution of visual acuities over time for treated eyes (n = 348) and natural history eyes (n = 408) was estimated by LOESS regression (solid line) with 95% CI around the fitted curve (shaded area). Visual acuity values > 52 months were assigned to the 52-month time point using the next observation carried backward method. Smoothing parameter: 0.315 for treated eyes and 0.408 for natural history eyes. The statistically significant difference between treated and natural history eyes is illustrated by the non-overlapping CIs of LOESS curves. Mean differences at month 18 [15; 21], month 24 [21; 30], month 36 [30; 42] and month 48 [42; 54] were estimated by a mixed-model ANCOVA with repeated measures: *P = 0.03, **P = 0.02 and ***P < 0.01 versus natural history; and with Kruskal Wallis test: ^#P < 0.01 versus natural history (details in Table 3).

Fig. 2

Eye responder rate at month 48 since vision loss and at last observation. logMAR logarithm of the minimal angle of resolution, n number of eyes. Response rates (%) are defined as the proportion of eyes with visual acuity values ≤ 1.6 logMAR (left panel) or ≤ 1.3 logMAR (right panel). Error bars represent 95% confidence interval. ^#P < 0.05, ^##P < 0.01: statistically significant difference vs. natural history eyes using chi-squared test. *P < 0.05, **P < 0.01: statistically significant difference vs. natural history eyes using a generalized linear mixed model with repeated measures taking into account the inter-eye correlation of each patient