GenSight Biologics Announces Publication of Indirect Comparison Showing Treatment Effect of Lumevoq Versus Natural History
GenSight Biologics announced that the journal Frontiers in Neurology has published results of the indirect comparison of the evolution of visual outcomes in patients treated with Lumevoq gene therapy with the spontaneous evolution in natural history (NH) studies of Leber hereditary optic neuropathy (LHON) patients carrying the m.11778G>A ND4 mutation (MT-ND4 patients).
The paper,* published in the May issue under the title, “Intravitreal Gene Therapy vs. Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison,” found a statistically and clinically relevant difference in visual acuities in favor of Lumevoq-treated patients versus untreated NH patients. Lumevoq-treated patients’ best-corrected visual acuity (BCVA) experienced progressive and sustained improvement from Month 12 to Month 52 after vision loss, whereas NH patients showed deteriorating visual acuity over the same time period.
“Detailed analysis of what the literature can tell us about the natural history of this devastating blinding disorder does confirm its poor visual prognosis,” Nancy J. Newman, MD, lead and corresponding author, RESCUE principal investigator and LeoDelle Jolley Professor of Ophthalmology and Neurology at the Emory University School of Medicine in Atlanta, said in a company news release.
The publication represents a peer-review validation of the analyses submitted in Lumevoq’s Marketing Authorization Application in Europe, which was filed in September 2020. Review of the dossier is ongoing, with the EMA decision expected in H1 2022.
Overview of the indirect comparison methodology
The indirect comparison approach was pursued because an unexpected and significant contralateral effect in the RESCUEa and REVERSEb phase III trials effectively eliminated the sham-injected eyes as a control group for the drug-injected eyes. For a better characterization of Lumevoqefficacy, a natural history, or untreated, pool had to be assembled from patients carrying the same mutation as those in the clinical trials.
The authors formed the “efficacy pool” by combining all visual acuity observations from inclusion to Week 96 in the 76 RESCUE and REVERSE patients, with those of patients who accepted to participate in the long-term follow-up study RESTORE (CLIN06). Because of the contralateral effect, visual acuity measurements for sham-treated eyes were included in the efficacy dataset.
The natural history pool was formed from patients who were not treated with Lumevoq; they could, however, have been treated with idebenone. The dataset was created using visual outcome data from the REALITY LHON registryc and 10 published studies on LHON that were identified after a systematic review of the literature.d Only studies with patient- and eye-level visual acuity values, along with documentation of the time after vision loss in cohorts with at least five MT-ND4 patients, were included (208 patients).
Month 12 after vision loss was selected as the starting point of the indirect comparison, as nearly all (93%) of the eyes in the efficacy pool had been treated at that point. The evolution of the visual acuity was estimated using a locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model.
Key findings from the indirect comparison
Treated eyes had better visual acuity compared to natural history eyes at 12, 18, 24, 36 and 48 months after vision loss. The difference in mean visual acuity was statistically significant at all time points, with the clinically meaningful difference at 48 months amounting to +16.5 ETDRS letters equivalent (more than +3 lines on the ETDRS vision chart) in favor of treated eyes. The treatment effect was confirmed even after confounding covariates, such as age at onset of vision loss, gender and duration of follow-up, were taken into account using multivariate analysis.
The treatment effect was similarly reflected in eye responder rates, which was approximately double when patients were treated, regardless of the responder measure selected (e.g., percentage of eyes with on-chart visual acuity at Month 48 and at last observation; percentage of eyes above the WHO criteria for blindness at Month 48 and at last observation).
The paper can be obtained at https://www.frontiersin.org/articles/10.3389/fneur.2021.662838/full.
*About the paper:
Intravitreal Gene Therapy vs. Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison