GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), based in Paris, France, have announced the publication of updated efficacy results from a pooled analysis of four Phase 3 studies suggesting an improvement in visual acuity in ND4-LHON patients treated with lenadogene nolparvovec (“LUMEVOQ”), a novel gene therapy improvement. According to the company, treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. A mean improvement of acuity, versus natural history, was – 0.30 logMAR (+ 15 ETDRS letters equivalent) at a last observation with a maximal follow-up of 3.9 years after injection (P<0.01).
Lenadogene nolparvovec is to be 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 proposes 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.
Following the recent announcement of the clinically relevant visual acuity change of -0.30 logMAR, the company additionally commented that 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). The company stated that “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). From a pooled analysis of four Phase 3 studies, Valerio Carelli, MD, PhD, Professor of Medical Genetics, University of Bologna School of Medicine stated that the results “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”.