GenSight Biologics (Euronext: SIGHT), announced that the French Competent Authority, the National Agency for Medicines and Health Products Safety (Agence Nationale de Sécurité du Médicament et des produits de santé or ANSM), has granted a Cohort Temporary Authorization for Use (“ATU de Cohorte” or ATUc) for LUMEVOQ (GS010; lenadogene nolparvovec) in the treatment of Leber Hereditary Optic Neuropathy (LHON) caused by a mutated ND4 gene. According to the company, “LUMEVOQ” was first approved for early access in France in December 2019 when the ANSM authorized a Named Patient ATU (“ATU Nominative” or ATUn) for the CHNO des Quinze-Vingts Hospital in Paris. The company stated that “the Cohort ATU greatly simplifies the process by which patients gain access to LUMEVOQ® prior to EU marketing authorization expected in H1 2022”.
LHON has an estimated prevalence of 1 in 40,000 in Europe, and GenSight expects that 1,100 to 1,200 LHON patients will 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. Mitochondrial ND4 can only be translated inside the mitochondria (rather than on cytoplasmic ribosomes) as the TGA codon at amino acid 16 of the gene is read as tryptophan in the mitochondria but as a stop codon by the nuclear genetic code. An estimated 50% of LHON patients harbour the G11778A mutation and, as such, it represents a significant patient population addressable with an ND4 gene therapy. The challenge in devising therapeutic strategies to tackle such mitochondrial disorders is to develop reliable delivery systems to transfer DNA into mitochondria by specially adapted techniques. The company had recently reported two trials in progress – the “RESCUE” and “REVERSE” studies – two separate randomized, double-masked, sham-controlled Phase III trials designed to evaluate the efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in subjects affected by LHON due to the G11778A mutation in the mitochondrial ND4 gene. The trials were conducted in parallel, in 37 subjects for REVERSE and 39 subjects for RESCUE, in 7 centers across the United States and the EU.
According to the Chief Executive Officer of GenSight, Mr. Bernard Gilly, commented that, “the decision of the French ANSM to authorize LUMEVOQ to be administered under a Cohort ATU will facilitate early access to treatment for patients with LHON and indeed attests to the safety and efficacy of LUMEVOQ. The compassionate use and expanded access programs already running in Europe and the US will also allow GenSight to collect additional data that will bolster the already impressive evidence on LUMEVOQ’s clinical benefit and the safety profile and support our drive to obtain marketing authorization in Europe and North America.”