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GenSight Biologics Inc. reports completion of Phase III enrolment for a gene therapy treatment for Leber’s Hereditary Optic Neuropathy (LHON)

GenSight Biologics Inc., (EURONEXT: SIGHT), Paris, France, have announced that their experimental GS010 treatment for LHON has completed enrollment in the company’s Phase III clinical trial. The Phase III study termed “RESCUE” is one of two parallel randomized, double-masked, controlled, multi-center pivotal trials designed to evaluate the efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in patientss affected by LHON due to the G11778A mutation in the mitochondrial ND4 gene.  The study has enrolled 37 patients with an onset of vision loss of less than 6 months while a second trial (“REVERSE”), completed enrollment in February 2017 of 36 patients with an onset of vision of 7-12 months. Both studies are being conducted in seven centers in Europe and in the United States.


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, represent 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.


According to the company, patient data collected at 78 weeks showed that a mean change of visual acuity from baseline in the treated eyes was -0.61 LogMAR (p<0.001), or a mean improvement of +30 ETDRS letters. Control untreated eyes in contrast were reported to have a mean change from baseline of -0.31 LogMAR (p=0.0866), or +15 ETDRS letters. The company has stated that such data indicates a treatment effect of +15 letters (p=0.11) in favor of treated worse-seeing eyes however, no peer-reviewed primary data has been made available to date. Commenting on the completion of Phase III enrolment, Dr. Mark Moster, MD, investigator in the study and neuro-ophthalmologist, Wills Eye Hospital, Philadelphia, Pennsylvania (USA), stated, “We are very excited to be part of the RESCUE and REVERSE trials with GS010. Safety and pharmacodynamics results seen in the Phase I/II study are particularly encouraging, and if confirmed in these Phase III trials, GS010 could be a potentially transformative treatment for LHON, and a fantastic hope for patients and their families.”