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Topline data from GenSight’s Phase III REVERSE study provide an unusual and unexpected outcome


GenSight Biologics S.A. (Euronext: SIGHT) has announced topline results from the company’s Phase III “REVERSE” clinical study of an experimental gene therapy, ”GS010”, designed for the treatment of Leber Hereditary Optic Neuropathy (LHON). According to the company, the study evaluated the safety and efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in 37 subjects with vision loss due to the ND4-G11778A mutation. Patients enrolled in the clinical trial had symptoms commencing between 6 and 12 months prior to study treatment.   The results of the study demonstrated a favourable safety and tolerability profile for GS010 however, both treatment and sham injected eyes recorded a clinically meaningful improvement of +11 ETDRS letters in all 37 patients at 48 weeks. As a result, the trial did not meet its primary endpoint of demonstrating a difference in VA improvement between sham and treated eyes.


The novel gene therapy, “rAAV2/2-ND4” (GS010) comprises a recombinant, replication-defective, adeno-associated virus (AAV), serotype 2, containing a modified cDNA encoding the human wild-type mitochondrial ND4 protein. Each subject in the Phase III study had one eye randomly selected to receive a single injection of GS010 while the other eye received a sham injection. Treatment was delivered via intravitreal injection containing 9 × 109 vector genomes in 90μL balanced salt solution (BSS) plus 0.001% Pluronic F68 and the study design masked treatment from sham for patient, care provider, investigator and outcome assessor. The unusual result showing that both sham and treated eyes benefitted equivalently is difficult to explain. Assuming the company have conducted multiple testing and audit exercises to exclude the more obvious explanations of logistiical / humam / data error, the result, if reproducible, may indicate an extremely novel and interesting finding.   Partial spontaneous recovery for the indication is recorded at between 8% and 22%, which fails to explain the result for all the patients tested. It would be difficult to contemplate a physical explanation for GS010 migration from treated to sham eye and therefore some other phenomenological explanation would need to considered, and would need to be consistent with the secondary outcome data which showed a statistically significant difference between treatment and sham.


Commenting on the result, Bernard Gilly, Chief Executive Officer of GenSight stated, “this meaningful improvement of untreated eyes observed at week 48 was totally unexpected given what is known and has been published about the natural history of this devastating disease. We will continue to analyze the data to better understand our results, but they suggest that GS010 benefits both eyes in a way that is still to be understood”.