rAAV2/2-ND4 for the Treatment of LHON: 72-week Data from the REVERSE Phase III Clinical Trial (Plen02.002)

Objective: To assess the efficacy of a single intravitreal injection of rAAV2/2-ND4 (GS010), an investigational gene therapy for vision loss due to ND4-LHON. Background: LHON is a mitochondrial inherited disease that causes bilateral central vision loss. A point mutation in the mitochondrial ND4 gene accounts for 75% of all LHON cases. rAAV2/2-ND4 is a gene therapy enabling allotopic expression and delivery of the wildtype ND4 protein to mitochondria of retinal ganglion cells. Design/Methods: REVERSE (NCT02652780) is a Phase III, randomized, multicenter, double-masked, sham-controlled trial of 37 LHON subjects with the G11778A-ND4 mutation. All received a single unilateral intravitreal injection of rAAV2/2-ND4. Visual functions and measurements of relevant retinal anatomy were monitored for 72 weeks following treatment. Results: At Week 72 an improvement of +15 ETDRS letters was seen in rAAV2/2-ND4 treated eyes. Sham-treated eyes also showed improvement in acuity (+12 ETDRS letters). Contrast sensitivity also improved: - GS010-treated and sham-treated eyes gained respectively on average +0.21 LogCS and +0.15 LogCS, compared to baseline. The proportion of GS010-treated eyes that achieved a clinically meaningful improvement of at least 0.3 LogCS (45.9%) was statistically significantly higher than that of sham-treated eyes (24.9%; p=0.0047). Ganglion cell layer (GCL) volume, papillo-macular bundle thickness and total macular ETDRS thickness were significantly preserved in treated vs. sham eyes; all 3 differences reaching statistical significance. Conclusions: Seventy-two weeks after rAAV2/2-ND4 administration, a clinically meaningful improvement in visual functions and sustained preservation of LHON-relevant retinal anatomy were seen in drug-treated eyes, suggesting that the biological targets of this gene therapy were successfully engaged. Disclosure: Dr. Moster has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Gensight and Sanofi Genzyme. Dr. Moster has received research support from GenSight. Dr. Sadun has received research support from GenSight. Dr. Klopstock has received research support from GenSight. Dr. Vignal-Clermont has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GenSight. Dr. Newman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GenSight Biologics and Quark Pharmaceuticals. Dr. Newman has received research support from GenSight Biologics and Santhera Pharmaceuticals. Dr. Carelli has received research support from GenSight. Dr. Yu-Wai-Man has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GenSight Biologics. Dr. Yu-Wai-Man has received research support from GenSight. Dr. Sahel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GenSight, Pixium, Tilak, Prophesee, Chronolife, Sparing Vision, Spark, Stargazer, Sanofi. Dr. Sahel has received research support from GenSight. Dr. Katz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Gensight Biologics.