rAAV2/2-ND4 for the Treatment of Leber Hereditary Optic Neuropathy (LHON): 72-Week Data from the REVERSE Phase III Clinical Trial

Abstract

Purpose : LHON is a mitochondrially inherited disease causing bilateral central loss of vision. A point mutation in the mitochondrial ND4 gene at nucleotide position 11778 accounts for about 75% of LHON cases. rAAV2/2-ND4 is a gene therapy vector enabling allotopic expression and delivery of the wild-type ND4 protein to mitochondria within retinal ganglion cells. The clinical efficacy of rAAV2/2-ND4 (GS010) is currently being assessed in Phase 3 trials of ND4-LHON subjects.

Methods : REVERSE (NCT02652780) is a randomized, multicenter, double-masked, sham-controlled trial of 37 LHON subjects carrying the m.11778G>A (ND4) mitochondrial DNA mutation. All subjects received a single unilateral intravitreal injection of rAAV2/2-ND4. Multiple visual function parameters and spectral-domain OCT measurements of retinal anatomy were monitored over 72 weeks.

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 visual acuity (+12 ETDRS letters). Contrast sensitivity also improved with rAAV2/2-ND4-treated and sham-treated eyes gaining respectively on average +0.21 LogCS and +0.15 LogCS compared with baseline. The proportion of rAAV2/2-ND4-treated eyes that achieved a clinically meaningful improvement of 0.3 LogCS or greater (45.9%) was statistically significantly higher than that of sham-treated eyes (24.9%; p=0.0047). A generalized estimating equation model showed drug treated eyes to be significantly more likely to achieve vision of 20/200 or better than sham-treated eyes (p=0.0012). Ganglion cell layer (GCL) volume, papillomacular bundle thickness and total macular ETDRS thickness were significantly preserved in treated compared with sham eyes with all 3 metrics reaching statistical significance.

Conclusions : Seventy-two weeks after rAAV2/2-ND4 was administered, a clinically meaningful improvement in visual function and sustained protection of LHON-relevant retinal anatomy were seen in drug-treated eyes. These findings suggest that the biological targets of the GS010 gene therapy vector were successfully engaged. Week 96 readout of results is expected in mid-2019.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.