GS-101 Antisense Oligonucleotide Eye Drops Inhibit Corneal Neovascularization Interim Results of a Randomized Phase II Trial

Purpose: Pathologic corneal neovascularization not only reduces corneal transparency and visual acuity, but also is one of the most significant preoperative and postoperative risk factors for graft rejection after corneal transplantation. The aim of this study was to test tolerability and efficacy of gene signal (GS)-101 eye drops, an antisense oligonucleotide against insulin receptor substrate-1, versus placebo on inhibition of progressive corneal neovascularization. Design: Randomized, double-blind, multicenter, phase II clinical study. Participants and Controls: Interim analysis on 40 patients with progressive corneal neovascularization resulting from various underlying diseases being nonresponsive to conventional therapy. Interventions: Four groups of 10 patients were treated for 3 months in this dose-finding study comparing 3 doses of GS-101 (eye drops twice daily; 43, 86, and 172 mu g/day total) with placebo (10 patients per group). Main Outcome Measures: The primary end point was the area covered by pathologic corneal blood vessels, which was measured morphometrically on digitized slit-lamp pictures using image analysis techniques. Results: GS-101 eye drops were well tolerated. All serious and 95% of all other adverse events were categorized by the investigators as unrelated. In 3 patients, there was a potentially related side effect of ocular surface discomfort. At a dose of 86 mu g/day (43 mu g/drop), GS-101 eye drops produced a significant inhibition and regression of corneal neovascularization (-2.04 +/- 1.57% of total corneal area; P = 0.0047), whereas the low dose tended to stabilize it (0.07 +/- 2.94%; P = 0.2088) compared with placebo (0.89 +/- 2.15%), where corneal neovascularization progressed in all patients. There was no apparent benefit to the higher dose (1.60 +/- 7.63%). Conclusions: The interim results of this phase II study suggest that GS-101 eye drops at an optimal dose of 86 mu g/day are an effective and noninvasive approach specifically to inhibit and regress active corneal angiogenesis, a major risk factor for corneal graft transplantation and graft rejection. Safety concerns were not detected.