Antisense Oligonucleotide Eye Drops Against IRS-1 Inhibit Corneal Neovascularization: Interim Results of a Randomized Phase II Clinical Trial

Abstract

Purpose: : Pathologic corneal neovascularization not only reduces corneal transparency and visual acuity, but also is one of the strongest pre- and postoperative risk factors for graft rejection after corneal transplantation. Aim of this study was to test efficacy and tolerability of GS-101 eye drops, an antisense oligonucleotide against insulin receptor substrate-1 (IRS-1), versus placebo, on inhibition of progressive corneal neovascularization.

Methods: : Randomized, double-blind, multicentre phase II clinical study. Interim analysis on 40 patients with progressive corneal neovascularization due to various underlying diseases being non-responsive to conventional therapy. Four groups of 10 patients were treated for three months in this dose finding study comparing 3 doses of GS-101 (eye drops: 2x/day; 43, 86 and 172 mg/day total) to placebo (10 patients per group). Primary endpoint was the area covered by pathologic corneal blood vessels, which was measured morphometrically on digitized slit-lamp pictures using image analysis techniques.

Results: : GS101 eye drops were well tolerated: All serious and 95% of all other adverse events were unrelated. In 3 patients there was a potentially related side effect of ocular surface discomfort. At a dose of 86 mg/day (43 µg/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), while the low dose tended to stabilize it (0.07±2.94; p=0.2088) compared to placebo (0.89±2.15) where corneal neovascularization progressed in all patients. The high dose was of no additional benefit (1.60±7.63).

Conclusions: : The interim results of this phase II study suggest GS-101 eye drops at an optimal dose of 86 mg/day to be an effective, safe, and non-invasive approach to specifically inhibit and regress active corneal angiogenesis, a major risk factor for corneal graft transplantation and graft rejection. These promising results support the start of a phase III clinical study in this orphan drug indication.

Clinical Trial: : Eudract database: 2004-005015-29 GS101-P2-CG

Keywords: neovascularization • cornea: clinical science • vascular endothelial growth factor