Abstract
Purpose:
Aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, has previously been shown to inhibit corneal neovascularization when applied as eye drops in a dose-finding Phase II study. Here we aimed to confirm these results in a Phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL) and need for transplantation.
Methods:
Multicenter, double-masked, randomized, placebo-controlled Phase III study. Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 µg/day/eye) or placebo twice daily for 90 days and were followed up to day 180. The primary endpoint was VA. Secondary endpoints included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL.
Results:
Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative area of corneal neovascularization after 90 days by 26.20% (p=0.014). This improvement persisted after 180 days (26.67%, p=0.012). Although not statistically significant (p=0.087), aganirsen tended to lower the need for transplantation in the Intent-To-Treat (ITT) population at day 180. In the subgroup of patients with viral keratitis and central neovascularization, a significant reduction in the need for transplantation was achieved (p=0.048). No significant differences between groups were observed in the risk of graft rejection. QoL analyses revealed a significant improvement with aganirsen in composite and near activity sub-scores (p=0.039 and 0.026, respectively) at day 90 in the Per Protocol population. Ocular and treatment related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared to placebo.
Conclusions:
This first Phase III study on a topical inhibitor of corneal angiogenesis showed aganirsen eye drops to significantly inhibit corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well-tolerated.
Keywords: 609 neovascularization •
479 cornea: clinical science •
741 transplantation