Phase ii, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration

Abstract

Purpose: This study assessed the safety, tolerability, and pharmacodynamics of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in subjects with geographic atrophy associated with dry age-related macular degeneration.

Methods: Subjects were randomly assigned to oral emixustat (2, 5, 7, or 10 mg once daily) or placebo (3:1 ratio) for 90 days. Recovery of rod photoreceptor sensitivity after a photobleach was measured by electroretinography. Safety evaluations included analysis of adverse events and ophthalmic examinations.

Results: Seventy-two subjects (54 emixustat and 18 placebo) were evaluated. Emixustat suppressed rod photoreceptor sensitivity in a dose-dependent manner. Suppression plateaued by Day 14 and was reversible within 7 days to 14 days after drug cessation. Most systemic adverse events were not considered treatment related. Dose-related ocular adverse events (chromatopsia, 57% emixustat vs. 17% placebo and delayed dark adaptation, 48% emixustat vs. 6% placebo) were mild to moderate in severity, and the majority resolved on study or within 7 days to 14 days after study drug cessation. Reversibility of these adverse events with long-term administration, however, is undetermined.

Conclusion: In this Phase II study, emixustat produced a dose-dependent reversible effect on rod function that is consistent with the proposed mechanism of action. These results support further testing of emixustat for the treatment of geographic atrophy associated with dry age-related macular degeneration.

Fig. 1. Study Design

Fig. 2

Mean b-wave rod responses at (A) baseline, (B) Day 14 of dosing, and (C) 7 to 14 days following drug cessation (means for the 10 mg group were affected by one subject with outlying values). The ERG procedure included maximal dilation of each subject's pupils followed by a 30-minute period of dark adaptation, and a subsequent 10-minute period of light adaptation prior to photobleaching for 3 minutes. Rod responses were recorded immediately after the photobleach (0 minutes) and at 10, 20, and 30 minutes.

Fig. 3. Subject Disposition