Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator

ACU-4429 is a first in class small-molecule visual cycle modulator that inhibits the isomerase complex and, in mouse models of retinal degeneration, prevents the accumulation of A2E. The purpose of this study was to assess the tolerability, pharmacokinetics, pharmacodynamics, and safety of a single, orally administered dose of ACU-4429 in healthy subjects.

Sequential cohorts were administered single doses ranging from 2 mg to 75 mg. Full-field electroretinograms were recorded before and after exposure to full-field bleaching light. Pharmacokinetics samples were taken at predetermined times. Safety assessments included adverse events, vital signs, clinical laboratory assays, electrocardiograms, and ophthalmologic examination.

After 45-minute dark adaptation, electroretinographic findings demonstrated a dose-related slowing of the rate of recovery that reached its maximum on Day 2 and returned to baseline by Day 7. Mean area under the concentration curve and peak plasma concentration increased proportionally with increasing doses. Median time to peak concentration was 4 hours postdose. Mean elimination mean half-life was 4 hours to 6 hours. Adverse events were mild and visual in nature (dyschromatopsia and alteration in dark adaptation), transient, and resolved within a few days. Adverse event frequency was dose dependent.

Oral administration of ACU-4429 produced a dose-dependent inhibition of the b-wave of the electroretinograms, was well tolerated up to 75 mg, and demonstrated linear pharmacokinetics across doses.