Phase 1, Dose-Escalating Study of the Safety, Tolerability, and Pharmacokinetics of ACU-4429 in Healthy Volunteers

Abstract

Purpose: : This study assessed the safety, tolerability, and pharmacokinetics (PK) of single-dose oral administration of ACU-4429, a novel non-retinoid visual cycle modulator, in healthy volunteers aged 55-80 years. Additionally, electroretinographic (ERG) measurements were performed to assess the effect of ACU-4429 on rod-mediated retinal activity.

Methods: : This was a single-center, randomized, double-masked, placebo-controlled, dose-escalation study. Three cohorts of 6 subjects each (5 ACU-4429, 1 placebo) received a single oral dose of placebo or ACU-4429, starting at 2 mg (approximately 0.03 mg/kg for a 70-kg individual). The study involved 5 visits: screening (up to 35 days before Day -1); baseline (Day -1, predose); treatment and inpatient period (Day 1 dosing and Day 2 inpatient follow-up); outpatient follow-up (Day 3); and study exit (Days 6-7). Full-field ERGs were recorded following dark adaptation and at 10-minute intervals after exposure to a bleaching light.

Results: : Oral administration of ACU-4429 was well tolerated up to 20mg. No significant or unexpected adverse events were reported. One case of mild and transient alteration in dark adaptation was reported in the 20mg cohort. Plasma concentrations were generally below the level of assay for the 2mg cohort. For the higher cohorts, AUC and C_max increased approximately proportional to dose. C_max was 1.42ng/mL and 4.54ng/mL in the 7mg and 20mg cohorts, respectively; median T_max is 4-6 hours postdose. Mean T_1/2 is 4 hours for the 7mg cohort and 6 hours for the 20mg cohort. Mean residence time was approximately 8-10 hours postdose. Dark-adapted ERGs were not affected. However, most subjects demonstrated a marked slowing of the time course of recovery following the bleach for 24 to 48 hours postdose. The slowing persisted on Day 2, but was not seen at the exit visit.

Conclusions: : ACU-4429 is safe and well tolerated when taken orally by healthy volunteers aged 55-80 years. PK data indicate ACU-4429 has a half life of approximately 4-6 hours. The prolonged course of ERG dark adaptation seen in most subjects indicates ACU-4429 may effectively slow the rod visual cycle.

Clinical Trial: : www.clinicaltrials.gov NCT00703183

Keywords: age-related macular degeneration • retina • degenerations/dystrophies