Phase 1 Study to Investigate the Safety, Tolerability, and Pharmacokinetics of EPI-589 in Healthy Participants

EPI-589 attenuates oxidative stress due to the radical scavenging activity of the reduced form and affects mitochondrial energy metabolism as a substrate of quinone-oxidoreductases. Given the effects of EPI-589 on oxidative stress and mitochondrial dysfunction, EPI-589 shows promise as a potential therapy for patients with amyotrophic lateral sclerosis. This phase 1 study evaluated the safety, tolerability, and pharmacokinetic profiles of EPI-589. Sixty-eight healthy participants were randomly assigned to EPI-589 or placebo. All adverse events were mild or moderate in severity, and no severe adverse events were reported. After single-dose administration under fasting conditions, time to maximum plasma concentration (t_max ) occurred 0.25 to 1.00 hour after administration. Both peak plasma concentration (C_max ) and area under the plasma concentration-time curve (AUC) were approximately linear with increases in single doses over a dose range of 250-1000 mg. Under fed conditions, the C_max decreased to 62.6% of the C_max under fasting conditions, the AUC was slightly increased, and the t_max was delayed by 1 hour. When EPI-589 was administered daily on days 1 and 7 with twice-daily dosing on days 2 through 6, the plasma trough concentration appeared to reach steady state by day 3. At both doses studied (500 mg twice daily and 750 mg twice daily), C_max, t_max , and AUC were generally comparable between day 1 and day 7 and between the Japanese and White participants. EPI-589 was well tolerated as a single daily dose up to 1000 mg and as twice-daily doses up to 750 mg, with a linear pharmacokinetic profile.