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

Abstract

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.

An Exploratory Trial of EPI-589 in Amyotrophic Lateral Sclerosis (EPIC-ALS): Protocol for a Multicenter, Open-Labeled, 24-Week, Single-Group Study

“…Patients will be administered EPI-589 at 500 mg (2 tablets of 250 mg) 3 times daily at least 60 minutes before meals during the 24-week treatment period. Based on the previous phase 1 results [ 22 ], when administered under fed conditions, the C max decreased to 62.6% of the C max under fasting conditions. Area under the curve was comparable between the fasted and fed states.…”

“…A phase 1 trial in healthy participants (jRCT2071210022) [ 22 ] revealed that EPI-589 was safe and well-tolerated as a single daily dose of up to 1000 mg. In addition, EPI-589 was safe and well-tolerated when participants received 750 mg 2 times daily (1500 mg per day) in the multiple-dose part.…”

“…In our trial, we set the dose of EPI-589 to 500 mg 3 times daily because 1500 mg per day is the maximum daily dose used in the previous phase 1 study. Although EPI-589 500 mg 2 times daily showed possible efficacy on ALS progression in a phase 2 open-label trial (NCT02460679), given that the terminal elimination half-life of EPI-589 is relatively short [ 22 ], dosing 3 times a day rather than 2 times a day is preferable to maximize the efficacy.…”

“…Given the apparent oxidative stress and mitochondrial dysfunction involvement in ALS pathogenesis, EPI-589 may hold promise as a potential therapeutic agent. In a phase 1 study, EPI-589 at 1500 mg per day was well-tolerated [ 22 ]. An early phase 2 trial (ClinicalTrials.gov identifier NCT02460679) revealed that EPI-589 at 500 mg twice daily was safe and well-tolerated with effects on disease progression in patients with ALS.…”

Clinical Trial Highlights: Modulators of Mitochondrial Function

“…Its reduced form can scavenge free radicals. EPI-589 is also able to oxidise itself back to its original form [ 87 ]. It has been demonstrated that EPI-589 protects against oxidative stress and prevents the 8-hydroxy-deoxyguanosine increase in urine [ 88 ].…”