First‐in‐Human Studies of Pharmacokinetics and Safety of Utreloxastat (PTC857), a Novel 15‐Lipooxygenase Inhibitor for the Treatment of Amyotrophic Lateral Sclerosis

Utreloxastat (PTC857) is a 15‐lipoxygenase inhibitor being developed to treat amyotrophic lateral sclerosis. This first‐in‐human study investigated the safety and pharmacokinetics of utreloxastat in healthy volunteers (N = 82) in a double‐blind, placebo‐controlled trial. The effects of a single ascending dose (100–1000 mg), multiple ascending doses (150–500 mg), and food (500 mg) on the pharmacokinetics and safety of utreloxastat were evaluated. Following single doses, the time to maximum plasma concentration (Cmax) was observed ≈4 hours after dosing and the terminal half‐life ranged from 20 to 25.3 hours. The Cmax and area under the concentration‐time curve (AUC) increased slightly over dose proportionally. Following multiple doses (once daily/twice daily), the apparent clearance reduced and terminal half‐life was ≥33 hours. There was no apparent difference of exposure following morning or evening doses. Varying diets increased the Cmax and AUCs of utreloxastat but did not alter time to Cmax. There were no gender‐based differences in exposure. Utreloxastat showed no marked safety signal following single doses up to 1000 mg and multiple doses over 14 days of 500 mg once daily or 250 mg twice daily. The results support further development of utreloxastat for the treatment of patients with amyotrophic lateral sclerosis at a 250‐mg twice‐daily dose administered with food.