A double-blind, placebo- and active comparator-controlled, randomized, single-ascending-dose study was conducted to investigate the safety, pharmacokinetics, and pharmacodynamics of ACT-462206, a novel dual orexin receptor antagonist. Healthy male subjects received single oral doses of 5, 25, 100, 200, 400, 1,000, and 1,500 mg ACT-462206 (n = 6 per group) or placebo (n = 2 per group). In addition, subjects in the 400-mg group received a single oral dose of 400 mg almorexant (two-way crossover). ACT-462206 was generally well tolerated. Sleepiness, headache, and fatigue were the most frequently reported adverse events. The incidence of sleepiness appeared dose-dependent. ACT-462206 was absorbed with a median tmax of 1.5-4.0 hours. The elimination half-life varied from 4.8 to 11.2 hours. A clinically relevant reduction in vigilance and attention, alertness, and motor coordination was recorded at ACT-462206 doses ≥200 mg. The onset was between 20 and 45 minutes after drug intake, the maximum effect between 1 and 2 hours after drug administration, and these impairing effects largely disappeared within 8 hours post-dose. Doses of 400-1,000 mg ACT-462206 were similarly efficacious to 400 mg almorexant, with a trend for an earlier onset of action with ACT-462206. The present results confirm the activity of ACT-462206 as an orexin antagonist.