First-in-human study with ACT-539313, a novel selective orexin-1 receptor antagonist

Abstract

Aims: The orexin system is involved in anxiety behaviour and corresponding physiological reactions and constitutes a target for treatment of anxiety disorders. ACT-539313 is a potent, selective orexin-1 receptor antagonist being developed for the treatment of anxiety disorders. This first-in-human study investigated its single-dose pharmacokinetics (PK) including food effect, pharmacodynamics (PD), safety and tolerability. Methods: This double-blind, placebo-controlled, randomized study included 40 healthy male subjects. Ascending oral doses of 10–400 mg ACT-539313 were investigated in 5 dose groups of 8 subjects (of whom 2 received placebo per dose group). At 100 mg, subjects received ACT-539313 in fasted and fed conditions in a fixed sequential design. PK, PD (objective and subjective measures of sedation and effects on central nervous system), safety and tolerability were assessed. Results: In fasted conditions, ACT-539313 was rapidly absorbed (median time to maximum plasma concentration [Cmax] 0.7–3.5 h) and cleared from plasma with a mean terminal half-life of 3.3–5.7 h across dose levels. A 1.63-fold (90% confidence interval: 1.26–2.11) increase in Cmax and no change in area under the concentration–time curve extrapolated to infinity was observed under fed compared to fasted conditions. No relevant PD signals were detected except for a trend of reduced saccadic peak velocity around time to Cmax. The most commonly reported adverse events were somnolence and headache. All adverse events were transient and of mild or moderate intensity. No treatment-related effects on vital signs, clinical laboratory or 12-lead electrocardiogram were observed. Conclusions: ACT-539313 exhibits good safety and tolerability at single doses of up to and including 400 mg that warrant further investigations.