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

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 [C ] 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 C 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 C . 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.