Multiple-dose clinical pharmacology of the selective orexin-1 receptor antagonist ACT-539313

Compounds that selectively target orexin-1 receptors may be beneficial for the treatment of various disorders. The role of selective orexin-1 receptor antagonists (1-SORAs) in addictive behavior and stress/anxiety-related disturbances has been demonstrated in animals. ACT-539313, an orally active, potent 1-SORA, has been assessed in a clinical single-ascending dose study and exhibited good safety and tolerability. In the two reported studies on ACT-539313, multiple-dose pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability were investigated and in a proof-of-mechanism study a CO₂ challenge was applied as pharmacological model for induction of anxiety and panic symptoms (sequential inhalation of air, 7.5% CO₂, and 35% CO₂).

Two double-blind, placebo-controlled, randomized, multiple-dose studies included 58 healthy male and female subjects. In Study 1, multiple-ascending oral doses of 30, 100, and 200 mg twice daily (b.i.d.) ACT-539313 were investigated in 3 dose groups of 8 or 12 subjects (of whom 2 received placebo per dose group). Study 2 was conducted as a randomized two-way crossover design, enrolling 21 male and 9 female subjects who received 200 mg ACT-539313 or matching placebo b.i.d. for 2.5 days followed by a CO₂ challenge, with a washout period in between. PK, PD (objective and subjective measures of sedation, alertness, effects on central nervous system (CNS), and anxiety/panic symptoms), safety, and tolerability were assessed.

At steady state, ACT-539313 was rapidly absorbed with a median time to maximum plasma concentration of 1.8-2.3 h and eliminated with a mean half-life of 3.8-6.5 h. Overall exposure increased dose-proportionally. In Study 1, PD effects confirmed activity of ACT-539313 on the CNS, without consistent or marked effects of sedation, reduced alertness or visuo-motor impairment. In the CO₂ challenge, cortisol concentrations were lower during initial air inhalation after treatment with ACT-539313 compared to placebo, while no difference was detected after CO₂ inhalation. Trends for lower scores in subjective anxiety assessments were observed for ACT-539313. Besides reports of stress related to the challenge, the most frequently reported adverse events were somnolence and headache. No clinically relevant effects in other safety assessments were observed.

Multiple-dose administration of ACT-539313 was safe and well tolerated up to multiple doses of 200 mg b.i.d. The drug's PK properties as well as the pattern of a decrease in stress-related symptoms after the CO₂ challenge support further investigations of ACT-539313.