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.

Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans

“…After administration of a single dose of JNJ-61393215, peak and total exposure increased in a dose-proportional manner up to 30 mg. JNJ-61393215 did not produce any pharmacodynamic effects as a single dose up to 90 mg in healthy male subjects, consistent with preclinical data that show no detectable pharmacodynamic or behavioral effects in naive/unchallenged animals. The safety profile of JNJ-61393215 is consistent with the recently reported clinical data for another selective OX1R antagonist, ACT-539313, where the most commonly reported adverse events were somnolence and headache 31 .…”

Impact of the Selective Orexin‐1 Receptor Antagonist ACT‐539313 on the Pharmacokinetics of the CYP3A Probe Drug Midazolam in Healthy Male Subjects

“…Concentrations of midazolam, 1-OH midazolam, and ACT-539313 in plasma were measured using previously described validated liquid chromatography methods with tandem mass spectrometry. 18,19 The lower limit of quantification was 0.1 ng/mL for both midazolam and 1-OH midazolam and 1.0 ng/mL for ACT-539313. For midazolam and 1-OH midazolam, interbatch precision expressed as coefficient of variation (CV%) was ࣘ3.8% and ࣘ4.4%, respectively, whereas the interbatch accuracy expressed as a relative deviation from nominal value (RD%) ranged from −5.7 to −2.4% and from −2.7 to 1.8%, respectively.…”

Hypocretins (orexins): The ultimate translational neuropeptides

“…To date, a number of Hcrt‐R1 selective antagonists have been described in the scientific and patent literature (reviewed in [6, 29]; see also [90]). Clinical data of Hcrt‐R1 drug candidates have been published for ACT‐539313 [Idorsia Pharmaceuticals Ltd., 91, 92]–the first report of a Hcrt‐R1 antagonist in humans and JNJ‐61393215 [Janssen Research & Development LLC; 93]. ACT‐539313 was tested for PK/PD, single and multiple ascending dose safety and tolerability and drug‐drug interaction potential [91, 92, 237].…”

“…Clinical data of Hcrt‐R1 drug candidates have been published for ACT‐539313 [Idorsia Pharmaceuticals Ltd., 91, 92]–the first report of a Hcrt‐R1 antagonist in humans and JNJ‐61393215 [Janssen Research & Development LLC; 93]. ACT‐539313 was tested for PK/PD, single and multiple ascending dose safety and tolerability and drug‐drug interaction potential [91, 92, 237]. A Phase I study with JNJ‐61393215 provided positive proof of concept in CO 2 ‐induced panic in male healthy volunteers [93].…”

“…These data are promising for the advancement of Hcrt-R1 antagonists into clinical investigations for binge eating and possibly bulimia nervosa. Idorsia is developing ACT-539313, an Hcrt-R1 antagonist for various indications including binge eating and first in humans data have been published [91,92,237]. On the other hand, very extensive Phase III studies with the DORAs suvorexant, lemborexant and daridorexant, which lasted up to 12-14 months, have not resulted in weight reduction in these insomnia patients whether lean or obese (or for that matter in healthy controls) [see 55,59,60,129,238].…”