Effects of TS-142, a novel dual orexin receptor antagonist, on sleep in patients with insomnia: a randomized, double-blind, placebo-controlled phase 2 study

Abstract

Rationale: Novel compound with potent antagonistic activity against orexin receptors may be new treatment option for patients with insomnia.

Objective: The aim was to investigate the efficacy and safety of single oral doses of the dual orexin receptor antagonist TS-142 in patients with insomnia.

Methods: This multicenter, double-blind, crossover randomized clinical trial included non-elderly patients with insomnia. Patients were randomized to receive single doses of placebo and TS-142 at doses of 5, 10, and 30 mg in one of four different sequences, with a 7-day washout period between treatments. Primary efficacy endpoints were latency to persistent sleep (LPS) and wake time after sleep onset (WASO) measured by polysomnography.

Results: Twenty-four patients were included (mean age 50.3 ± 10.5 years; mean duration of insomnia 5.71 ± 8.68 years). Least-squares mean differences (95% confidence interval) from placebo in LPS with 5, 10, and 30 mg TS-142 were - 42.38 (- 60.13, - 24.63), - 42.10 (- 60.02, - 24.17), and - 44.68 (- 62.41, - 26.95) minutes, respectively (all p < 0.001). Least-squares mean differences (95% confidence interval) from placebo in WASO with 5, 10, and 30 mg TS-142 were - 27.52 (- 46.90, - 8.14), - 35.44 (- 55.02, - 15.87), and - 54.69 (- 74.16, - 35.23) minutes, respectively (all p < 0.01). Self-reported aspects of sleep initiation and sleep quality, determined using the Leeds Sleep Evaluation Questionnaire (LSEQ), were also improved with TS-142 administration versus placebo. TS-142 was well tolerated; all adverse events were mild or moderate and none were serious.

Conclusion: Single-dose TS-142 was well tolerated and had clinically relevant effects on objective and subjective sleep parameters in patients with insomnia.

Clinical trial registration: JapicCTI173570 (www.

Clinicaltrials: jp); NCT04573725 (www.

Clinicaltrials: gov).

Keywords: Clinical Trial; Insomnia; ORN0829; Orexin; Orexin Receptor Antagonists; Polysomnography; Randomized Controlled Trial; Sleep Initiation and Maintenance Disorders; Sleep diary; TS-142.