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.

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).