Efficacy and safety of vornorexant in Japanese patients with insomnia: a randomized, placebo-controlled phase 3 pivotal study.

STUDY

OBJECTIVES

A placebo (PBO)-controlled phase 3 study was conducted to evaluate the efficacy and safety of vornorexant, a novel dual orexin receptor antagonist, in Japanese patients with insomnia.

METHODS

Following a 2-week PBO run-in period, 596 patients with insomnia were randomized to receive 5 mg of vornorexant (VOR5), 10 mg of vornorexant (VOR10), or PBO for 2 weeks in a 1:1:1 ratio in double-blind manner, followed by a 1-week PBO run-out period. The primary and key secondary efficacy endpoints were subjective sleep latency and subjective sleep efficiency, respectively, assessed by sleep diary.

RESULTS

Subjective sleep latency was significantly improved at week 2 in both groups compared to PBO (differences of the least-squares mean [LSM] changes from baseline in VOR5, -10.6 min [95% CI = -14.2% to -7.0%] p < .001, and VOR10, -10.1 min [-13.8% to -6.5%] p < .001). Subjective sleep efficiency was also significantly improved at 2 weeks in both groups compared to PBO (LSM changes from baseline in VOR5, 3.41% [1.87% to 4.96%] p < .001, and VOR10, 2.94% [1.40% to 4.48%] p < .001). The most common adverse event (AE) was somnolence (VOR5: 3.1%, VOR10: 3.6%, PBO: 1.5%). No AEs of cataplexy, fall, muscular weakness, sleep paralysis, hypnagogic or hypnopompic hallucination, or excessive daytime sleepiness were reported. No withdrawal symptoms or rebound insomnia were observed in the PBO run-out period.

CONCLUSIONS

Treatment with 5 and 10 mg of vornorexant significantly improved sleep onset latency and sleep efficiency compared with PBO without relevant safety concerns.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05453136. Japan Registry of Clinical Trials ID: jRCT2031220209. A Multi-center, Randomized, Double-blind, Parallel-group, Placebo-controlled Phase 3 Study of TS-142 in Patients with Insomnia Disorder. https://clinicaltrials.gov/study/NCT05453136. https://jrct.mhlw.go.jp/en-latest-detail/jRCT2031220209. Statement of Significance Sleep disturbances lead to physical and mental health issues. Some pharmacotherapies for individuals with insomnia are available, but most of these have concerns including withdrawal, dependence, and next-day residual effects. Therefore, alternative treatment with minimal impact on these issues is highly desirable. This phase 3 study was conducted to confirm the efficacy and safety of vornorexant, a novel dual orexin antagonist having pharmacokinetic characteristics of rapid absorption and elimination, in patients with insomnia. Consequently, both tested doses showed superior efficacy compared to placebo, with significant reductions in subjective sleep latency and increases in sleep efficiency. These findings position vornorexant as a new treatment option for insomnia, offering improvements in sleep while avoiding the concerns associated with traditional hypnotics.