The preclinical profiles and the clinical efficacy and safety of vornorexant (Vorzzz^® tablets), a new orexin receptor antagonist

Abstract

Traditionally, benzodiazepines and non-benzodiazepines have been primary pharmacological treatments for insomnia. The introduction of orexin receptor antagonists has provided safer alternatives. Orexin is a neuropeptide involved in maintaining wakefulness, and blockade of its receptors OX₁ and OX₂ is considered to promote sleep with minimal disruption to the natural sleep. Vornorexant (Vorzzz^® tablets 2.5 mg, 5 mg, 10 mg) is a dual orexin receptor antagonist developed in Japan and approved in August 2025 for insomnia. Designed with a short elimination half-life, vornorexant aims to minimize next-day residual effects—a common limitation of conventional hypnotics. In rat electroencephalogram studies, vornorexant increased both non-REM and REM sleep. Phase I trials confirmed rapid absorption and elimination in healthy volunteers. In Phase III trials, vornorexant improved sleep onset, sleep maintenance, and daytime functioning in both short- and long-term use. In a Phase II trial, improvements in both sleep onset latency and sleep maintenance were observed through polysomnographic assessment, confirming efficacy of the intervention based on objective measures. Regarding safety, an increase in the incidence of somnolence with increasing dose was observed, but no adverse events of major clinical concern were identified. No events of dependence, withdrawal, rebound insomnia, or suicidal ideation/behavior were observed. Consistent with its short elimination half-life, findings from clinical trials indicated that vornorexant at doses up to 10 mg did not impair next-day functioning including driving performance, suggesting minimal residual effects. These findings support vornorexant as a promising new therapeutic option for insomnia, offering both efficacy and safety.