Current and novel dual orexin receptor antagonists for the treatment of insomnia: the emergence of vornorexant

Insomnia is a serious public health concern. As the widely prescribed hypnotics that positively modulate gamma-aminobutyric acid (GABA)A receptor activity have various safety concerns, there is a growing demand for the development of novel hypnotics that act on targets other than GABAA receptor signaling to overcome the drawbacks of current medications. As an alternative target to generate novel hypnotics, the orexin system has recently gained much attention, and 3 dual orexin receptor antagonists (DORAs)-suvorexant, lemborexant, and daridorexant-were launched. However, some doses of these DORAs are associated with a higher incidence of somnolence compared to placebo. Vornorexant is a novel DORA designed to have an improved pharmacokinetic profile-rapid absorption and the shortest half-life among existing DORAs to reduce the risk of residual activity, which has been confirmed in humans. Indeed, it has shown rapid sleep-promoting effects in patients with insomnia, maintaining its activity throughout the night but having a low incidence of next-day residual effects. In this review, we first provide an overview of the role of the orexin system in sleep/wake balance and then describe the profile of a newly developed DORA, vornorexant, from drug discovery to clinical results.