SEATTLE, WA—Suvorexant (Belsomra; Merck) is the first orexin receptor antagonist approved for the treatment of insomnia (August, 2014). The blocking of orexin signaling has been shown to reduce wakefulness and promote sleep across species, reported Christopher J. Winrow, PhD of Merck Research Laboratories, West Point, PA, at SLEEP 2015.

Orexin/hypocretin neuropeptides signal through the orexin (OX1R and OX2R) receptors and play a role as key regulators of wakefulness across species. The orexin stimulus is active during wakefulness but silent during normal sleep. Through preclinical and clinical studies, a series of antagonists were thoroughly characterized, leading to the first approval of an orexin receptor antagonist for the treatment of insomnia.

Suvorexant, a potent selective and reversible orexin receptor antagonist (ORA) reduces wake and proportionally increases NREM and REM sleep in rodents, dogs, monkeys, and humans, in a dose-dependent manner. Murine, canine, and human narcolepsy has been found to be connected with reduced orexinogenic neurons, suggesting a role for orexin in promoting sleep. The relationship between orexin and narcolepsy generated interested in developing small-molecule orexin receptor antagonists (ORAs) as novel therapy for the treatment of insomnia.

Suvorexant demonstrated its difference from GABAA receptor modulators in its effect on sleep architecture, qEEG spectra, arousability to salient stimuli, tolerance, locomotor activity, alcohol interaction, and cognitive performance.

Three major Phase 3 safety trials, involving 2,800 patients of diverse ages, or 750 person-years of data, found it to be safe and well-tolerated. In particular, its impact on cognition was found to be favorable. In pre-clinical and clinical trials, treatment with suvorexant preserved the ability to wake to emotionally meaningful stimuli while maintaining uninterrupted sleep during irrelevant noise. By contrast, GABAA receptor antagonists compromise cognitive function, even at lower, non-sleep producing doses, while suvorexant does not cause similar impairments, even at higher, sleep-producing doses.

Dr. Winrow concluded that suvorexant “provides a novel approach for the treatment of insomnia” through its “safe and effective blockade of orexin signaling to promote sleep.”