Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders

ABSTRACT

Introduction

The last two decades have witnessed a rapid increase in the knowledge about the role of the orexin system, particularly in the regulation of wakefulness and arousal. Dual orexin receptor antagonists (DORAs) have been approved for the treatment of insomnia disorders (suvorexant, lemborexant) and drugs with a distinctive profile (daridorexant) or orexin-2 receptor selectivity (seltorexant) are in development.

Areas covered

This review discusses pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety properties of orexin receptor antagonists (ORAs).

Expert opinion

In general, the drugs described have a similar effect on sleep characteristics although their pharmacokinetic variables differ. ORAs have the potential to revolutionize the pharmacological treatment of insomnia because they not only improve sleep, but, in addition, appear to have no dependence – and tolerance-inducing effects, which makes them suitable for long-term-treatment.

The safety and tolerability profile of ORAs clearly differ from those of more traditional sleep-promoting drugs. Further research is needed to demonstrate benefits to patients suffering from insomnia disorder, e.g., with respect to improving not only sleep but also daytime functioning. In addition, ongoing and future research will show whether ORAs may have beneficial effects in patients with various psychiatric and neurodegenerative disorders, including Alzheimer’s disease.

KEYWORDS:

• Efficacy
• orexin
• pharmacodynamics
• pharmacokinetics
• performance
• receptor
• review
• safety
• selectivity
• sleep

Article highlights

• Insomnia is a highly prevalent disorder and not well served by traditional pharmacological treatments.

• Accumulating evidence points to the pivotal role of the orexin system in the regulation of wakefulness and arousal.

• DORAs (suvorexant, lemborexant) have been approved as sleep-promoting compounds whereas daridorexant and seltorexant are under development and offer a distinctive and orexin-2 receptor selective profile, respectively.

• Beneficial effects on sleep onset, sleep maintenance, and sleep architecture have been demonstrated in large clinical studies whereas a distinction in efficacy between dual and selective antagonists needs further investigation.

• The pharmacokinetic profile of these drugs and their active metabolites (if any) is to be viewed in relation to the propensity to elicit next-day (residual) effects.

• The drugs mentioned share an overall good tolerability and safety profile without indications of rebound insomnia, withdrawal or dependence potential.

This box summarizes key points contained in the article.

Declaration of interest

C Muehlan, C Vaillant, I Zenklusen and J Dingemanse are employees of Idorsia Pharmaceuticals Ltd. The views expressed in this article are those of the authors and do not necessarily reflect those of their company (Idorsia Pharmaceuticals Ltd). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.