No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
EEG power spectral profile of the orexin receptor antagonist suvorexant (MK-4305) in patients with primary insomnia and in healthy subjects
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, call The Formulary at 800-322-4349. The January 2015 monograph topics are ledipasvir/sofosbuvir, eliglustat, naloxegol, pembrolizumab, and dulaglutide injection. The Safety MUE is on ledipasvir/sofosbuvir.
Purpose of Review
This paper focuses on the role of orexin receptors in sleep as evidenced in recent preclinical and clinical work. Orexin A and B and their two receptors (OX1R and OX2R) play essential roles in arousal and sleep/wake regulation, addiction, and stress. The absence of orexin producing cells in the lateral hypothalamus or of orexins in the CSF results in narcolepsy with cataplexy in humans. This finding and others on sleep phenotypes in orexin or orexin receptor knockout mice have triggered drug discovery programs on orexin receptor (OXR) antagonists for the treatment of insomnia and other disorders.
Recent Findings
Several OXR antagonists, most of which are dual OX1R/OX2R antagonists (dual orexin receptor antagonists (DORAs)), have now reached phase II/III clinical trials. Suvorexant (Belsomra®), recently registered in Japan, USA, and Australia for insomnia, is the first orexinergic hypnotic principle of this new class. DORAs promote sleep primarily by increasing REM sleep, with little effect on slow wave sleep (SWS). Based on rodent studies, it is clear that the OX2R is the primary target mediating sleep promotion by DORAs. We briefly review preclinical and clinical data of OXR antagonists in situations of unperturbed and perturbed sleep, e.g., insomnia and various neurological diseases.
Summary
We propose that REM sleep enhancement by DORAs may provide opportunities to treat specific neurological disorders. By contrast, OX2R antagonists such as seltorexant (JNJ-54717793/MIN-202) or MK-1064 may have broader applications as they appear to promote balanced sleep architecture in preclinical models and should, in theory, have a lower narcoleptic/cataplectic potential. These concepts require further validation as more OXR antagonists move beyond early stages of clinical development.
Suvorexant (Belsorma(®)) is the first orexin receptor antagonist approved by the US FDA (August 2014) for insomnia treatment. Following comprehensive Phase II/III studies, with up to 12 months of treatment in adult and elderly patients, there is little doubt that suvorexant induces and maintains sleep. However, the FDA and sponsor disagreed about effective versus safe doses (November 2012). The FDA considered that 5-15 mg were efficient and probably safe, whereas the sponsors had proposed 15-40 mg. The final approved doses are 5, 10, 15 and 20 mg. The major issues are next-morning somnolence and safety as seen in driving tests, with possible signs of muscle weakness, weird dreams, sleep walking, other nighttime behaviors and suicidal ideation. Despite its limitations, suvorexant's market entry offers a truly novel treatment for insomnia, paving the way for follow-up compounds and opening therapeutic avenues in other disorders for orexin receptor modulating compounds.
Orexins A and B (hypocretins 1 and 2) and their two receptors (OX1R and OX2R) were discovered in 1998 by two different groups. Orexin A and B are derived from the differential processing of a common precursor, the prepro-orexin peptide. The neuropeptides are expressed in a few thousand cells located in the lateral hypothalamus (LH), but their projections and receptor distribution are widespread throughout the brain. Remarkably, prepro peptide and double (OX1R/OX2R) receptor knock out (KO) mice reproduce a sleep phenotype known in humans and dogs as narcolepsy/cataplexy. In humans, this disease is characterized by the absence of orexin producing cells in the LH, and severely depleted levels of orexin the cerebrospinal fluid. Null mutation of the individual OX1R or OX2R in mice substantially ameliorates the narcolepsy/cataplexy phenotype compared to the OX1R/OX2R KO, and highlights specific roles of the individual receptors in sleep architecture, the OX1R KO demonstrating an a attenuated sleep phenotype relative to the OX2R KO. It has therefore been suggested that orexin is a master regulator of the sleep-wake cycle, with high activity of the LH orexin cells during wake and almost none during sleep. Less than 10years later, the first orexin antagonist, almorexant, a dual orexin receptor antagonist (DORA), was reported to be effective in inducing sleep in volunteers and insomnia patients. Although development was stopped for almorexant and for Glaxo's DORA SB-649868, no less than 4 orexin receptor antagonists have reached phase II for insomnia, including Filorexant (MK-6096) and Suvorexant (MK-4305) from Merck. Suvorexant has since progressed to Phase III and dossier submission to the FDA. These four compounds are reported as DORAs, however, they equilibrate very slowly at one and/or the other orexin receptor, and thus at equilibrium may show more or less selectivity for OX1R or OX2R. The appropriate balance of antagonism of the two receptors for sleep is a point of debate, although in rodent models OX2R antagonism alone appears sufficient to induce sleep, whereas OX1R antagonism is largely devoid of this effect. Orexin is involved in a number of other functions including reward and feeding, where OX1R (possibly OX2R) antagonists display anti-addictive properties in rodent models of alcohol, smoking, and drug self-administration. However, despite early findings in feeding and appetite control, orexin receptor antagonists have not produced the anticipated effects in models of increased food intake or obesity in rodents, nor have they shown marked effects on weight in the existing clinical trials. The role of orexin in a number of other domains such as pain, mood, anxiety, migraine and neurodegenerative diseases is an active area of research. The progress of the orexin field is thus extraordinary, and the community awaits the clinical testing of more receptor selective antagonists in sleep and other disorders, as well as that of orexin agonists, with the latter expected to produce positive outcomes in narcolepsy/cataplexy and other conditions.
ResearchGate has not been able to resolve any references for this publication.