Therapeutics

Suvorexant

Overview

Name: Suvorexant
Synonyms: Belsomra, MK-4305
Chemical Name: [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Approved)
Company: Merck
Approved for: Insomnia, Insomnia in mild to moderate Alzheimer's disease

Background

This orexin receptor antagonist was approved by the U.S. FDA in 2014 to treat insomnia. In February 2020, Suvorexant became the first medication to be approved for treating sleep disorders in Alzheimer’s disease (company press releaseFDA prescribing information). Suvorexant is taken by mouth.

Orexin is a neuropeptide produced by the hypothalamus. It promotes wakefulness, and blocking its receptor promotes sleep. 

Many people with AD suffer from disruption of circadian rhythms that leads to poor sleep, nighttime activity and daytime sleepiness. Circadian disruption is a frequent cause of institutionalization (Harper et al., 2005). Changes in sleep/wake cycles also occur in preclinical AD, and are linked to increased amyloid deposition and risk of cognitive decline (Oct 2013 news; Ju et al., 2013; Musiek et al., 2018). Thus, sleep aids are of interest as potential disease modifiers. CSF orexin levels are elevated in Alzheimer's disease (Oct 2014 news).

In the APP/PS1 mouse model of AD, suvorexant was shown to improve circadian rhythms and cognitive function, restore hippocampal synaptic plasticity, and reduce Aβ plaque deposition in hippocampus and cortex (Zhou et al., 2020).

Findings

In May 2016, Merck began a Phase 3 trial to test whether suvorexant would ease sleep disturbances in 277 people with mild to moderate AD and insomnia. Participants took placebo for two weeks, followed by a baseline overnight polysomnography sleep study. They were then randomized to suvorexant or placebo for four weeks, starting at 10 mg daily and escalating after two weeks to 20 mg as tolerated. After four weeks, participants underwent a final overnight polysomnography session.

In May 2019, company scientists presented results at the American Academy of Neurology meeting (May 2019 conference news). Suvorexant was efficacious on both primary outcomes. It lengthened total nighttime sleep time by 28 minutes compared with placebo, and shortened nighttime waking time by 15 minutes. Importantly, suvorexant did not impair cognition. Adverse events occurred in fewer than 5 percent of participants, and included daytime drowsiness, dry mouth, and falls. Trial data are published (Herring et al., 2020).

In late 2016, a study conducted at Washington University, St. Louis, started to measure whether improving sleep efficiency with suvorexant affects CSF Aβ. Sixty cognitively normal participants take 10 or 20 mg suvorexant or placebo on two consecutive nights, and sleep in a research hospital while undergoing repeated CSF sampling to monitor Aβ production, clearance, and concentration. The study is set to run until mid-2021.

Suvorexant is also being evaluated for insomnia related to multiple sclerosis, bipolar disorder, PTSD, major depressive disorder, panic disorder, and restless legs syndrome.

For details on suvorexant trials, see clinicaltrials.gov.

Last Updated: 16 Jul 2020

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References

News Citations

  1. Drug Reported to Help Alzheimer’s Patients Sleep Better
  2. From ApoE to Zzz’s—Does Sleep Quality Affect Dementia Risk?
  3. Wake Up and Smell the … Orexin? Peptide Percolates in Alzheimer’s Brain

Paper Citations

  1. . Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial. Alzheimers Dement. 2020 Mar;16(3):541-551. Epub 2020 Jan 15 PubMed.
  2. . Disturbance of endogenous circadian rhythm in aging and Alzheimer disease. Am J Geriatr Psychiatry. 2005 May;13(5):359-68. PubMed.
  3. . Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013 May 1;70(5):587-93. PubMed.
  4. . Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):582-590. PubMed.
  5. . Suvorexant ameliorates cognitive impairments and pathology in APP/PS1 transgenic mice. Neurobiol Aging. 2020 Jul;91:66-75. Epub 2020 Mar 3 PubMed.

External Citations

  1. clinicaltrials.gov
  2. company press release
  3. FDA prescribing information

Further Reading

Papers

  1. . The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia. Annu Rev Pharmacol Toxicol. 2017 Jan 6;57:509-533. PubMed.
  2. . Review of Safety and Efficacy of Sleep Medicines in Older Adults. Clin Ther. 2016 Nov;38(11):2340-2372. Epub 2016 Oct 15 PubMed.
  3. . Considerations and Current Trends in the Management of the Geriatric Patient on a Consultation-Liaison Service. Curr Psychiatry Rep. 2020 Apr 13;22(5):21. PubMed.
  4. . Suvorexant for the treatment of insomnia in patients with Alzheimer's disease. Aust N Z J Psychiatry. 2018 Feb;52(2):207-208. Epub 2017 Dec 14 PubMed.
  5. . Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis. Sleep Med Rev. 2017 Oct;35:1-7. Epub 2016 Oct 28 PubMed.
  6. . Preventive Effects of Suvorexant on Delirium: A Randomized Placebo-Controlled Trial. J Clin Psychiatry. 2017 Sep/Oct;78(8):e970-e979. PubMed.
  7. . A Review of Suvorexant, Doxepin, Ramelteon, and Tasimelteon for the Treatment of Insomnia in Geriatric Patients. Consult Pharm. 2017 Mar 1;32(3):156-160. PubMed.
  8. . Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase III Randomized Controlled Clinical Trials. Am J Geriatr Psychiatry. 2017 Jul;25(7):791-802. Epub 2017 Mar 8 PubMed.