Therapeutics

Lemborexant

Overview

Name: Lemborexant
Synonyms: E2006
Chemical Name: (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide)
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Eisai Co., Ltd.

Background

Lemborexant is a brain-penetrant, small molecule orexin/hypocretin receptor antagonist in development to treat insomnia. The neuropeptide orexin regulates wakefulness; inhibiting orexin receptor signaling promotes sleep. Lemborexant has been reported to inhibit the orexin signaling pathway and promote both REM and non-REM sleep in mice and rats; preclinical pharmacological and pharmacokinetic data are formally published (Beuckmann et al., 2017Beuckmann et al., 2019Ueno et al., 2019).

People with AD experience poor sleep and disruption of circadian rhythms that lead to nighttime activity and daytime sleepiness (Harper et al., 2005). Changes in circadian rhythms also occur in preclinical AD, and are linked to increased amyloid deposition and risk of cognitive decline (Oct 2013 newsJu et al., 2013; Musiek et al., 2018). There are no treatments for sleep/wake rhythm disorders associated with AD.

Findings

In December 2016, Eisai began a Phase 2 trial to test the effect of lemborexant on multiple sleep parameters in 162 people with mild to moderate AD dementia and circadian rhythm sleep disorder. Participants had their activity recorded around the clock for two weeks with a motion-detecting wrist device. Sixty-two participants who met the criteria of excessive day time sleep or nighttime wakefulness were randomized to placebo or 2.5, 5, 10, or 15 mg of lemborexant, taken by mouth five minutes before bedtime, for one month. Primary endpoints were change from baseline in 12 different parameters related to circadian rhythm, and daytime and nighttime sleep, during each week of treatment. 

Eisai announced results in an October 2018 press release and presented at the CTAD conference the same month. All participants completed the study, giving data for 12 or 13 people per dose arm. Doses of 2.5, 5 and 15 were associated with lower nighttime activity during the four weeks of treatment; 5 and 15 mg improved circadian rhythmicity as measured by an increased ratio of daytime to nighttime activity. Other endpoints showed no statistically significant changes, but trends toward less daytime sleepiness, and better, longer sleep at night.

Side effects were similar to those in the insomnia program for which this drug was originally developed. They included constipation, drowsiness, joint pain, headache, and nightmares, but no falls, confusion, or worsening cognition as measured by the MMSE or ADAS-Cog over the course of the study. For more details, see AAIC poster 2019. An ongoing, 30-month, open-label extension of the trial is expected to end in April, 2020.

A separate trial in 48 healthy volunteers was reported to not impair next-morning driving (Vermeeren et al., 2019).

For all trials of lemborexant, see clinicaltrials.gov.

Last Updated: 12 Oct 2019

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References

News Citations

  1. From ApoE to Zzz’s—Does Sleep Quality Affect Dementia Risk?

Paper Citations

  1. . Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013 May 1;70(5):587-93. PubMed.
  2. . Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):582-590. PubMed.

External Citations

  1. press release
  2. AAIC poster 2019
  3. Vermeeren et al., 2019
  4. clinicaltrials.gov
  5. Beuckmann et al., 2017
  6. Beuckmann et al., 2019
  7. Ueno et al., 2019
  8. Harper et al., 2005

Further Reading

Papers

  1. . Sleep Disorders Associated With Alzheimer's Disease: A Perspective. Front Neurosci. 2018;12:330. Epub 2018 May 31 PubMed.
  2. . Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp Mol Med. 2015 Mar 13;47:e148. PubMed.
  3. . Insomnia in Elderly Patients: Recommendations for Pharmacological Management. Drugs Aging. 2018 Sep;35(9):791-817. PubMed.
  4. . Concentration-Response Modeling of ECG Data From Early-Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk - Experience From the Development Program of Lemborexant. J Clin Pharmacol. 2017 Jan;57(1):96-104. Epub 2016 Aug 4 PubMed.