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 release; FDA prescribing information). Suvorexant is taken by mouth.

Suvorexant was reported to have a lower potential for abuse, and be generally safer, than other sleep medications frequently used in aging populations, such as benzodiazepines (Okino et al., 2023; Moline et al., 2023; Pan et al., 2023; Katsuta et al., 2023).

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 285 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. Thirty-eight cognitively normal participants took 10 or 20 mg suvorexant or placebo on two consecutive nights, and slept in a research hospital while undergoing repeated CSF sampling to monitor Aβ production, clearance, and concentration, and tau levels. The study was completed in March 2021. According to published results, 20 mg suvorexant decreased the phospho-tau181/tau ratio by 10-15 percent within hours, but did not affect p-tau202 or p-tau217 to tau ratios. The drug lowered Aβ by 10 to 20 percent compared to placebo starting five hours after dosing (Lucey et al., 2023).

In May 2022, a Phase 2 study began at Washington University to assess the effect of two years of suvorexant on the accumulation of brain amyloid. The study plans to enroll 200 cognitively normal participants with PET evidence of amyloid accumulation and poor sleep, who will take 20 mg suvorexant or placebo nightly. The primary outcome will be change in brain amyloid by PET scan. Secondary outcomes include tau PET, cognitive measures, and changes in plasma and CSF markers of Aβ and tau, as well as blood and CSF transcriptomic, proteomic, and lipidomic analysis, and microbiome evaluation. Completion is anticipated in May 2026.

Suvorexant is also being evaluated for insomnia related to Parkinson’s disease, progressive supranuclear palsy, opioid and alcohol use disorder, multiple sclerosis, PTSD, major depressive disorder, and restless legs syndrome.

For details on suvorexant trials, see clinicaltrials.gov.