Suvorexant (Belsomra, Merck) an orexin receptor antagonist for the treatment of adults with insomnia, has met its primary and secondary end points in a phase 3 polysomnography study in patients with mild-to-moderate Alzheimer disease dementia.1

The data, which were presented at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia, Pennsylvania, showed that suvorexant improved the mean total sleep time by 28.2 minutes (95% CI, 11.1 to 45.2) for the patients receiving the treatment (n = 135) versus placebo (n = 139), a significant increase from baseline (P <.005). At baseline, total sleep time was 278 (standard deviation [SD], 77) and 274 (SD, 84) minutes for the drug and placebo groups, respectively.

“Insomnia and other sleep disturbances are more common in people with Alzheimer’s disease dementia, but evidence for the efficacy and safety of sleep medications in this population remains limited,” said W. Joseph Herring, MD, PhD, associate vice president, Global Clinical Research, Neuroscience, Merck Research Laboratories, in a statement. Estimates suggest that up to 45% of patients with Alzheimer disease also have insomnia.

“We are encouraged by the efficacy and safety results of Belsomra in those living with Alzheimer’s disease dementia. Merck plans to file these data with the US Food and Drug Administration for potential inclusion into the Belsomra prescribing information,” Herring added.

The increase in total sleep observed with suvorexant corresponded to a mean increase of 73.4 minutes (95% CI, 61.3 to 85.5) compared to only 45.2 minutes (95% CI, 33.3 to 57.2) with placebo.

All told, the phase 3 trial randomized patients to either 10-mg suvorexant (with a dosing increase option up to 20 mg based on the response, of which 77% did in the second week) or placebo. The patients’ sleep was measured by overnight polysomnography in a sleep laboratory, at 14 days prior to randomization, at 7 days prior to randomization (baseline), and following the 4-week double-blind study period. The trial consisted of a 3-week screening period with a 2-week single-blind placebo run-in followed by a 4-week double-blind randomized treatment period.

The secondary efficacy end point was the mean wake after persistent sleep onset (WASO), measured in minutes and defined as the total wake time over the polysomnography recording period (after the first period of continuous sleep which lasted ≥10 minutes). The suvorexant group was shown to have a 41.8-minute reduction in WASO from baseline compared to a reduction of 32.5 minutes with placebo (95% CI, –28.1 to –3.3; P = .01), for a difference of 15.7 minutes.

As for safety, adverse events (AEs) occurred in 22.5% (n = 32) of patients in the treatment arm, compared to 16.1% (n = 23) of patients in the placebo group. Each group saw a single patient discontinue due to AEs. Somnolence, in mild-to-moderate severity, was the most commonly recorded AE, occurring in 4.2% (n = 6) of patients in the suvorexant-treated group and 1.4% (n = 2) of placebo-treated patients.

Other AEs included headache (suvorexant: n = 5; placebo: n = 6), dry mouth (suvorexant: n = 3; placebo: n = 1) and falls (suvorexant: n = 3; placebo: n = 0).

In a 2014 study of suvorexant, Michael W. Neville, PharmD, and colleagues pointed out that benzodiazepines and nonbenzodiazepines have significant drawbacks—unlike suvorexant. “Both classes exert effects on γ-aminobutyric acid (GABA) and have more global inhibitory effects in the brain,” they wrote. This results in amnesia, next-day limited sedation, and rebound insomnia, and both of these drug classes can be habit forming and could promote dependence. Suvorexant does not share the same drawbacks, largely because rather than inducing sleep, the therapy works by deactivating the mechanisms that cause wakefulness.2

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REFERENCES
1. Merck’s BELSOMRA® (suvorexant) C-IV Meets Primary Efficacy Endpoint in Phase 3 Trial for the Treatment of Insomnia in People with Mild-to-Moderate Alzheimer’s Disease Dementia [press release]. Kenilworth, NJ: Merck; Published May 7, 2019. mrknewsroom.com/news-release/research-and-development-news/mercks-belsomra-suvorexant-c-iv-meets-primary-efficacy-en. Accessed May 13, 2019.
2.  Bennett T, Bray D, Neville MW. Suvorexant, a dual orexin receptor antagonist for the management of insomnia. P T. 2014;39(4):264-266. ptcommunity.com/journal/article/full/2014/4/264/suvorex­ant-dual-orexin-receptor-antagonist-management-insomnia. Accessed May 13, 2019.