Merck's Belsomra (Suvorexant) Demonstrates Efficacy in Phase 3 Trial for Insomnia in Mild-to-Moderate Alzheimer’s Disease Dementia

The 2019 Annual Meeting of the American Academy of Neurology (AAN) was held in Philadelphia, USA, from May 4 to 10. At this meeting, Merck & Co. presented data from a Phase III clinical study evaluating the efficacy and safety of the insomnia medication Belsomra (suvorexant), a Schedule IV controlled substance (C-IV), for the treatment of insomnia in patients with mild-to-moderate Alzheimer’s disease dementia. This study was the first Phase III polysomnography (PSG) trial to assess an insomnia drug in this patient population, and the results demonstrated that both primary and secondary endpoints were met.

This was a randomized, double-blind study conducted in patients with mild-to-moderate Alzheimer’s disease dementia (Mini-Mental State Examination [MMSE] scores of 12–26) and insomnia (mean total sleep time of less than 6 hours) to evaluate the efficacy and safety of Belsomra at a 10 mg dose compared with placebo. The dose could be increased to 20 mg based on clinical response (77% of patients receiving Belsomra had their dose increased from 10 mg to 20 mg after Week 2 of treatment). Sleep was measured by overnight polysomnography (PSG) in a sleep laboratory. The study consisted of a 3-week screening period, a 2-week single-blind placebo run-in period, followed by a 4-week double-blind randomized treatment period. Overnight PSG measurements of patient sleep were performed in the sleep laboratory at the visit 14 days before randomization, at the baseline visit 7 days before randomization, and after the 4-week double-blind treatment period. The primary endpoint was the change from baseline in mean total sleep time (TST; higher scores indicate improved sleep) as measured by PSG at Week 4 of treatment. The secondary endpoint was the mean duration of wake after sleep onset (WASO), measured in minutes, defined as the total time spent awake during the PSG recording period after at least 10 minutes of continuous sleep (lower scores correspond to better sleep). Additional exploratory measures included the Clinician’s Global Impression of Severity of Insomnia (CGI-S) assessed by physicians and the Subjective Sleep Quality Rating (SSQR) reported by caregivers.

Among subjects who completed the study (Belsomra group, n=136; placebo group, n=141), the mean (SD) baseline total sleep time (TST) for patients receiving Belsomra and placebo was 278 (77) minutes and 274 (84) minutes, respectively. Regarding the primary endpoint, after 4 weeks of treatment, the mean TST in the Belsomra group increased significantly by 28.2 minutes compared with the placebo group (model-based least squares mean change from baseline in TST: 73.4 minutes for the Belsomra group vs. 45.2 minutes for the placebo group; difference = 28.2 minutes [95% CI: 11, 45]; p < 0.005). Secondary endpoint measurements showed an improvement in wake after sleep onset (WASO) in the Belsomra group compared with the placebo group (model-based least squares mean change from baseline in WASO: -41.8 minutes for the Belsomra group vs. -32.5 minutes for the placebo group; difference = 15.7 minutes [95% CI: -28, -3.3]; p = 0.01).

Safety was assessed in accordance with the study protocol through adverse event reporting, laboratory analyses, electrocardiograms, and physical examinations. Adverse events were reported in 22.5% (n=32/142) of the Belsomra group and 16.1% (n=23/143) of the placebo group. One patient in each group discontinued treatment due to adverse events. The most frequently reported adverse event was somnolence, occurring in 4.2% (n=6) of the Belsomra group and 1.4% (n=2) of the placebo group. The severity of somnolence was mild to moderate. Other adverse events included headache (5 cases in the Belsomra group vs. 6 cases in the placebo group), dry mouth (n=3 vs. n=1), and falls (n=3 vs. n=0).

Belsomra: The World’s First Orexin Receptor Antagonist for Insomnia

Studies have shown that insomnia affects 45% of patients with Alzheimer’s disease. There are many factors contributing to insomnia, including instances where wake-promoting signals in the brain overwhelm sleep-promoting signals. In the human brain, numerous neurotransmitters regulate wakefulness, including the orexin signaling system. Research has found elevated levels of orexin in the cerebrospinal fluid of patients with Alzheimer’s disease. Changes in the brain tissue of Alzheimer’s patients are associated with cognitive decline and are also believed to disrupt the sleep-wake cycle, thereby leading to sleep problems. Many patients with Alzheimer’s disease wake up more frequently and remain awake for longer periods compared to those without the disease, which may result in significant alterations in sleep-wake patterns.

The active pharmaceutical ingredient of Belsomra is suvorexant, a first-in-class, oral, highly selective orexin receptor antagonist. Orexin is a neurotransmitter located in specific regions of the brain that helps maintain wakefulness. Belsomra is believed to exert its therapeutic effect through antagonism of orexin receptors.

The drug was approved by the FDA in the United States in August 2014 for the treatment of adult patients with insomnia. This approval made Belsomra the first newly classed insomnia medication—an orexin receptor antagonist—to be approved globally. The currently marketed dosage forms are 5 mg, 10 mg, 15 mg, and 20 mg tablets.

Dr. W. Joseph Herring, Vice President of Global Clinical Research in Neuroscience at MSD Research Laboratories, stated, “Insomnia and other sleep disorders are more common in patients with Alzheimer’s disease dementia, but evidence regarding the efficacy and safety of sleep medications in this population remains limited. We are highly encouraged by the efficacy and safety profile of Belsomra for the treatment of insomnia in patients with Alzheimer’s disease dementia. We plan to submit these data to the U.S. FDA for inclusion in the prescribing information for Belsomra.” (Sina)PharmaceuticalsCompilation/Newborn)

Reference: 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

Source: Sina Medical News