Clinical Profile of the Orexin Receptor Antagonist Suvorexant for the Treatment of Insomnia in Phase-3 Clinical Trials (PL1.001)

BACKGROUND: Night-time administration of orexin receptor antagonists is hypothesized to dampen orexin-mediated wakefulness, facilitating sleep. Here, we provide an overview of the clinical profile of suvorexant, an investigational orexin receptor antagonist for the treatment of insomnia, in Phase-3 trials. DESIGN/METHODS: The Phase-3 program comprised two 3-month confirmatory efficacy trials (Trial-1 and Trial-2) and a 1-year safety trial (Trial-3). All trials were randomized, double-blind, placebo-controlled, parallel-group, studies in non-elderly (18-64 years) and elderly (蠅65 years) patients with insomnia. Doses of 40mg (non-elderly) and 30mg (elderly) were evaluated in all three trials; 20mg (non-elderly) and 15mg (elderly) were also evaluated in Trials-1&2. Elderly dose-adjustments were made to match non-elderly exposures. In Trials-1&2, efficacy was assessed at Week-1, Month-1, and Month-3 by subjective endpoints (reported on a patient daily diary) of total-sleep-time (sTST), time-to-sleep onset (sTSO), and wake-time-after-sleep-onset (sWASO), and at Night-1, Month-1, and Month-3 by polysomnographic (PSG) endpoints of Latency-to-onset-of-Persistent-Sleep (LPS) and Wakefulness-After-persistent Sleep-Onset (WASO). In Trial-3, efficacy was assessed over 1-year and in a 2-month relapse prevention phase by sTST, sTSO, and sWASO. RESULTS: The number of patients randomized was 1021 in Trial-1, 1019 in Trial-2, and 781 in Trial-3. In Trial-1 and Trial-2, suvorexant 40/30mg and 20/15mg were significantly superior to placebo on most subjective and PSG endpoints at Night-1/Week-1, Month-1 and Month-3. In both trials, the magnitude of improvement appeared dose-related. In Trial-3, suvorexant 40/30mg was superior to placebo at each month over 1-year. In the relapse prevention phase of Trial-3, insomnia symptoms returned after suvorexant discontinuation, suggesting the improvement over the previous year was attributable to suvorexant. Suvorexant was generally well-tolerated in all three trials, without evidence of clinically important rebound or withdrawal upon discontinuation. CONCLUSIONS: Suvorexant improved sleep onset and maintenance over 3-months in two confirmatory Phase-3 trials and over 1-year in a long-term trial, and was generally well-tolerated without evidence of clinically important rebound or withdrawal effects following discontinuation. Study Supported by: Merck Disclosure: Dr. Herring has received personal compensation for activities with Merck & Co. Inc., as an employee. Dr. Herring holds stock and/or stock options in Merck & Co. Dr. Snyder has received personal compensation for activities with Merck & Co. Inc., as an employee. Dr. Snyder holds stock and/or stock options in Merck & Co. Inc. Dr. Ivgy-May has received personal compensation for activities with Merck & Co. Inc. as an employee. Dr. Ivgy-May holds stock and/or stock option in Merck & Co. Inc. Dr. Connor has received personal compensation for activities with Merck & Co., Inc. Dr. Connor has received research support from Merck & Co., Inc. Dr. Snavely has received personal compensation for activities with Merck & Co. Inc. Dr. Snamely holds stock and/or stock options in Merck & Co. Inc. Dr. Michelson has received personal compensation for activities with Merck & Co., Inc. Dr. Michelson holds stock and/or stock options in Merck & Co., Inc.