Nighttime safety of daridorexant: Evaluation of responsiveness to an external noise stimulus, postural stability, walking, and cognitive function

Background: Daridorexant is a dual orexin receptor antagonist approved for the treatment of chronic insomnia disorder. Aims: Investigate the auditory awakening threshold (AAT), postural stability, and cognitive function during the night following evening administration of daridorexant 25 and 50 mg. Methods: Double-blind, placebo-controlled, randomized, 3-way (placebo, 25, 50 mg) crossover study in 36 healthy male and female nonelderly adult and elderly subjects (1:1 sex/age ratio). Four hours after bedtime administration, the AAT was determined, followed by investigation of the main pharmacodynamic endpoint nocturnal postural stability (body sway) as well as functional mobility using the Timed Up and Go (TUG) test, and cognitive function/memory using the Visual Verbal Learning Test (VVLT). Results: All 36 subjects completed the study. The average AAT was approximately 60 dB across treatments, i.e., there were no differences between daridorexant and placebo. Daridorexant marginally increased body sway by approximately 22%, while it had no clinically meaningful effect on the time to complete the TUG test (⩽1 s increase), and the VVLT (immediate and delayed number of correctly recalled words) showed minimal and clinically not meaningful differences of up to one word, all compared to placebo. Delayed word recognition was not different from placebo. The increase in body sway in the overall population was driven by nonelderly adults, as effects in elderly subjects were similar to placebo. Conclusions: Following bedtime administration, daridorexant maintained the ability to awaken to an external noise stimulus in the middle of the night, allowing subjects to function safely. ClinicalTrials.gov Identifier: NCT05702177.