328. Nighttime safety of daridorexant: response to noise stimuli, and effects on postural stability, walking and memory

Abstract

Abstract Background Daridorexant is a dual orexin receptor antagonist approved for the treatment of adult patients with insomnia disorder. Aims & Objectives Ideally, safe and effective pharmacological treatments of insomnia should facilitate initiation/maintenance of sleep while minimizing alterations of responsiveness. This ensures that patients can safely operate during the night if necessary. Following single-dose administration at bedtime to healthy non-elderly and elderly subjects, pharmacodynamics (PD) and safety were investigated in the middle of the night (MOTN) after forced awakening to a noise stimulus. Method Double-blind, placebo-controlled, randomized, 3-way crossover study (placebo, 25, and 50 mg daridorexant in the evening) in 36 male and female non-elderly and elderly subjects (1:1 sex/age ratio). Four h after bedtime administration, the auditory awakening threshold (AAT) was determined (increasing noise signal up to 100 dB). Next, the main PD endpoint postural stability (body sway) as well as basic functional mobility (Timed Up and Go (TUG) test), and cognitive function/memory using the Visual Verbal Learning Test (VVLT) were assessed. Thereafter, subjects returned to bed. Results All 36 subjects completed the study. The average AAT was approximately 60 dB across treatments with no differences between daridorexant and placebo. Body sway showed a small, dose-dependent increase vs placebo with differences in least square means (LSM) 95% confidence interval (CI) of 36.7 (2, 71) and 65.9 (31, 100) mm, for daridorexant 25 and 50 mg, respectively. The overall increased body sway was driven by non-elderly subjects, as effects in elderly were similar to placebo. Subjects completed the TUG test in 6–8 s across treatments, with a small, dose-dependent increase vs placebo with a difference in LSM (95% CI) of 0.14 (0.02, 0.27) and 0.47 (0.34, 0.59) s for daridorexant 25 and 50 mg, respectively. The VVLT (immediate and delayed number of correctly recalled words) showed minimal differences in LSM (95% CI) to placebo of up to –1.0 (–1.5, –0.5) and –0.7 (–1.2, –0.2) words for daridorexant 25 and 50 mg, respectively. During delayed word recognition, subjects correctly recognized 77–79% true positive and true negative words across treatments with no difference to placebo for either daridorexant dose. Discussion & Conclusions Following bedtime administration, daridorexant preserved the ability to respond to external noise stimuli and subjects were able to operate safely during the night.