Nighttime Safety of Daridorexant: Response to Noise Stimuli, and effects on Postural Stability, Walking and Memory

Introduction: Daridorexant is a dual orexin receptor antagonist approved for the treatment of adult patients with chronic insomnia. Following single-dose administration at bedtime to healthy younger adult and older adult (≥65 years) subjects, pharmacodynamics and safety were investigated in the middle of the night after forced awakening to a noise stimulus.

Methods: Double-blind, placebo-controlled, randomized, 3-way crossover study (placebo, 25, and 50 mg daridorexant in the evening) in 36 male and female young adult and older adult subjects (1:1 sex/age ratio). Four hours post-bedtime administration, the auditory awakening threshold (AAT) was determined (increasing noise signal up to 100 dB). 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 also assessed. 

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 increased body sway was driven by younger adult subjects, effects in older adults were similar to placebo. Subjects completed the TUG test in 6–8s 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 showed minimal differences with daridorexant 25mg and 50mg compared to placebo. 

Conclusion: Following bedtime administration, daridorexant preserved the ability to respond to external noise stimuli and subjects were able to operate safely during the night. 

Support: Idorsia Pharmaceuticals

Originally presented at Sleep Europe 2024, Seville, Spain, P1213