Daridorexant, a New Dual Orexin Receptor Antagonist to Treat Insomnia Disorder

• Published in: Annals of neurology Vol. 87; no. 3; pp. 347 - 356
• Main Authors: Dauvilliers, Yves, Zammit, Gary, Fietze, Ingo, Mayleben, David, Seboek Kinter, Dalma, Pain, Scott, Hedner, Jan
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-03-2020; Wiley Subscription Services, Inc; Wiley
• Subjects: Adult; adults; Benzimidazoles; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Benzimidazoles - therapeutic use; clinical-practice guideline; combining multiple comparisons; Dose-Response Relationship, Drug; Double-Blind Method; efficacy; Human health and pathology; Humans; Imidazoles; Insomnia; Latency; Life Sciences; Medication; Middle Aged; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; Orexin Receptor Antagonists; Orexin Receptor Antagonists - adverse effects; Orexin Receptor Antagonists - therapeutic use; Orexins; Pharmaceutical sciences; Psychiatrics and mental health; Pyrrolidines; Pyrrolidines - administration & dosage; Pyrrolidines - adverse effects; Pyrrolidines - therapeutic use; Randomization; Reduction; safety; Sleep; Sleep and wakefulness; Sleep disorders; Sleep Initiation and Maintenance Disorders; Sleep Initiation and Maintenance Disorders - drug therapy; Time dependence; Treatment Outcome; Triazoles; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - therapeutic use; Zolpidem; Zolpidem - therapeutic use
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.25680

Objective
To evaluate the dose–response relationship of daridorexant, a new dual orexin receptor antagonist, on sleep variables in subjects with insomnia disorder.
Methods
Adults (≤64 years) with insomnia disorder were randomized (1:1:1:1:1:1) to receive daily oral placebo, daridorexant (5, 10, 25, or 50mg), or 10mg zolpidem for 30 days. The primary efficacy outcome was the change in wake time after sleep onset from baseline to days 1 and 2. Secondary outcome measures were change in latency to persistent sleep from baseline to days 1 and 2, change in subjective wake time after sleep onset, and subjective latency to sleep onset from baseline to week 4. Safety was also assessed.
Results
Of 1,005 subjects screened, 359 (64% female) were randomized and received ≥1 dose. A significant dose–response relationship (multiple comparison procedure‐modeling, 2‐sided p < 0.001) was found in the reduction of wake after sleep onset and latency to persistent sleep from baseline to days 1 and 2 with daridorexant. These reductions were sustained through to days 28 and 29 (p = 0.050 and p = 0.042, respectively). Similar dose‐dependent relationships were observed for subjective wake after sleep onset and subjective latency to sleep onset. The incidence of treatment‐emergent adverse events was 35%, 38%, 38%, and 34% in subjects treated with 5, 10, 25, and 50mg daridorexant, respectively, compared with 30% for placebo, and 40% for 10mg zolpidem. There were no clinically relevant treatment‐related serious adverse events. Four subjects withdrew due to adverse events.
Interpretation
Daridorexant induced a dose‐dependent reduction in wake time after sleep onset in subjects with insomnia disorder (Clinicaltrials.gov NCT02839200). Ann Neurol 2020;87:347–356