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Background: Daridorexant (ACT-541468) is a potent dual orexin receptor antagonist under development for the treatment of sleep disorders. Concomitant intake of ethanol and hypnotics has been shown to result in additive/supra-additive depression of the central nervous system, resulting in pronounced sedation., Objective: The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between ethanol and daridorexant., Method: This was a single-center, double-blind, placebo-controlled, randomized, four-way crossover study conducted in 19 healthy male/female subjects. Subjects received the following four treatments: ethanol with daridorexant, daridorexant alone, ethanol alone, and placebo. Daridorexant 50 mg and the matching placebo were administered as single oral tablets. Ethanol was infused intravenously and clamped at a level of 0.6 g/L for 5 h. The PK of ethanol and daridorexant were assessed and a battery of PD tests performed., Results: Concomitant administration of ethanol prolonged the time to reach maximum plasma concentrations (t max ) of daridorexant (median difference 1.25 h). No other relevant PK interactions were observed. Coadministration with ethanol produced a numerically greater impairment on saccadic peak velocity, body sway, visual analog scale (VAS) alertness, VAS alcohol intoxication, smooth pursuit, and adaptive tracking compared with daridorexant alone. All treatments were generally well tolerated without serious adverse events (AEs). The most commonly reported treatment-emergent AEs following coadministration of daridorexant and ethanol included somnolence, headache, fatigue, sudden onset of sleep, and dizziness., Conclusions: Apart from a shift in t max , no relevant changes in PK parameters were observed following coadministration of daridorexant and ethanol. The coadministration led to reinforced drug actions that were, at most, indicative of infra-additive effects on certain PD markers. Patients will be advised not to consume ethanol with daridorexant., Clinical Trials Registration Number: NCT03609775 (ClinicalTrials.gov Identifier).

Background: Daridorexant, a dual orexin receptor antagonist approved in early 2022, reduces wake after sleep onset without reducing the number of awakenings in patients with insomnia. The objective of this post hoc analysis was to explore the effect of daridorexant on the number, duration, and distribution of night-time wake bouts, and their correlation with daytime functioning., Methods: Adults with insomnia disorder were randomized 1:1:1:1:1:1 to placebo, zolpidem 10 mg, or daridorexant 5, 10, 25, or 50 mg in a phase II dose-finding study, and 1:1:1 to placebo or daridorexant 25 or 50 mg in a pivotal phase III study. We analyzed polysomnography data for daridorexant 25 and 50 mg, zolpidem 10 mg, and placebo groups. Polysomnography was conducted at baseline, then on Days 1/2, 15/16, and 28/29 in the phase II study, and Months 1 and 3 in the phase III study. The number, duration, and distribution of wake bouts (≥ 0.5 min) were assessed., Results: Data from 1111 patients (phase II study: daridorexant 50 mg [n = 61], zolpidem 10 mg [n = 60], placebo [n = 60]; phase III study: daridorexant 25 mg [n = 310], daridorexant 50 mg [n = 310], placebo [n = 310]) were analyzed. Long wake bouts were defined as > 6 min. Compared with placebo, daridorexant 50 mg reduced overall wake time (p < 0.05; all time points, both studies), the odds of experiencing long wake bouts (p < 0.001; Months 1 and 3, phase III study), and the cumulative duration of long wake bouts (p < 0.01; all time points, both studies). Reductions in long wake bouts were sustained through the second half of the night and correlated with improvements in daytime functioning. An increase in the cumulative duration of short wake bouts was observed with daridorexant 50 mg (p < 0.01 vs placebo, Months 1 and 3, phase III study); this was uncorrelated with daytime functioning., Conclusion: Daridorexant reduced the number and duration of longer wake bouts throughout the night compared with placebo, corresponding with improved daytime functioning., Clinical Trials: Clinicaltrials.gov NCT02839200 (registered July 20, 2016), NCT03545191 (registered June 4, 2018)., (© 2023. The Author(s).)

Daridorexant (Quviviq™) is a useful option for the treatment of insomnia disorder, which has shown efficacy in younger and older adults. It antagonises the orexin receptors, thereby reducing the wake drive. Daridorexant is the first dual orexin receptor antagonist to be approved for the treatment of chronic insomnia in the EU and has been approved for insomnia in the USA. In phase 3 clinical trials, daridorexant dose-dependently improved objective latency to persistent sleep, objective wake time after sleep onset, subjective total sleep time and, at the 50 mg dose, subjective daytime functioning compared with placebo. Daridorexant was generally well tolerated. Adverse events (AEs) commonly associated with insomnia drugs, such as somnolence, fatigue and dizziness, occurred at a similar or slightly greater frequency with daridorexant than with placebo. Falls occurred at a similar or lower frequency with daridorexant than with placebo. Most AEs were mild in severity and the incidence was not dose-dependent. The efficacy of daridorexant was maintained during a 12-month extension trial, with no new safety or tolerability concerns., (© 2023. Springer Nature.)

Background and Objective: Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. In two phase III, 12-week studies in patients with insomnia disorder, daridorexant improved sleep and daytime functioning while maintaining a favorable safety profile. The objective of this 40-week extension study was to assess the long-term safety and tolerability of daridorexant. Methods: Adults with insomnia disorder who completed the 12-week studies were invited to enroll in this double-blind extension study. Patients originally randomised to daridorexant (10 mg/25 mg/50 mg) remained on their respective treatments; patients randomised to placebo were re-randomised to daridorexant 25 mg or placebo. The 40-week treatment period was followed by a 7-day placebo run-out. The primary objective was to assess safety/tolerability. Exploratory objectives were to evaluate the efficacy of daridorexant on sleep (self-reported total sleep time) and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire). Results: In total, 804 patients were enrolled in the study, of whom 801 received at least one dose of the study treatment and 550 patients (68.4%) completed the study. Overall incidence of treatment-emergent adverse events was similar across groups (35–40%). Daridorexant did not induce next-morning sleepiness and no withdrawal-related symptoms or rebound were observed after treatment discontinuation. Improvements in sleep and daytime functioning were maintained through to the end of the study and were most pronounced with daridorexant 50 mg. Daridorexant 50 mg, compared with placebo, increased self-reported total sleep time by a least-squares mean of 20.4 (95% confidence interval [CI] 4.2, 36.5), 15.8 (95% CI − 0.8, 32.5) and 17.8 (95% CI − 0.4, 35.9) minutes and decreased (i.e., improved) Insomnia Daytime Symptoms and Impacts Questionnaire total scores by a least-squares mean of − 9.3 (95% CI − 15.1, − 3.6), − 9.5 (95% CI − 15.4, − 3.5) and − 9.1 (95% CI − 15.6, − 2.7), at weeks 12, 24 and 36 of the extension study, respectively. Conclusions: Treatment with daridorexant, for up to 12 months, was generally safe and well tolerated. Exploratory efficacy analyses suggest that the sustained improvements in sleep and daytime functioning with daridorexant 50 mg support its use for long-term treatment of insomnia disorder, without concerns of new safety signals. Clinical Trial Registration: ClinicalTrials.gov (NCT03679884) [first posted: 21 September, 2018], https://clinicaltrials.gov/ct2/show/NCT03679884. Plain Language Summary: Insomnia disorder is the long-term inability to fall asleep or stay asleep with a significant impact on daily life. Left inadequately treated, this disorder may increase the risk of other health problems. For patients with insomnia disorder who require a sleep medication, many drugs are not recommended for long-term use and there is an unmet need for one that can be used safely and effectively over the long term. Daridorexant is a new insomnia treatment that was approved for adults following positive results in two 12-week clinical studies. Both studies showed that, in patients with insomnia disorder, daridorexant improved night-time sleep and patients' ability to function during the day, while avoiding major safety concerns. Patients who completed these two studies could continue into a 40-week extension study enabling the safety and tolerability of daridorexant to be investigated for up to 1 year. Treatment remained double blind for the entire 1-year period. The extension study showed that daridorexant, at all doses studied (10 mg, 25 mg, 50 mg), continued to be generally safe and well tolerated. Patients showed no signs of tolerance, physical dependence, rebound nor any excessive daytime sleepiness. Exploratory efficacy analyses suggest that improved night-time and daytime symptoms of insomnia were sustained, in particular with the highest approved dose, 50 mg, and there were no signs that the benefits of the drug were wearing off at the end of the 1 year. These results support the use of daridorexant 50 mg for the long-term treatment of insomnia disorder in adults. [ABSTRACT FROM AUTHOR]