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Effect of the New Dual Orexin Receptor Antagonist Daridorexant On SLEEPJ, 2021, 1–11 doi: 10.1093/sleep/zsaa275 Advance Access Publication Date: 11 December 2020 Original Article Original Article Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021 Effect of the new dual orexin receptor antagonist daridorexant on nighttime respiratory function and sleep in patients with mild and moderate obstructive sleep apnea Marie-Laure Boof1,*, , Jasper Dingemanse1, , Katharina Lederer2, , Ingo Fietze2 and Mike Ufer1, 1Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland and 2Advanced Sleep Research GmbH, Berlin, Germany *Corresponding author. Marie-Laure Boof, Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, Switzerland. Email: [email protected]. Abstract In this randomized, double-blind, placebo-controlled, two-period crossover study, the effect of the dual orexin receptor antagonist daridorexant was evaluated on nighttime respiratory function and sleep in 28 patients with mild and moderate obstructive sleep apnea (OSA). In each period, 50 mg daridorexant or placebo was administered every evening for 5 days. The primary endpoint was apnea/hypopnea index (AHI) during total sleep time (TST) after the last dosing. Other endpoints included peripheral oxygen saturation (SpO2), sleep duration, latency to persistent sleep (LPS), wake after sleep onset (WASO), and sleep efficiency index (SEI). Pharmacokinetics, safety, and tolerability were also assessed. The mean treatment difference for AHI during TST (i.e. daridorexant − placebo) after the last dosing was 0.74 events/hour (90% confidence interval [CI]: –1.43, 2.92). The corresponding treatment difference for SpO during TST was 0.16% [90% CI: –0.21, 0.53]. 2021 2 Overall, there was no clinically relevant effect of daridorexant on AHI or SpO2-related data after single and repeated dosing irrespective of sleep phase (i.e. rapid eye movement [REM] vs non-REM). Moreover, after single and repeated dosing, daridorexant prolonged TST by 39.6 minutes (90% CI: 16.9, 62.3) and 38.8 minutes (19.7, 57.9), respectively, compared with placebo and favorably modulated other sleep-related endpoints (i.e. increased SEI, decreased WASO, and shortened LPS). It attained expected plasma concentrations and was well tolerated in patients with mild and moderate OSA. These results indicate that single and repeated doses of 50 mg daridorexant do not impair nighttime respiratory function and improve sleep in patients with mild and moderate OSA. Clinical Trial Registration: ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/ NCT03765294. Statement of Significance Obstructive sleep apnea (OSA) is highly prevalent and often associated with insomnia-related symptoms. However, many sleep medications impair nighttime respiration and, therefore, require cautionary use in respiratory-depressed patients. Daridorexant is a new dual orexin receptor antagonist under development for the treatment of insomnia with presumably limited respiratory effects. This randomized, double-blind, placebo-controlled, two-period crossover study evaluated the effect of daridorexant on nighttime respiratory function in patients with mild and moderate OSA. At the highest phase-3 dose of 50 mg, daridorexant did not impair nighttime respiratory function based on apnea/hypopnea index and peripheral oxygen saturation data regardless of OSA severity. In addition, daridorexant improved sleep characteristics in this population that did not present insomnia symptoms at baseline. Key words: obstructive sleep apnea; dual orexin receptor antagonist; daridorexant; pharmacokinetics; polysomnography; nighttime respiration; safety Submitted: 26 June, 2020; Revised: 30 October, 2020 © Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail [email protected]. 1 2 | SLEEPJ, 2021, Vol. 44, No. 6 Introduction maximum recommended daily dose. However, due to the high inter- and intra-individual variability observed in the study, Obstructive sleep apnea (OSA) is a sleep-related breathing dis- suvorexant should be used with caution in patients with com- order characterized by repeated reduction (i.e. hypopnea) or ces- promised respiratory function and at the lowest effective dose sation (i.e. apnea) of breathing due to the temporary obstruction [35]. At the highest approved dose of 10 mg, lemborexant did of the upper airway during sleep [1, 2]. A close association be- not impair nighttime respiratory function in patients with mild tween OSA and the occurrence of cardiovascular diseases such OSA, while data for patients with moderate OSA have not been as systemic hypertension, coronary artery disease, heart failure generated [36]. [3, 4], or type 2 diabetes [5] has been reported. Furthermore, Daridorexant (ACT-541468) is a new DORA with favorable OSA has also short-term effects, mainly increased daytime pharmacokinetic (PK) and pharmacodynamic (PD) properties, sleepiness, leading to an increased risk of car accidents [6, 7] that is, quick absorption (median time to reach maximum con- and impaired quality of life [8]. Despite approximately one bil- centration 0.8–1.0 hours), short terminal half-life (5.9–8.8 hours lion patients with OSA worldwide and a prevalence exceeding across the tested doses), no relevant accumulation, and no ap- Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021 50% in some countries [2, 9, 10], it often remains undiagnosed parent next-day residual PD effects after evening administra- in more than 70% of population at high risk of developing OSA tion in adults or elderly healthy participants [37, 38]. In phase-2 [11], as associated symptoms (e.g. excessive daytime sleepiness, studies, daridorexant demonstrated dose-dependent efficacy in- tiredness, and reduced performance) that usually trigger con- dicated by a significant reduction of the objective sleep param- sultation in a sleep clinic are often not prominent [12]. eters wake after sleep onset (WASO) and latency to persistent OSA tends to coexist with insomnia [13–17], leading to chal- sleep (LPS) [39, 40]. After repeated dosing, daridorexant was safe lenges in the therapeutic approach for the treatment of both and well tolerated in both healthy participants (up to 75 mg) and disorders. Although continuous positive airway pressure (CPAP) patients with insomnia (up to 50 mg) [37–41]. therapy is an effective treatment for moderate to severe OSA, it is The present study evaluated the effect of single and repeated not well tolerated by patients with coexisting insomnia [17–19]. dosing with 50 mg daridorexant (i.e. the highest dose used in the Benzodiazepines, “Z-drugs,” and melatonin receptor agonists are phase-3 program) on nighttime respiratory function, and sleep at present the most commonly used approved drugs for short- characteristics, in patients with mild and moderate OSA. term treatment of insomnia [20]. Some of these drugs might im- pair nighttime respiratory function in patients with OSA, which is of safety relevance particularly when OSA is undiagnosed. Methods Benzodiazepines (e.g. triazolam or flurazepam) or “Z-drugs” (e.g. zolpidem or zaleplon) are suspected to decrease oxygen satur- Study design ation during nighttime in patients with OSA [21–26]. Only a few This randomized, double-blind, placebo-controlled, two-period sleep medications do not seem to impair nighttime respiratory crossover study aimed to investigate the effects of daridorexant function in patients with OSA such as the gamma-aminobutyric on nighttime respiratory function and sleep characteristics in acid (GABA)-A receptor agonist eszopiclone or the melatonin re- patients with mild and moderate OSA. It was approved by the ceptor agonist ramelteon [26–28]. German health authority (Bundesinstitut für Arzneimittel und Based on the above, there is a need for a safe sleep medication Medizinprodukte, BfArM) and by the local Ethics Committee that does not impact nocturnal breathing in patients primarily (Ethik-Kommission des Landes Berlin, Berlin, Germany). The treated for insomnia symptoms who present comorbid OSA study was conducted at a single site in accordance with the whether or not diagnosed. It is, therefore, of safety relevance to Declaration of Helsinki principles, International Council for investigate the effect of novel sleep agents on nighttime respira- Harmonisation Good Clinical Practice guidelines, and applicable tory function in patients with OSA. In recent years, orexin recep- regulations and laws. All patients provided written informed tors have evolved as a new promising target for the treatment consent prior to any screening procedures. of insomnia [29, 30]. Neurons synthesizing the neuropeptides After a screening period, 28 patients were enrolled and ran- orexin A and orexin B, originating from the hypothalamus, pro- domized in a 1:1 ratio to receive 50 mg daridorexant followed by ject in various brain areas, including the forebrain, corticolimbic matching placebo or vice versa. Daridorexant and placebo were structures, and brainstem involved in the regulation of the sleep– orally administered at nighttime for five consecutive days. Both wake cycle. They promote alertness/wakefulness by interacting
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