Daridorexant under FDA & EMA review for insomnia after Phase III success

Insomnia is a common sleep disorder with a prevalence ranging from 5.8–20.0%1 and associated with various comorbidities and major societal and economic impacts. Currently, guidelines recommend combining psychological and pharmacological therapies, which mainly include benzodiazepine and melatonin receptor agonists, sedating antidepressants and other sedating drugs. Although these drugs can reduce latency to sleep onset (LSO) and wake after sleep onset (WASO), they are associated with tolerance and numerous side effects such as somnolence and drowsiness.2 In particular, benzodiazepine receptor agonists are only approved for short-term use due to dependence and long-term cognitive side effects.3 Therefore, effective and well-tolerated drugs to treat insomnia represent an unmet clinical need.

Dual orexin receptor antagonists (DORAs) recently emerged as a promising novel approach to treat insomnia. In 2014, the first DORA was approved for insomnia, suvorexant. Whilst suvorexant effectively reduces LSO and WASO, it also causes dose-dependent next-morning residual effects.2 Lemborexant, another DORA, was approved in 2019.4

Daridorexant (ACT-541468) is a recently developed candidate DORA for the treatment of insomnia. By binding to orexin receptors, daridorexant inhibits binding of wake-promoting orexin neuropeptides to their cognate G-protein-coupled receptors (GPCRs), thereby inhibiting activation of downstream orexin signaling pathways involved in various physiological functions, notably including sleep-wake rhythm.5 In comparison to other DORAs, daridorexant has improved pharmacokinetic and pharmacodynamic properties allowing an appropriate duration of action without next-morning residual activity.2

At the European College of Neuropsychopharmacology congress 2021, Diego Garcia-Borreguero, MD, PhD, Sleep Research Institute, Madrid, Spain, gave an overview of the role of orexin (also known as hypocretin) in sleep physiology and the development of DORAs to date, outlining recent findings from trials evaluating daridorexant.

Initiated in 2016, a Phase II study evaluating the efficacy and safety of daridorexant at different doses (5, 10, 25, 50 mg daily) on objective and subjective sleep parameters in subjects with insomnia (NCT02839200) reported a significant and sustained dose-response relationship in the reduction of LSO and WASO from baseline to days 28 and 29 (P <0.001), with a tolerable safety profile.2

This led to a Phase III registration program comprised of two pivotal studies testing 25 and 50 mg daridorexant (NCT03545191) and 10 mg daridorexant (NCT03575104) compared to placebo. A total of 1,850 subjects with insomnia were enrolled in the trials and received treatment for 3 months, followed by an extension period of up to one year. Results presented in August 2020 demonstrated promising improvements in sleep onset, sleep maintenance, subjective total sleep time and daytime performance at 25 and 50 mg.6 The mean change from baseline in WASO was -18.4 (P<0.0001), and -29.0 minutes (P<0.0001) at 1 month for 25mg and 50mg, respectively, compared to -6.2 minutes for placebo.6 The mean change from baseline in LPS was -28.2 (P=0.0005) and -31.2 (P<0.0001) at 1 Month for 25mg and 50mg, respectively, compared to -19.9 minutes for placebo. Daytime functioning, reflected by a mean score reduction from baseline in the sleepiness/tiredness domain of the IDSIQ, was significantly improved at the 50mg dose only (P<0.0001).6 Importantly, these benefits were maintained over a period of three months and there were no next-morning residual effects or withdrawal symptoms after treatment discontinuation. In July 2020, efficacy results for patients receiving 10 mg daridorexant were reported, showing that none of the efficacy measures reached statistical significance.7

In both trials, the rate of treatment-related adverse events was comparable between daridorexant and placebo (at 25 mg and 50 mg daridorexant: 37.7% vs 34% for placebo; at 10 mg daridorexant: 38.2% vs 32.7% for placebo). Common side effects included nasopharyngitis, headache, somnolence and fatigue, and serious adverse events were rare.6,7

In March 2021, a new drug application (NDA) for daridorexant was submitted to the FDA and EMA for review. If approved, daridoxerant is expected to launch in the US in the first half of 2022.

Prof. Garcia-Borreguero further commented on the potential impact of daridorexant approval in chronic insomnia: “This will be a major new development because we will be able to treat pharmacologically patients with chronic insomnia with a new drug for which so far we have not seen any tolerance or relevant cognitive effects over the long-term, which were the two main problems of both Z-drugs and classic benzodiazepines.”

Written by Elitsa Kamberska


  1. Bjorøy I, Jørgensen V. A, Pallesen S, et al. The Prevalence of Insomnia Subtypes in Relation to Demographic Characteristics, Anxiety, Depression, Alcohol Consumption and Use of Hypnotics. Front Psychol. Mar 2020; 11:527.
  2. Dauvilliers Y, Zammit G, Fietze I, et al. Daridorexant, a New Dual Orexin Receptor Antagonist to Treat Insomnia Disorder. Ann Neurol. Mar 2020; 87(3):347–356.
  3. Asnis G, Thomas M, Henderson M. Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians. Int J Mol Sci. Dec 2015; 17(1):50.
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  7. Idorsia. Idorsia announces positive results in the second Phase 3 study of daridorexant. [Press Release]. Jul 2020. (Last accessed 26/10/2021).