The Lancet Neurology reports impact of daridorexant on both nighttime symptoms and daytime functioning in adults with insomnia

Idorsia Ltd (SIX: IDIA) today announced the publication of "Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials" in The Lancet Neurology. Daridorexant 25 mg and 50 mg improved sleep outcomes, and daridorexant 50 mg also improved daytime functioning, in people with insomnia disorder, with a favorable safety profile.¹ The overall incidence of adverse events was comparable between treatment groups in adults and older adults (aged 65 and over) with insomnia.¹ As reported, daridorexant 50 mg demonstrated statistically significant improvements in the primary endpoints of sleep onset and maintenance as well as the secondary endpoints of total sleep time and daytime sleepiness.¹

 Importantly, the trials were the first to investigate the effect of an insomnia treatment on daytime functioning, using a validated patient-reported outcomes tool, which includes three different domains (alert/cognition, mood, and sleepiness).¹ Daridorexant 50 mg, which was evaluated in one of the two trials, demonstrated improvements compared to baseline across all daytime functioning domains with a high level of consistency.¹

Emmanuel Mignot, MD, Professor of Psychiatry and Behavioral Sciences at Stanford University and lead author, commented: “People with insomnia often complain of impaired daytime functioning. This is a major issue often ignored in treating insomnia and in fact many sleep promoting drugs can impair daytime functioning when they have residual effects. In this program, not only did we see efficacy of daridorexant on sleep induction, maintenance and patient-reported sleep quantity and quality, but importantly, at the dose of 50 mg, on daytime functioning, notably in the sleepiness domain as measured with a new scale, the IDSIQ. Participants in the daridorexant 50 mg group reported improvements in multiple aspects of daytime functioning, as assessed by this newly developed and validated instrument that assessed mood, alert/cognition, and sleepiness. It is exciting to see that insomnia is finally not solely viewed as a nighttime problem but as a cause of daytime suffering.”

Efficacy and Safety Outcomes

Daridorexant 50 mg significantly improved sleep onset, sleep maintenance and self-reported total sleep time at months one and three compared to placebo.¹ The largest effect was observed with the highest dose (50 mg), followed by 25 mg, while the 10 mg dose did not have a significant effect.¹ In all treatment groups the proportions of sleep stages were preserved, in contrast to findings reported with benzodiazepine receptor agonists.¹

A major focus of the trials was to evaluate the impact of daridorexant on daytime functioning in patients with insomnia, as assessed by the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). IDSIQ is a validated patient-reported outcomes instrument specifically developed according to FDA guidelines, including patient input, to measure daytime functioning in patients with insomnia.^1,2 The sleepiness domain score of the IDSIQ was evaluated as a key secondary endpoint in both pivotal studies and comparisons to placebo included control for multiplicity. Daridorexant 50 mg demonstrated highly statistically significant improvement in daytime sleepiness at month one and month 3.¹ The sleepiness domain score was not significantly improved on 25 mg in either study at either timepoint.¹ Daridorexant 50 mg also improved the additional IDSIQ domain scores (alert/cognition domain, mood domain) and total score (p-values < 0.0005 versus placebo not adjusted for multiplicity).¹ Improvements in daytime functioning by daridorexant 50 mg progressively increased over the three months of the study.¹

The overall incidence of adverse events was comparable between treatment groups.¹ Adverse events occurring in more than 5% of participants were nasopharyngitis and headache.¹ There were no dose-dependent increases in adverse events across the dosing range, including somnolence and falls.¹ Further, no dependence, rebound insomnia or withdrawal effects were observed upon abrupt discontinuation of treatment.¹ Across treatment groups, adverse events leading to treatment discontinuation were numerically more frequent with placebo than daridorexant.¹

Martine Clozel, MD, and Chief Scientific Officer of Idorsia, commented: “These data published in The Lancet Neurology highlight the depth of evidence generated in the daridorexant development program and the properties of the drug that I believe explain the results. The drug was designed to have efficacy for sleep onset and maintenance at optimally efficacious doses while avoiding residual morning sleepiness. This profile, together with the equal blockade of both orexin receptors – which may lead to an inhibition of the chronic sympathetic hyperactivity characteristic of insomnia – may explain the improvement we see in daytime functioning with 50 mg of daridorexant.”

Daridorexant in insomnia

Insomnia disorder is characterized by difficulties initiating or maintaining sleep and is associated with distress or impairment in daytime functioning.¹ A wide range of daytime complaints, from fatigue and reduced energy to mood alteration and cognitive difficulties, are reported by people with insomnia.¹ Insomnia is associated with an overactive wake system.³

 Daridorexant, a novel dual orexin receptor antagonist, was designed and developed by Idorsia for the treatment of insomnia. Daridorexant targets the excessive wakefulness characteristic of insomnia by blocking the activity of orexin.^1,4 Daridorexant specifically targets the orexin system by competitively binding with both receptors, thereby reversibly blocking the activity of orexin.⁵

About insomnia

Insomnia is defined as a combination of dissatisfaction with sleep and a significant negative impact on daytime functioning.⁶ Dissatisfaction with sleep refers to the difficulty to initiate and/or maintain sleep on at least three nights per week for at least three months, despite adequate opportunity to sleep.⁶

Insomnia is a condition of overactive wake signaling and studies have shown that areas of the brain associated with wakefulness remain more active during sleep in patients with insomnia.^7,8

Insomnia is a common problem with a prevalence of approximately 10% of the adult population.⁹ On this basis, and assuming a US adult population of around 250 million, there are approximately 25 million adults in the US who suffer from insomnia. In Europe, the estimated prevalence of insomnia is 6-12%¹⁰ and in Canada, insomnia affects an estimated 10%.¹¹

Insomnia as a disorder is quite different from a brief period of poor sleep, and it can take its toll on both physical and mental health.¹² It is a persistent condition with a negative impact on daytime functioning.⁶ Idorsia’s research has shown that poor quality sleep can affect many aspects of daily life, including the ability to concentrate, mood, and energy levels.

The goal of treatments for insomnia is to improve sleep quality and quantity, as well as daytime functioning, while avoiding adverse events and next-morning residual effects. Current recommended treatment of insomnia includes sleep hygiene recommendations, cognitive behavioral therapy, and pharmacotherapy.¹³

About the orexin system

Wake and sleep signaling is regulated by intricate neural circuitry in the brain. One key component of this process is the orexin system, which helps promote wakefulness.^13,14,15 There are two forms of orexin neuropeptides – small protein-like molecules used by nerve cells (neurons) to communicate with each other in the brain – orexin A and orexin B.¹⁴ Orexin promotes wakefulness through its receptors OX1R and OX2R. Together, these neuropeptides and receptors make up the orexin system. The orexin system stimulates targeted neurons in the wake system – leading to the release of several chemicals (serotonin, histamine, acetylcholine, norepinephrine) – to promote wakefulness.¹⁶ Under normal circumstances, orexin levels rise throughout the day as wakefulness is promoted and then fall at night.¹³ Overactivity of the wake system is an important driver of insomnia.^7,8

References

1. Mignot E, et al. Lancet Neurol. 2022; 21: 125–39
2. Hudgens S, et al. Patient. 2020. doi:10.1007/s40271-020-00474-z.
3. Nofzinger EA, et al. Am J Psychiatry. 2004;161(11):2126-2128
4. Wang C, et al. Front Mol Neurosci. 2018;11:220.
5. Muehlan, C., et al. Clin Pharmacol Ther. 2018;104(5): 1022-1029.
6. The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5; American Psychiatric Association, 2013).
7. Levenson JC, et al. Chest. 2015;147(4):1179-1192.
8. Buysse DJ, et al. Drug Discov Today Dis Models. 2011;8(4):129-137.
9. Schlack R, et al. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2013;56(5-6):740-748.
10. Riemann D, et al. Sleep. 2017;26(6):675-700.
11. Chaput, Statistics Canada; 2018 Dec 19;29(12):16-20.
12. Wardle-Pinkston S, et al. Sleep Med Rev.2019;48:101205.
13. Muehlan C, et al. Expert Opinion on Drug Metabolism & Toxicology. 2020 16(11), pp.1063–1078.
14. Muehlan, C., et al. J Psychopharmacol. 2020;34(3): 326-335.
15. Boof, M. L., et al. Eur J Clin Pharmacol. 2019;75(2): 195-205.
16. The sleep switch: hypothalamic control of sleep and wakefulness. Clifford B. Saper, Thomas C. Chou and Thomas E. Scammell. TRENDS in Neurosciences Vol.24 No.12 December 2001