Long-term safety and tolerability results with daridorexant in patients with
insomnia disorder published in CNS Drugs Daridorexant, taken every night for up
to 12 months, was well-tolerated with no signs of tolerance (loss of effect) or
physical dependence, and no evidence of withdrawal or rebound insomnia upon
treatment discontinuation Exploratory efficacy endpoints show sustained
improvements in nighttime sleep variables and daytime functioning
Allschwil, Switzerland – December 1 2 , 2022
Idorsia Ltd (SIX: IDIA) today announced the publication of “ Long-term safety
and tolerability of daridorexant in patients with insomnia disorder ” in CNS
Drugs 1 . The publication reports the results from the 40-week safety extension
study with daridorexant in patients with insomnia disorder, which found that
treatment with daridorexant, taken every night for up to 12 months, was well
tolerated, consistent with the 12-week study findings as published by Mignot,
E., et al. Lancet Neurol. 2022;21:125–39 .
Dieter Kunz, MD, Clinic for Sleep- & Chronomedicine , St. Hedwig- Krankenhaus
Berlin and lead author , commented:
“It is interesting to see how different the mechanism of dual orexin receptor
antagonism works for patients with insomnia disorder. Rather than inducing
sleep through broad inhibition of the brain, the over-active wakefulness
causing their insomnia is gradually brought under control with nightly
administration of daridorexant. The improvement in sleep onset, sleep
maintenance and daytime functioning seen with 50 mg daridorexant were sustained
for up to 12 months. Importantly, as we publish in this manuscript, long-term
treatment with daridorexant was not associated with any tolerance or physical
dependence, neither did we see withdrawal symptoms nor rebound insomnia upon
cessation of administration.”
The Phase 3, international, randomized, double-blind, parallel-group,
placebo-controlled extension study was designed to evaluate the long-term use
of daridorexant in patients with insomnia disorder who had completed one of the
two pivotal 12-week Phase 3 studies. The primary objective was to assess the
long-term safety and tolerability of daridorexant. Exploratory objectives were
to evaluate the efficacy of daridorexant on sleep (self-reported total sleep
time, sTST) and daytime functioning (Insomnia Daytimes Symptoms and Impacts
Questionnaire, IDSIQ). In total, 804 adults with insomnia disorder who
completed the 12-week studies were included in this extension study. Patients
originally randomized to daridorexant 10 mg, 25 mg, or 50 mg remained on their
respective treatments; patients randomized to placebo were re-randomized to
either daridorexant 25 mg or placebo. The 40-week treatment period was followed
by a 7-day placebo run-out.
The overall incidence of treatment-emergent adverse events was similar across
groups (35-40%). The most commonly reported TEAE during double-blind treatment
in all groups was nasopharyngitis. All other TEAEs, including falls, headache
and somnolence were reported in < 3% of patients, with dizziness and fatigue in
< 2% of patients in any group. Daridorexant did not induce next-morning
sleepiness and no withdrawal-related symptoms or rebound insomnia were observed
after treatment discontinuation. Improvements in sleep and daytime functioning
were maintained through to end of the treatment and were most pronounced with
daridorexant 50 mg. The authors conclude that treatment with daridorexant for
up to 12 months, was well tolerated and that 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
Notes to the editor
A bout insomnia disorder
Insomnia disorder is defined as difficulty initiating or maintaining sleep,
causing clinically significant distress or impairment in important areas of
daytime functioning. 5 This impact on sleep quantity or quality should be
present for at least three nights per week, lasts for at least three months,
and occurs despite an adequate opportunity to sleep. 5
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. 10,11 It is a common problem with an estimated
prevalence in Europe of 6-12% of the adult population. 4
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. 5,6 It is a
persistent condition with a negative impact on daytime functioning. 5 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 therapy, cognitive behavioral therapy, and pharmacotherapy.
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. 9,12 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. 8, 9 Orexin promotes wakefulness
through its receptors OX1R and OX2R. 8, 9 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.
13 Under normal circumstances, orexin levels rise throughout the day as
wakefulness is promoted and then fall at night. 14 Overactivity of the wake
system is an important driver of insomnia. 7 , 12
Idorsia’s research team has been working on the science of orexin and orexin
receptors since they were first described in 1998. The team’s initial work led
to the conclusion that antagonism of the orexin system was the key to
preserving a natural sleep architecture for patients with insomnia. With this
as the target, the team designed dual antagonists with the goal of rapid onset
of effect and duration of action sufficient to cover the night but short enough
to minimize any negative next-morning residual activity at optimally effective
Daridorexant is a dual orexin receptor antagonist, which blocks the binding of
the wake-promoting neuropeptides orexins. Rather than inducing sleep through
broad inhibition of brain activity, daridorexant blocks only the activation of
orexin receptors. Consequently, daridorexant is thought to decreases the wake
drive, allowing sleep to occur, without altering the proportion of sleep
Global regulatory status of daridorexant
In January 2022, QUVIVIQ (daridorexant) was approved by the US Food and Drug
Administration (FDA) and subsequently made commercially available in May 2022.
For more information about QUVIVIQ (daridorexant) CIV in the US, see the Full
Prescribing Information 2 . In April 2022, marketing authorization of QUVIVIQ
was granted by the European Commission and subsequently by the Medicines and
Healthcare products Regulatory Agency (MHRA) in Great Britain via the European
Commission Decision Reliance Procedure. For more information about QUVIVIQ in
the EU, see the Summary of Product Characteristics 3 . Launch preparations are
underway in the major European markets and QUVIVIQ was made available in both
Italy and Germany in November 2022. Marketing authorization of QUVIVIQ was
granted by Swissmedic in December 2022, the company aims to make QUVIVIQ
available to patients in Switzerland around mid-2023. For more information
about QUVIVIQ in Switzerland, see the Patient Information and Information for
Healthcare Professionals . Daridorexant is under review with Health Canada.
The daridorexant Phase 3 registration program 7
The Phase 3 registration program comprised two three-month studies, together
with a long-term double-blind extension study. The program enrolled a total of
1,854 patients with insomnia disorder. As insomnia often presents later in
life, and older adults are more susceptible to experience fragmented sleep,
early awakening and daytime sleepiness, 15 around 40% of the recruited
population was at least 65 years of age.
The placebo-controlled studies investigated the effects of three doses of
daridorexant (10 mg, 25 mg, and 50 mg) on sleep and daytime functioning
parameters, objectively in a sleep lab by polysomnography and subjectively with
a daily patient diary at home. The impact of insomnia on patients’ daytime
functioning was measured daily using the sleepiness domain score from the
Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ © ) – a
patient-reported outcome (PRO) instrument developed and validated according to
the FDA Guidance for Industry.
More than 800 patients continued treatment in the 40-week extension study,
which measured the effect of all three doses vs. placebo, generating data for
long-term treatment of insomnia disorder.
Phase 3 data has been reported in The Lancet Neurology: The pivotal studies
demonstrated that daridorexant 50 mg significantly improved sleep onset, sleep
maintenance and self-reported total sleep time at months one and three compared
to placebo. 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. In
all treatment groups the proportions of sleep stages were preserved, in
contrast to findings reported with benzodiazepine receptor agonists.
A major focus of the trials was to evaluate the impact of daridorexant on
daytime functioning in patients with insomnia disorder, as assessed by the
IDSIQ. IDSIQ is a patient-reported outcomes instrument specifically developed
and validated according to FDA guidelines, to measure daytime functioning in
patients with insomnia. 1 6 The sleepiness domain score of the IDSIQ was
evaluated as a key secondary endpoint in both pivotal studies and comparisons
to placebo included type I error control for multiplicity. Daridorexant 50 mg
demonstrated highly statistically significant improvement in daytime sleepiness
at month one and month three. The sleepiness domain score was not significantly
improved on 25 mg in either study at either timepoint.
The overall incidence of adverse events was comparable between treatment
groups. The most frequently reported adverse reactions were headache and
somnolence and, overall, the majority of adverse reactions were mild to
moderate in intensity. No evidence of a dose-relationship for the frequency or
severity of adverse reactions was observed.
Important Safety Information
Contraindications Hypersensitivity to daridorexant or any of the excipients
Narcolepsy Concomitant use with strong CYP3A4 inhibitors
Warnings and precautions for use
Use with caution in elderly patients because of the general risk of falls.
Efficacy and safety data in patients >75 are limited.
Patients should be cautioned about drinking alcohol during treatment.
Sleep paralysis and hypnagogic/hypnopompic hallucinations can occur, mainly
during the first weeks of treatment. Symptoms similar to mild cataplexy have
been reported with dual orexin receptor antagonists. Prescribers should explain
this to patients and should consider discontinuing in case events occur.
Use with caution in patients exhibiting symptoms of depression.
Use with caution in patients with psychiatric co-morbidities due to limited
efficacy and safety data.
Daridorexant did not have significant respiratory effects in patients with
mild or moderate OSA or moderate COPD. In the absence of data, use with caution
in patients with severe OSA and severe COPD.
There was no evidence of abuse or withdrawal symptoms indicative of physical
dependence upon treatment discontinuation in clinical studies with daridorexant
in subjects with insomnia. Because individuals with a history of abuse or
addiction to alcohol or other substances may be at increased risk for abuse of
QUVIVIQ, these patients should be followed carefully.
Use is not recommended in patients with severe hepatic impairment.
Effects on availability to drive and use machines
Patients should be cautioned about engaging in potentially hazardous
activities, driving, or operating heavy machinery unless they feel fully alert,
especially in the first few days of treatment. In order to minimize this risk,
a period of approximately 9 hours is recommended between taking QUVIVIQ and
driving or using machines.
About Dieter Kunz
Dieter Kunz graduated in 1989, performed residencies in neurology /
psychiatry, and was appointed supervising physician in 1996 at the Freie
Universität Berlin. After three years at Lübeck University, he was appointed
head of the Psychiatric University Clinic Charité in St. Hedwig Hospital in
2002. He transformed this former community-based clinic into an efficient
120-inpatient university clinic, established teaching, research, and clinical
practice in academic level. Dr. Kunz’s main interest, however, is
neurological/psychiatric sleep research. In January 2008, he was appointed head
of the newly founded Clinic of Sleep- & Chronomedicine in St. Hedwig Hospital.
He also is director of the group Sleep Research & Clinical Chronobiology at
Charité – Universitätsmedizin Berlin. Main areas of research are circadian
aspects of human sleep including the nonvisual effects of light and the
pharmacological effects of melatonin (hormone of darkness) on human physiology
Dr. Kunz is frequent grant reviewer such as for National Science Foundation
(NSF), the European Commission (EU), European Space Agency (ESA), and Wellcome
Trust. As principal investigator he successfully applied for public European
and German grants and industry grants including pharmacological phase-2 and -3
studies. He has published over 80 original papers in peer reviewed journals. Dr
Kunz serves as a consultant to Idorsia.
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Disorders (5th ed.; DSM–5; American Psychiatric Association, 2013).
Wardle-Pinkston S., et al. Sleep Med Rev. 2019;48. Mignot, E., et al. Lancet
Neurol. 2022;21:125–39. Muehlan, C., et al. Expert Opin. Drug Metab. Toxicol.
2020;16(11):1063–1078. Muehlan, C., et al. J Psychopharmacol.
2020;34(3):326-335. Buysse, D.J., et al. Drug Discov Today Dis Models.
2011;8(4):129-137. Levenson, J.C., et al. Chest. 2015;147(4):1179-1192. Boof,
M.L., et al. Eur J Clin Pharmacol. 2019;75(2):195-205. Clifford, B.S., et al.
Trends Neurosci. 2001;24(12).726-31. Gotter, A.L., et al. BMC Neuroscience.
2013;14(1):14-19. Patel, D., et al. J Clin Sleep Med. 2018;14(06):1017–1024.
Hudgens, S., et al. Patient. 2020. doi:10.1007/s40271-020-00474-z.
IDSIQ © 2020, University of Pittsburg. All rights reserved. IDSIQ-14
derivative created 2020 by Idorsia Pharmaceuticals Ltd under license and
distributed by Idorsia Pharmaceuticals Ltd under license. IDSIQ is further a
registered trademark of Idorsia Pharmaceuticals Ltd.
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