The Committee for Medicinal Products for Human Use ( CHMP ), the scientific Committee of the European Medicines Agency ( EMA ), adopted a positive opinion for the use of Quviviq ( Daridorexant ) as the first dual orexin receptor antagonist in the European Union ( EU ) for the treatment of adult patients with insomnia characterized by symptoms present for at least three months and considerable impact on daytime functioning.
The positive CHMP opinion is supported by pivotal phase 3 data, published in The Lancet Neurology, which have demonstrated that Daridorexant has improved nighttime symptoms and daytime functioning in adults with insomnia disorder at months one and three compared to placebo, with a favorable safety profile.
The efficacy and safety of Quviviq are further supported by a long-term follow-up extension study, which together with the pivotal trials, provides clinical data for up to 12 months of continuous treatment.
Insomnia disorder is defined as difficulty initiating or maintaining sleep, causing clinically significant distress or impairment in important areas of functioning. 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. A wide range of daytime complaints, from fatigue and reduced energy to mood alteration and cognitive difficulties, are reported by people with insomnia. Impaired daytime functioning is a critical concern of people living with insomnia disorder.
The phase 3 program with Daridorexant was the first to comprehensively measure the impact of pharmacological treatment on all aspects of the condition, including daytime functioning as perceived by patients.
Results have demonstrated that Daridorexant not only has significantly improved sleep onset, sleep maintenance and total sleep time in adults with insomnia disorder, but also patients’ daytime functioning, all while maintaining a favorable safety profile.
Insomnia is associated with overactive wake signaling in the brain. Quviviq is a dual orexin receptor antagonist, which blocks the binding of the wake-promoting neuropeptides orexins and is thought to turn down overactive wakefulness, as opposed to treatments that generally sedate the brain.
The phase 3 registration program comprised two three-month studies, together with a long-term double-blind extension study. The program enrolled around 1,850 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, 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 versus placebo, generating data for long-term treatment of insomnia disorder.
Phase 3 data has been reported in The Lancet Neurology: The pivotal studies have demonstrated that Daridorexant 50 mg has 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.
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 has 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. Adverse events occurring in more than 5% of participants were nasopharyngitis and headache.
There were no dose-dependent increases in adverse events across the dosing range, including somnolence and falls.
Further, no dependence, rebound insomnia or withdrawal effects were observed upon abrupt discontinuation of treatment.
Across treatment groups, adverse events leading to treatment discontinuation were numerically more frequent with placebo than Daridorexant. ( Xagena )
Source: Idorsia, 2022