Quviviq: New Sleeping Pill

Highlights

Quviviq (daridorexant) is a new drug indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

Quviviq, developed by Switzerland’ Idorsia Pharmaceuticals, is approved by the U.S. Food and Drug Administration (FDA).

The oral Quviviq is taken once daily within 30 minutes of going to bed, when it is at least 7 hours before you are scheduled to wake up.

Quviviq is in the same class of insomnia medications as Belsomra (suvorexant) and Dayvigo (lemborexant).

Pharmacy availability of Quviviq in the U.S. is expected in May 2022.

Quviviq is the first commercialized drug by Idorsia, which debuted on the Swiss stock market in June 2017. Idorsia’s founders are former executives of Actelion Pharmaceuticals, which was bought by Johnson & Johnson in January 2017 for $30 billion.

 

What Is Insomnia and How to Treat It

According to the International Classification of Sleep Disorders (ICSD), sleep disorders include sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, parasomnias, sleep-related movement disorders, and others. Among such disorders insomnia (sleeplessness) is the most common: approximately one third of the adult population suffers from its intermittent form.

Insomnia is accompanied by difficulty falling asleep, sleep maintenance problems, and poor sleep quality, leading to daytime consequences in the form of fatigue or malaise, poor attention, mood disturbance or irritability. Proper sleep quality sleep is critical to maintaining a healthy body. Otherwise the risks of hypertension, accidental injury, diabetes, obesity, depression, heart attack, stroke, dementia, and adverse changes in mood and behavior increase.

Insomnia therapy involves a multicomponent approach including sleep hygiene, lifestyle changes, avoidance of stimulants like caffeine and alcohol, regular physical activity, cognitive behavioral interventions, and additional and sometimes controversial techniques like bright light therapy, acupuncture and acupressure, moxibustion, musical relaxation, and aromatherapy.

When it comes to pharmacotherapy for insomnia, there are many medications suggested: benzodiazepine sleeping pills of the short and intermediate duration of action (nitrazepam, temazepam, lorazepam, estazolam, triazolam, flurazepam, quazepam), non-benzodiazepine sedative-hypnotics (zolpidem, zaleplon, eszopiclone, zopiclone), melatonin receptor agonists (ramelteon), sedative antidepressants (doxepin, trazodone, paroxetine, amitriptyline, mirtazapine). Nevertheless, there remains a medical need for new sleeping pills that are effective and have minimal adverse reactions.

 

Quviviq: Mechanism of Action of Daridorexant

Daridorexant (ACT-541468), formerly known as nemorexant, is an oral small-molecule competitive dual orexin receptor antagonist (DORA).

The orexin (hypocretin) neuropeptide signaling system is the main mechanism providing the waking state. Orexin-producing nerve cells are located in the hypothalamus and affect the brain neurons responsible for the wakefulness process.

Daridorexant triggers the physiological process of brain transition from wakefulness to sleep by reversibly blocking the binding of wake-promoting neuropeptides, orexin A and orexin B, to OX₁R and OX₂R receptors thereby suppressing the maintenance of wakefulness.

It is believed that DORAs promote not only non-rapid eye movement (NREM) but also rapid eye movement (REM), which GABA-mediated molecules do not do.

In general, targeting orexin signaling comes from the concept that insomnia should be perceived as a reflection of hyperactivity and wakefulness inappropriately timed for natural bedtime rather than as a failure of the brain to fall asleep. In other words, instead of drug stimulation of sleep-promoting signaling pathways, it is better to suppress the signaling pathways responsible for wakefulness.

 

Quviviq: Efficacy of Daridorexant for Insomnia Treatment

The clinical trials NCT03545191 and NCT03575104 phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) enrolled adult patients (n=1854) with insomnia.

Participants were administered placebo or daridorexant every night for 3 months.

Two primary endpoints of insomnia treatment efficacy, objectively assessed by polysomnography (PSG) monitoring, were established:

• The mean change in the wake after sleep onset (WASO) is defined as the sum of estimated minutes of wake during the night after initial sleep onset until the time the participant stopped trying to sleep for the night, operationalized as the time the participant got out of bed for the day. This score representing the fragmentation of sleep (sleep maintenance) is relevant to the facts of sudden awakening at night in insomnia.

• The mean change in the latency to persistent sleep (LPS) is defined by the number of minutes from lights off to the first 10 consecutive minutes of non-wakefulness. The indicator reflects the moment of sleep induction.

The secondary efficacy endpoint was the change in subjective total sleep time (sTST) as assessed by the patients themselves.

Administration of daridorexant provided a statistically significant difference with the placebo group (p<0.05) for all of the above efficacy endpoints of insomnia treatment after 1 and 3 months of therapy, except for the LPS score in the second clinical trial.

 

Quviviq: Safety of Daridorexant for Insomnia Treatment

The safety profile of daridorexant was characterized by acceptable tolerability. Adverse reactions to daridorexant administration included: headache (in 6% and 7% of patients taking the drug at doses of 25 and 50 mg, respectively — versus 5% in the placebo group), drowsiness or fatigue (6% and 5% vs. 4%), dizziness (2% and 3% vs. 2%), and nausea (0% and 3% vs. 2%).

Some subjects experienced rare cases of sleep paralysis, hypnagogic and hypnopompic hallucinations.

Because daridorexant is a central nervous system (CNS) depressant, its use may result in impaired daytime wakefulness in the form of drowsiness the next day. Drowsiness may persist for several days after withdrawal.

It is not recommended to use daridorexant with other CNS depressants such as benzodiazepines, opioids, tricyclic antidepressants, and alcohol because of its additive effect on psychomotor performance.

Administration of daridorexant may result in impairment of driving ability, especially if nighttime sleep was inadequate or the drug was taken at a dose higher than recommended.

 

Quviviq: Competitive Landscape Around Daridorexant

Daridorexant is not the first member of the DORA drugs. For example, Belsomra (suvorexant) developed by Merck & Co. appeared in August 2014, and Dayvigo (lemborexant) by Eisai saw the light in December 2019.

The clinical efficacy and safety profiles of Quviviq, Dayvigo, and Belsomra are broadly identical.

Healthcare providers and patients can base their decisions primarily on the pricing of these drugs. While a one-month course of Belsomra to treat insomnia costs a U.S. patient without health insurance $430, Dayvigo costs $317.

The price of Quviviq is not yet known.

Quviviq, Dayvigo, and Belsomra lack the negative side effects that accompany traditional insomnia medications. For example, benzodiazepine and non-benzodiazepine sleeping pills increase the inhibitory effects of GABA, the main inhibitory neurotransmitter of the brain, especially in the limbic system and cortex, which is reflected in motor coordination disorders, drowsiness and lethargy, slurred speech, dizziness, severe mood swings, fatigue. Prolonged use, leading to adaptation of GABA receptors, results in addiction and withdrawal syndrome. Daridorexant, lemborexant, and suvorexant, which target orexin signaling rather than the entire population of GABAergic neurons in the brain, are much more targeted, as evidenced by a significantly better safety profile.

Again, in April 2019, the FDA required the inclusion of a boxed warning about the risks of complex sleep behaviors that are traumatic and even fatal when a still not fully awake person begins walking, driving, and engaging in other activities, with no memory of it after waking up, in the prescribing information for non-benzodiazepine sedative-hypnotic drugs (zolpidem, zaleplon, eszopiclone).

The commercial prospects of Quviviq, Dayvigo, and Belsomra seem promising, but we should not count on rapid growth in sales, since the common sleeping pills have long passed into the generic category, and therefore are prescribed en masse due to their low cost. Thus, demand for Belsomra, the first DORA drug on the market, is growing slowly: while it earned $210 million and $260 million in 2017 and 2018, sales in 2019 and 2020 were $306 million and $327 million.

 

Extras

Quviviq (daridorexant). Prescribing information. U.S. [PDF]