New drug for insomnia is here, the latest FDA approval

*For medical professionals only, what is the target of action of the new drug? Why was it approved? What are the characteristics? On January 10, 2022, Swiss biotechnology company Idorsia Pharmaceuticals Ltd announced that the U.
S.
Food and Drug Administration (FDA) has approved Daridorexant (ACT-541468, DORA, Nemorexant; dosage form: film-coated tablet) for the treatment of difficulty falling asleep and and/or adult insomniacs with difficulty in maintaining sleep
.

Dual orexin receptor antagonists inhibit overactive wake pathways in insomniacs.
Insomnia is a serious sleep disorder characterized by difficulty falling asleep, sleep maintenance, decreased sleep quality, early awakening, decreased total sleep time, and at the same time With daytime dysfunction
.

Affected by the fast pace of modern life, high work pressure and fierce competition, the incidence of insomnia is increasing year by year, and it is getting younger.
In recent years, the incidence of insomnia in China is as high as 42.
5%
.

It is generally believed that the occurrence and maintenance of sleep-wake requires structural support from multiple brain regions and multiple neurotransmitter systems
.

Sleep depends on γ-aminobutyric acid (GABA) neurons in the ventral and intermediate preoptic areas, while wakefulness depends on the glutamic acid (Glu) system in the reticular structure of the brainstem, The cholinergic systems of the basal forebrain and brainstem, the noradrenergic, serotonergic, and dopaminergic systems of the brainstem, and the histaminergic and orexin systems of the hypothalamus
.

Figure 1: Orexin stimulates multiple wake-promoting signaling pathways
.

Orexinergic neurons regulate sleep and wakefulness, and orexinergic neuron activity is involved in both lethargy and sleep regulation
.

It is generally believed that orexinergic neurons promote wakefulness (Fig.
1) [1], and more orexinergic neuron activity is required to maintain prolonged wakefulness during sleep deprivation
.

Other related studies suggest that orexin deficiency may be the underlying pathogenesis of narcolepsy, which can lead to excessive daytime sleepiness and uncontrolled sleep episodes
.

Traditional benzodiazepines broadly calm the brain by acting on the alpha receptors of GABAergic neurons, but due to the high concentration of the drugs in the body, they often cause symptoms such as dizziness, drowsiness, fatigue and disorientation.
The patient suffers from a hangover
.

Unlike traditional drugs, the new drug Daridorexant acts as a dual orexin receptor antagonist that blocks the binding of the arousal neuropeptides orexin A and orexin B to their receptors to inhibit arousal drive and suppress hyperactivity in patients with insomnia The awakening pathway, and then play the role of sleep aid [2]
.

Approved based on the results of two clinical phase III studies The approval of the new drug Daridorexant is based on the test results of two multicenter, randomized, double-blind, placebo-controlled clinical phase III studies (Study1: NCT03545191 and Study2: NCT03575104) [1]
.

A total of 1854 patients with insomnia were included in the study and were randomized to receive Daridorexant or placebo (once a night for at least 3 months)
.

Study 1 randomly assigned 930 subjects to Daridorexant 50 mg (N=310), Daridorexant 25 mg (N=310), or placebo (N=310)
.

Study 2 randomly assigned 924 subjects to Daridorexant 25mg (N=309), 10mg (N=307) or placebo (N=308)
.

The demographic characteristics of Study1 and Study2 are shown in Figure 2 [1]
.

Figure 2: Demographic characteristics of the Daridorexant Phase III clinical study.
The primary efficacy endpoint of the trial was the change in the time required to enter sustained sleep (LPS) and wake after sleep onset (WASO) from baseline to months 1 and 3.

.

LPS is an indicator of sleep onset and WASO is an indicator of sleep maintenance
.

A secondary endpoint of the trial was patient-reported total sleep time (sTST)
.

Results showed that Daridorexant at a dose of 50 mg significantly improved objective measures of sleep onset and sleep maintenance, as well as patient-reported total sleep time, compared with placebo (Figure 3) [1]
.

Figure 3: The primary efficacy and secondary endpoints of the Daridorexant Phase III clinical study In addition, the study also showed that the 50 mg dose level of Daridorexant can significantly reduce daytime sleepiness in patients
.

In terms of safety, the most common adverse reactions were headache, somnolence or fatigue (Figure 4) [1]
.

Meanwhile, Daridorexant was not associated with next-morning residual effects, rebound insomnia, or withdrawal symptoms after drug discontinuation
.

Figure 4: Safety Assessment of Phase III Clinical Studies Listening to the voices of foreign authoritative persons What is the advantage of Daridorexant? Overall, Daridorexant effectively inhibits both orexin receptors and is rapidly absorbed at the onset of sleep, thus exerting a good sleep aid effect
.

At the same time, the drug has good pharmacokinetic characteristics, and about 80% of the drug components are cleared by the body after sleep at night, which can minimize residual effects [3]
.

Dr.
Martine Clozel, Chief Scientific Officer of Idorsia, commented: "Daridorexant was not discovered by accident, our research team has been working very hard to find a dual antagonist since the first study of orexin and its receptors in 1998
.

Not only does the molecule need to be able to act quickly, but its duration of action must be 'long enough at night and short enough during the day' to avoid any negative activity remaining the next morning
.

The results of the study we share today are very Valuable, it justifies a project we've stuck with for more than 20 years[4]
.

" Comments Dr.
Thomas Roth, director of the Sleep Disorders and Research Center at Henry Ford Hospital: "Medical treatment of insomnia is not only about helping patients fall asleep quickly, but also Maintain sleep, but also address the negative effects of poor sleep on daytime functioning
.

I think the best way to achieve this is to reduce the hyperarousal state that occurs in insomniacs by blocking the action of orexin
.

Enables patients to sleep through the night while avoiding the ill effects of many sleep medications through the broad sedative effects of the brain
.

The results seen in this 3-month Phase III study suggest that daridorexant may meet this requirement for insomniacs An important demand[4]
.

“It is reported that Daridorexant will be available in 25mg and 50mg tablets and is expected to be available in the United States in May 2022
.

Finally, drug research and development is very difficult.
After layers of trials, approvals, and countless efforts, I am very happy to see a new drug launched.
Although it is not easy to sit back and relax after it is launched, large-scale clinical studies are still needed to monitor all aspects of it.
, to further confirm the safety and effectiveness of the drug, let us wait for the results of the Phase IV clinical trial
.

Reference source: [1] Idorsia Company Presentation.
Retrieved April 19, 2020, from ttps:// [2] Roch, C .
, et al.
, Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia.
Psychopharmacology (Berl), 2021.
238(10): p.
2693-2708.
[3] Idorsia receives US FDA approval of Quviviq ( daridorexant) 25 and 50 mg for the treatment of adults with insomnia.
Retrieved January 10, 2022, from https:// announces positive results in the first Phase 3 study of daridorexant with improved overall sleep and daytime performance of patients with insomnia.
Retrieved April 20, 2020, from https://