Calantha Yan, PharmD, RPh

Insomnia disorder is defined in the International Classification of Sleep Disorders, Third Edition as a compliant of trouble initiating or maintaining sleep that is associated with daytime consequences and is not attributable to environmental circumstances or inadequate opportunity to sleep. The disorder is identified as chronic when it has persisted for at least 3 months at a frequency of at least 3 times per week.

Insomnia occurs in people of all ages and races and has been observed across cultures and populations.

 The prevalence of chronic insomnia disorder in industrialized nations is estimated to be at least 5% to 10%.

The prevalence is significantly higher in medically and mentally ill populations, as well as in older age groups. Chronic insomnia has been identified by multiple studies as a significant risk factor for the development of psychiatric disorders, increased relapse for depression and alcoholism, and cardiovascular disease.

In addition, chronic insomnia imposes considerable economic burdens on society. Estimates for insomnia in the United States suggest direct costs of $2 billion-$16 billion per year and indirect costs of $75 billion-$100 billion per year. The latter is largely accounted by worker absenteeism, presenteeism, and work-related accidents.

Current treatment and pharmacotherapy options

Although pharmacotherapy is considered for the treatment of insomnia, medication should not be the sole treatment for individuals diagnosed with insomnia. Cognitive behavioral therapy (CBT) is the current and preferred first-line treatment for chronic insomnia.

When moving to the use of any medication, they should be combined with CBT and healthy sleep habits (i.e., consistent sleep schedule, limit caffeine intake at night, avoidance of blue light near bedtime). Among the major classes of FDA-approved medications for the treatment of insomnia, all are considered appropriate first-line pharmacotherapy options, excluding the older benzodiazepine hypnotics (estazolam, flurazepam, and quazepam).

A general treatment algorithm for insomnia can be found 

. These older benzodiazepine hypnotic medications have longer half-lives and higher risk of dependence and may become habit forming. They are not appropriate as first-line due to the availability of safer options.

Current FDA-approved pharmacologic treatment options recommended by the American Academy of Sleep Medicine Clinical Practice Guideline published in 2017 include benzodiazepine receptor agonists (temazepam and triazolam), as well as the nonbenzodiazepine benzodiazepine receptor agonists (eszopiclone, zaleplon, and zolpidem); histamine receptor antagonists (low-dose doxepin); melatonin receptor agonists (ramelteon); and dual orexin receptor antagonists (suvorexant).

The dual orexin receptor antagonists represent the newest class of insomnia treatments with innovation outpacing current guidelines.

 Suvorexant was approved in 2014 followed by lemborexant in 2019.

Daridorexant mechanism of action, indication, and clinical evidence

Daridorexant (Quviviq) joined this class in the new year as an approved novel dual orexin receptor antagonist indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or maintenance.

 Daridorexant exhibits its effect through blocking the binding of wake-promoting neuropeptides orexin A and orexin B to the receptors OX1R and OXR2. The antagonism at these receptors is thought to suppress overactive wakefulness.

Researchers stated that daridorexant’s identification was the result of a bespoke discovery program aimed at identifying a sleep medication that addressed symptoms of nighttime insomnia, without the next-day effects of continued drowsiness and somnolence. To achieve this balance, scientists sought out an agent with an appropriate duration of action that was optimally efficacious throughout the night while avoiding next morning residual activity.

During human physiology-based pharmacodynamic and pharmacokinetic modeling, simulations of daridorexant suggested high and rapid peak orexin receptor occupancy followed by a quick decline. These simulated models were then verified in clinical studies that showed daridorexant’s half-life to be around 6 hours and peak plasma concentration to occur between 0.8- and 2-hours post-dose.

The efficacy and safety of daridorexant was further investigated during 2 phase 3 clinical studies that resulted in FDA-approval at 25 mg and 50 mg doses. A total of 1854 patients diagnosed with insomnia were randomized to receive daridorexant or placebo orally once daily, in the evening, for 3 months.

The studies also investigated a 10 mg dose that was ultimately not approved. Primary efficacy endpoints were the change from baseline to Month 1 and Month 3 Latency to Persistent Sleep (LPS), and Wake After Sleep Onset (WASO). LPS is a sleep induction measure, whereas WASO is a sleep maintenance measure. These endpoints were measured objectively by polysomnography in a sleep laboratory.

Investigators also measured daytime sleepiness using the sleepiness domain score from the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). At both the 50 mg and 25 mg doses, daridorexant demonstrated statistically significant improvement in WASO and LPS scores as compared to placebo.

Notably, at the 50 mg dose, significant improvement in the IDSIQ sleepiness domain score was noted. Clinical evidence also determined daridorexant’s half-life to be 8 hours, which is shorter than both suvorexant (~12 hours) and lemborexant (17-19 hours).

From a safety perspective, daridorexant exhibited a favorable profile and the most common adverse effects were headache and somnolence/fatigue.

The results of the phase 3 clinical program demonstrate that daridorexant at 25 mg and 50 mg improved sleep outcomes. Additionally, at 50 mg daridorexant showed improvement in daytime functioning for people diagnosed with insomnia.

So where does daridorexant fit within the insomnia treatment algorithm?

If pharmacologic therapy is needed beyond CBT, dariodexant can be considered as an option along with the other dual orexin receptor antagonists, low-dose doxepin, benzodiazepine hypnotics, and nonbenzodiazepine benzodiazepine receptor agonists. Based upon clinical evidence, daridorexent is likely an appropriate choice for patients with isolated sleep-onset insomnia, as well as sleep-maintenance or mixed insomnia.

Choice of daridorexant over other agents should be made considering individual patient factors, the unique properties of daridorexant, and with safe prescribing practices in mind. Following controlled substance scheduling by the US Drug Enforcement Administration, daridorexant is anticipated to be available in May 2022.

International Classification of Sleep Disorders

. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014. doi:10.5664/jcsm.4050

Johnson EO. Epidemiology of insomnia: from adolescence to old age. 

Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. 

. 2002;6(2):97-111. doi:10.1053/smrv.2002.0186

Ohayon MM. Observation of the natural evolution of insomnia in the American general population cohort. 

. 2009;4(1):87-92. doi:10.1016/j.jsmc.2008.12.002

Baglioni C, Battagliese G, Feige B, et al. Insomnia as a predictor of depression: A meta-analytic evaluation of longitudinal epidemiological studies. 

. 2011;135(1-3):10-19. doi:10.1016/j.jad.2011.01.011

Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: A longitudinal epidemiological study of young Adults. 

. 1996;39(6):411-418. doi:10.1016/0006-3223(95)00188-3

Bathgate CJ, Edinger JD, Wyatt JK, Krystal AD. Objective but not subjective short sleep duration associated with increased risk for hypertension in individuals with insomnia. 

. 2016;39(5):1037-1045. doi:10.5665/sleep.5748

Daley M, Morin CM, LeBlanc M, Grégoire JP, Savard J. The economic burden of insomnia: direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms, and good sleepers. 

Sateia Michael J., Buysse Daniel J., Krystal Andrew D., Neubauer David N., Heald Jonathan L. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an american academy of sleep medicine clinical practice guideline. 

Approval package for suvorexant. U.S. Food and Drug Administration. Updated August 13, 2014. Accessed February 3, 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204569Orig1s000Approv.pdf

Approval package for Lemborexant. U.S. Food and Drug Administration. Updated December 20, 2019. Accessed February 3, 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212028Orig1s000Approv.pdf

Fine L. Pharmacologic Approach to Insomnia. 

. 2020;31(2):255-264. doi:10.1016/j.pmr.2020.01.003

Zammit G, Dauvilliers Y, Pain S, Sebök Kinter D, Mansour Y, Kunz D. Daridorexant, a new dual orexin receptor antagonist, in elderly subjects with insomnia disorder. 

. 2020;94(21):e2222-e2232. doi:10.1212/WNL.0000000000009475

Idorsia receives US FDA approval of Quviviq (daridorexant) 25 and 50 mg for the treatment of adults with insomnia. Idorsia. News release. January 10, 2022. Accessed January 10, 2022. 

https://www.idorsia.us/documents/us/media-releases/2201_us-fda-approval-quviviq-announcement.pdf

Dayvigo. Prescribing Information. Eisai; 2019. Accessed February 3, 2022.

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212028s000lbl.pdf

Belsomra. Prescribing Information. Merck; 2014. Accessed February 3, 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204569s000lbledt.pdf

Articles

Although pharmacotherapy is considered for the treatment of insomnia, medication should not be the sole treatment for individuals diagnosed with insomnia.