New Insomnia Medication is More of the Same: Limited Efficacy With Serious Safety Concerns

The Food and Drug Administration (FDA) on Jan. 7, 2022, approved a new drug to treat insomnia in adults.[1] The drug, daridorexant (QUVIVIQ), is an orexin receptor antagonist and thus a “me too” drug, which is to say it is not the first in its chemical class. Unsurprisingly, the drug seems no better than others in its class, and safety concerns yet again outweigh the drug’s limited benefits.

Orexin is a neuropeptide (a small protein molecule that acts in the brain) that is tied to wakefulness. Thus, antagonizing (inhibiting) orexin’s activity may promote sleep, but the full physiology of orexin receptor antagonists remains poorly understood.[2]

The approval of daridorexant was based principally on two randomized clinical trials showing that the drug marginally decreases latency to sleep (the time it takes to get to sleep) and waking time (the waking time that disrupts sleep after it first begins).

Public Citizen’s Health Research Group has previously classified orexin receptor antagonists and other classes of drugs to treat insomnia as Do Not Use because nonpharmacologic approaches are safer and more effective.[3],[4] Review of clinical trial data on daridorexant led us to conclude it also should be classified as a Do Not Use drug.

Background on insomnia disorder

Standard diagnostic criteria define insomnia disorder as difficulty initiating or maintaining sleep that leads to clinically significant distress or impairment in daytime social, occupational, academic, behavioral or other important areas of functioning.[5] Such difficulties must last at least three months and occur at least three times per week for the diagnosis to be assigned, and the diagnosis is inappropriate if a coexisting mental (for example, post-traumatic stress disorder) or other medical (for example, joint or muscle pain) condition accounts for the sleep disruptions.

The American Sleep Association notes that insomnia is the most common sleep disorder and that approximately 10% of adults suffer from “chronic insomnia.”[6]

First-line treatments for insomnia include measures to improve sleep hygiene, as well as talk and behavioral interventions (psychotherapies), especially standardized interventions like cognitive behavioral therapy specifically designed to address sleep problems.

There are two classes of medications approved by the FDA specifically for insomnia: Z-drugs (eszopiclone [LUNESTA], zaleplon [SONATA] and zolpidem [AMBIEN, EDLUAR, ZOLPIMIST]) and orexin inhibitors (lemborexant [DAYVIGO], suvorexant [BELSOMRA], and the recently approved daridorexant), all of which we designate as Do Not Use.

Clinical trials of daridorexant[7],[8]

The first randomized, placebo-controlled clinical trial used by the FDA to justify the approval of daridorexant had three groups, each composed of 310 subjects with moderate-to-severe insomnia disorder. One group received 25 millgrams (mg) of daridorexant daily, another received 50 mg of daridorexant daily, and the third group received a placebo daily, all before bed for up to three months. The primary outcomes of interest were latency to sleep and waking time. Secondary outcomes were total self-reported sleep time and a standardized daytime “sleepiness” score.

Two-thirds of the trial subjects were female, 90% were White, and their mean age was 55 years. Their self-reported baseline sleep times averaged 5 hours and 13 minutes per night.

Three months after daily dosing was commenced in this first trial, there was a statistically significant reduction (compared with placebo) in latency to sleep for the groups that received 25- and 50-mg doses of daridorexant that averaged 8 and 12 minutes per night, respectively; for waking time, significant declines averaged 12 and 18 minutes per night, respectively. Total reported sleep time similarly increased compared with placebo by 10 and 20 minutes per night, respectively, while the daytime sleepiness score decreased by only 1 and 2 points, respectively, on a scale with a possible range of 0 to 40, where a 4-point or greater change is considered clinically meaningful. That sleepiness score reduction was not statistically significant for the 25-mg dose.

The second randomized trial usedby the FDA to justify daridorexant’s approval was similar to the first, the main difference being the lower doses selected. This second trial again involved three groups with 307 to 309 subjects per group who received either 10 mg of daridorexant, 25 mg of daridorexant or a placebo daily before bed for up to three months. The outcomes were the same as those for the first trial described above. The subjects in the second trial were 69% female and 88% White and had a mean age of 57 years and average self-reported baseline sleep times of 5 hours and 8 minutes per night.

Three months after daily dosing was commenced for this second study, statistically significant latency to sleep and waking time reductions (compared with placebo) were only evident with the 25-mg dose, averaging 10 minutes per night for latency and 9 minutes per night for waking time. The 25-mg dose also resulted in a statistically significant mean increase of only 19 minutes per night for total self-reported sleep time and a mean 1-point reduction in sleepiness-scalescore.

Accordingly, the two trials together demonstrated that daridorexant’s efficacy to treat insomnia is limited to only several minutes more of uninterrupted sleep time per night, which is not clinically meaningful, with even less evidence indicating that the drug yields better functioning during the daytime.

Additionally, as is the case with other insomnia drugs, daridorexant may cause numerous and in some cases potentially serious adverse effects, including dizziness, headaches, fatigue, daytime drowsiness, impaired driving, dependence and withdrawal effects, worsening suicidality and depression, sleep paralysis and other complex sleep-related problems (for example, sleepwalking), and pregnancy/fetal exposure risks (presently the focus of FDA-mandated post marketing surveillance studies).[9],[10]

What You Can Do

Do not take daridorexant or any other drug for sleep problems because risks associated with their use outweigh their marginal benefits.

To manage ongoing or recurrent sleep problems, rely on nondrug therapies for insomnia such as good sleep hygiene, cognitive behavioral therapy for sleep and behavioral interventions (such as sleep restriction and stimulus control). Examples of good sleep hygiene practices are avoiding caffeine-containing products, nicotine or alcohol (especially later in the day); avoiding heavy meals within at least two hours of bedtime; and creating an atmosphere conducive to sleep, such as using earplugs to block out noise and sleeping in a dark room.

It is also important to consult a health care professional about any medical condition or drugs that may be contributing to your insomnia.
 

References

[1] Food and Drug Administration. . Letter to Idorsia Pharmaceuticals Ltd approving Quviviq (daridorexant). January 7, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214985Orig1s000Approv.pdf. Accessed July 8, 2022.

[2] Food and Drug Administration. Center for Drug Evaluation and Research. Application Number: 214985Orig1s000 Integrated review for daridorexant. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214985Orig1s000IntegratedR.pdf. Accessed July 8, 2022.

[3] Worst Pills. Best Pills. Sleeping pills and tranquilizers. Worst Pills, Best Pills. November 5, 2004. https://www.worstpills.org/chapters/view/20. Accessed July 8, 2022.

[4] Dangers of sleep drug suvorexant still outweigh minimal benefits. Worst Pills, Best Pills News. December, 2016. https://www.worstpills.org/newsletters/view/1075. Accessed July 8, 2022.

[5] Substance Abuse and Mental Health Services Administration. Impact of the DSM-IV to DSM-5 Changes on the National Survey on Drug Use and Health [Internet]. Rockville (MD); 2016 June.

[6] American Sleep Association. Sleep and sleep disorder statistics. https://www.sleepassociation.org/about-sleep/sleep-statistics/. Accessed July 8, 2022.

[7] Mignot E, Mayleben D, Fietze et al. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol. 2022;21(2):125-139.

[8] Food and Drug Administration. Center for Drug Evaluation and Research. Application Number: 214985Orig1s000 Integrated review for daridorexant. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214985Orig1s000IntegratedR.pdf. Accessed July 8, 2022.

[9] Indorsia Pharmaceuticals US Inc. Label: daridorexant (QUVIVIQ). January 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf. Accessed July 8, 2022.

[10] Food and Drug Administration. . Letter to Idorsia Pharmaceuticals Ltd approving Quviviq (daridorexant). January 7, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214985Orig1s000Approv.pdf. Accessed July 8, 2022.