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Scientists Target Orexin Receptor to Treat Insomnia

Article In Brief

Daridorexant, a new dual orexin receptor antagonist, reduced wake-time after sleep onset in patients with insomnia and enabled them to fall asleep sooner and spend more time asleep. The drug had fewer side effects than other drugs in the same class.

Daridorexant, a new dual orexin receptor antagonist, reduced wake-time after sleep onset in patients with insomnia and enabled them to fall asleep sooner and spend more time asleep, according to a study published in the January 17 online issue of Annals of Neurology.

Like others in its class, the orexin receptor antagonist works on orexin receptors that are linked to wakefulness. Traditional insomnia medications target GABA neurotransmitters and don't always work. They also have side effects, including daytime drowsiness, that patients can't tolerate.

The first of this new class of medications, suvorexant, was approved by the US Food and Drug Administration in 2014. Suvorexant also reduces the time-to-sleep-onset and the time-to-wake after a person falls asleep. But it seems that the positive effects were seen at doses higher than currently approved and patients have complained of daytime sleepiness, too.

Yves Dauvilliers, MD, PhD, professor of neurology and physiology at the University of Montpellier in France, and his colleagues, set out to identify more potent medicines that block orexin receptors with fewer residual effects during the waking hours. The scientists tested tens of thousands of compounds and identified 20 that hit the orexin target.

“There was a high and rapid peak orexin receptor occupancy when daridorexant was taken, and it cleared rapidly,” Dr. Dauvilliers said. “The hope was that it would work at helping patients get to sleep and stay sleeping longer without altering their functioning during the day.”

Study Design, Findings

For the large double-blind clinical study, the researchers recruited 359 men and women (ages 18 to 64) from 38 sites in six countries at hospitals and sleep centers in Germany, Hungary, Israel, Spain, Sweden, and the United States. The patients were randomized to receive an oral placebo dose or one of four doses of daridorexant (5 mg, 10 mg, 25 mg, or 50 mg), or 10 mg zolpidem for 30 days.

The primary outcome measure was a change in wake time after sleep onset. They also looked at the change in latency to persistent sleep in the first few days, the change in subjective wake-time after sleep onset, and subjective latency to sleep onset from baseline to the end of the fourth week.

The study design included a screening period of 14 to 28 days, followed by a 30-day blinded treatment period. The research team continued to measure safety for an additional 30 days after the treatment phase was over. The study subjects completed a daily sleep diary for at least seven consecutive days during the screening period. They also obtained information from polysomnography recordings taken on two consecutive placebo-treated nights and continued to do more recordings several times throughout the active treatment phase to assess sleep variables.

The daily diaries, filled in every morning and evening, helped the team collect subjective sleep data, including data on the participants' quality of sleep and morning sleepiness, daytime alertness, and changes in the ability to function during the day.

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“While the results were promising, some of the limitations of this study besides the small sample size, include a relatively short follow-up duration and lack of race-ethnic diversity, with the vast majority of participants being white.”—DR. SALIM DIB

The scientists used a number of algorithms to assess the data and reported a significant dose-response in the reduction of wake after sleep-onset and latency to persistent sleep from baseline to the first few days on daridorexant. These reductions were sustained until the end of the month. They also reported strong dose-dependent relationships for subjective wakefulness after sleep-onset and subjective latency to sleep-onset.

The researchers reported that 35 percent of people taking the 5 mg dose had side effects—mainly daytime sleepiness—as did 38 percent of those takin the 0 mg and 25 mg dose, and 34 percent in those with the highest dose of 50 mg during the testing period. Forty percent of those on zolpidem reported side effects. None of the side effects were considered serious. Four people opted out of the study, citing troubling side effects.

Daytime sleepiness was no different between study subjects on the medications (any dose) and those on placebo. They were not able to assess whether the improvement in sleep had anything to do with the improved functioning the next day.

Many of the scientists in the study, including Dr. Dauvilliers, received funding from the company, Idorsia, that makes the medication. Dr. Dauvilliers is also on the board of Idorsia.

Expert Commentary

“This multicenter multinational study (including the US) shows a potential advantage of a new dual orexin receptor antagonist compared to currently available therapies on sleep parameters and reported side effects,” said Salim Dib, MD, FAAN, associate professor of clinical neurology and chief of neurology at the University of Miami Hospital and Clinics, and associate vice chair for the neurology outpatient clinical programs at the University of Miami, Miller School of Medicine.

“While cognitive behavioral therapy for insomnia remains the recommended long- term treatment, a number of patients rely on sedative-hypnotics for variable lengths of time. Suboptimal efficacy (including non-lasting medication effect), and/or intolerable side effects (including morning grogginess) are common complaints about the currently available medications used by patients.”

“Being able to fall asleep quickly and stay asleep through the night without feeling groggy the next morning would be an insomnia patient's dream,” he added. “While the results were promising, some of the limitations of this study besides the small sample size, include a relatively short follow-up duration and lack of race-ethnic diversity, with the vast majority of participants being white. Future large prospective studies will hopefully help determine the clinical significance and application of such medication, in addition to potential for medication tolerance, which is a fairly common occurrence with sedative-hypnotics.”

Rachel Salas, MD, MEd, FAAN, associate professor of neurology at Johns Hopkins Medicine, said that this new class of sleep medicines is trying to reduce wakefulness at night “so sleep can naturally take its course. We need new treatment options. It would be good if this medication is more specific for the orexin receptor, but we will have to see in future studies. It is way too early to know how this will translate clinically.”

She said that the gold standard for insomnia is cognitive behavioral therapy for insomnia and that “everyone is still looking for a ‘magic’ pill but most don't work that well or have a lot of side effects.”

Disclosures

Dr. Dauvilliers reported serving on the board, as a consultant, and as a lecturer for Idorsia, which sponsored the study. Drs. Dib and Salas had no disclosures.

Link Up for More Information

• Dauvilliers Y, Zammit G, Fietze I, et al. Daridorexant, a new dual orexin receptor antagonist to treat insomnia disorder https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25680. Ann Neurol 2020; Epub 2020 Jan 17.
    • Treiber A, de Kanter R, Roch C, et al. The use of physiology-based pharmacokinetic and pharmacodynamic modeling in the discovery of the dual orexin receptor antagonist ACT-541468 http://jpet.aspetjournals.org/content/362/3/489/tab-article-info. J Pharmacol Exp Ther 2017;362(3):489–503.
    • Muehlan C, Heuberger J, Juif PE, et al. Accelerated development of the dual orexin receptor antagonist ACT-541468: integration of a microtracer in a First-in-Human Study https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1046. Clin Pharmacol Ther 2018;104(5):1022–1029.