Daridorexant shows promise as insomnia therapy, safe in OSA subset
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A survey of patients with insomnia who participated in two phase 3 trials investigating daridorexant reported that “improved daytime functioning” was the most important treatment outcome for their condition.
The study was one of several abstracts on the oral sleep therapy daridorexant (Idorsia Pharmaceuticals) that were presented during the virtual SLEEP 2021 meeting.
Daridorexant is an orexin receptor 2 agonist that was developed for the treatment of insomnia. It is currently awaiting approval from the FDA, Emmanuel Mignot, MD, PhD, a professor of sleep medicine at Stanford University who has studied the drug, told Healio Primary Care.
“The orexin system keeps the brain awake, so it induces sleep differently from classical benzodiazepine‐acting sleeping pills such as zolpidem, which work by decreasing overall neuronal activity,” he said.
Traditional treatments for insomnia may cause memory difficulties and morning sedation, according to Mignot.
Mignot, who discovered the cause of narcolepsy and the main function of the orexin receptor 20 years ago, said he was “excited” to see the FDA accept daridorexant’s new drug application earlier this year.
“The most remarkable aspect of the work with daridorexant is that it was shown to improve daytime functioning” Mignot said.
Patient preferences
Previous phase 3 data demonstrated the safety and efficacy of daridorexant, according to Sebastian Heidenreich, PhD, an associate director at the research and consulting company Evidera, and colleagues.
To learn more about the drug, the researchers conducted a benefit-risk assessment by surveying 602 patients from the phase 3 trials. The mean age of the cohort was 58.6 years; 68% were women; and 28.3% had an Insomnia Severity Index score of “severe.” All respondents were asked to make treatment trade-offs on seven outcomes: “time to fall asleep,” “total time asleep,” “daytime functioning,” “likelihood of daytime dizziness/grogginess,” “likelihood of abnormal thoughts and behavioral changes,” “likelihood of falls in the night” and “treatment withdrawal.”
Heidenreich and colleagues reported that patients significantly valued all seven outcomes, but improving daytime functioning (relative attribute importance [RAI)] = 33.7%) and avoiding treatment withdrawal (RAI = 27.5%) were most important. Patients were also willing to accept an additional 18.8% risk (P < .001) for abnormal thoughts and behavioral changes for an improvement in daytime functioning from “difficulty functioning to restricted functioning,” according to the researchers.
The patient-centered benefit-risk assessment also revealed that patients preferred 50-mg and 25-mg doses of daridorexant compared with placebo and the 50-mg dose compared with the 25-mg dose, “even after accounting for uncertainty in clinical outcomes” (P for both comparisons < .001), according to Heidenreich and colleagues.
Absence of withdrawal symptoms, rebound
In another analysis of the phase 3 trials, Damien Leger, MD, PhD, director of the Clinical Sleep and Vigilance Center at the Université de Paris, evaluated the effects of daridorexant after treatment discontinuation.
The first trial included 851 patients aged 18 to 64 years who received either placebo, 25 mg or 50 mg of daridorexant, and the second trial included 852 patients aged 65 years and older who were administered either placebo, 10 mg or 25 mg of daridorexant. After approximately 3 months of treatment, both trials had a 7-day, single-blind, placebo runout period to assess patients’ withdrawal symptoms and rebound insomnia.
Leger and colleagues found no increase in Benzodiazepine Withdrawal Symptom Questionnaire scores from the time that patients stopped treatment to the end of the placebo runout period, and no scores topped 20 points. Overall, Leger and colleagues said there was no evidence of drug withdrawal.
In addition, mean minutes of wake-after-sleep onset and latency-to-persistent sleep dropped from baseline to the placebo runout period while subjective total-sleep time increased, suggesting to the researchers that there were no rebound effects.
The results provide “a deep understanding of the safety and tolerability profile of daridorexant,” Antonio Olivieri, MD, senior vice president and head of global medical affairs at Idorsia Pharmaceuticals, told Healio Primary Care. The findings suggest daridorexant could be an “innovative insomnia treatment,” he said.
OSA subset
Two other abstracts presented at the virtual SLEEP meeting showed that daridorexant was safe and improved sleep in a subset of patients with obstructive sleep apnea.
“Obstructive sleep apnea is highly prevalent and often occurs concomitantly with insomnia,” Olivieri said. “In these respiratory‐depressed patients, there is a need for sleep medications which do not impair nighttime respiration, while improving sleep.”
Researchers from Idorsia and several European sleep centers analyzed data from a randomized, double-blind, placebo-controlled, two-period, crossover study involving 25 patients with either mild or moderate OSA. One of the patients had mild insomnia symptoms prior to the study. All patients were asked to take one 50-mg dose of daridorexant or placebo nightly for 5 consecutive nights.
The researchers reported that compared with placebo, daridorexant increased mean duration of total sleep time. The orexin receptor 2 agonist also shortened mean latency-to-persistent sleep, reduced mean wake-after-sleep onset, prolonged length of sleep in the second part of the night, and decreased length of awakenings and total number of awakenings. However, the CI for these variables was only 90%.
“Daridorexant improved objective sleep parameters without modifying sleep architecture,” Olivieri said. “Results demonstrate the potential for daridorexant to be administered to patients with mild/moderate OSA.”
Next steps
The FDA accepted daridorexant’s new drug approval application in March, according to a press release from Idorsia Pharmaceuticals. The company said it hopes to make the product available in the United States during the first 6 months of 2022.
“We now stand by to work with the FDA to answer any questions that might arise concerning the effect of daridorexant on sleep, daytime functioning and its safety profile,” Idorsia Pharmaceuticals CEO Jean-Paul Clozel, MD, said in the press release.
References:
Boof M-L, et al. Abstract 357. Presented at: SLEEP; June 10-13 (virtual meeting).
Boof M-L, et al. Abstract 358. Presented at: SLEEP; June 10-13 (virtual meeting).
Clinicaltrials.gov. Study to Assess the Efficacy and Safety of ACT-541468 in Adult and Elderly Subjects Suffering From Difficulties to Sleep. Available at: https://clinicaltrials.gov/ct2/show/NCT03575104. Accessed June 14, 2021.
Clinicaltrials.gov. Study to Assess the Efficacy and Safety of ACT-541468 in Adult and Elderly Subjects With Insomnia Disorder. Available at: https://clinicaltrials.gov/ct2/show/NCT03545191. Accessed June 14, 2021.
Evideria. Who we are. Available at: https://www.evidera.com/who-we-are/about-us/. Accessed June 14, 2021.
Heidenreich S, et al. Abstract 343. Presented at: SLEEP; June 10-13, 2021 (virtual meeting).
Idorsia. FDA accepts the new drug application for review of Idorsia’s daridorexant for the treatment of adult patients with insomnia. Available at: https://www.idorsia.com/investors/news-and-events/media-release-details?newsId=2474626. Accessed June 14, 2021.
Leger D, et al. Abstract 348. Presented at: SLEEP; June 10-13 (virtual meeting).
Perspective
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Daniel McNally, MD
There probably is a subset of people with insomnia who have different levels of central nervous system activity than others, in which cognitive behavioral therapy and other insomnia therapies do not work as well and a pharmacologic approach using a drug like daridorexant may do better.
Most insomnia drugs work on the GABA receptor in the brain. However, these drugs can alter a patient’s memory and cognition, and can promote unusual behaviors (like eating episodes for which the patient has no recall) at the transitions between wakefulness and sleep. In addition, the receptor is adaptable, meaning if a patient has been taking some of these drugs for a time, they may get less effect from them and may escalate their dose to achieve the desired effect. Other over-the-counter insomnia drugs contain antihistamines, which make patients sleepy but make some people feel groggy the next day. There are melatonin products that are relatively safe and useful to initiate sleep, but less effective at maintaining it.
Orexin receptors in the brain are active during wakefulness. Narcolepsy with cataplexy in humans is mediated by a loss of orexin neurons. Daridorexant and other orexin antagonists like suvorexant promote sleep by blocking the effect of orexin, shifting the balance in brain chemistry away from wakefulness and toward sleep. Unlike the drugs which work on the GABA receptor, orexin antagonists may be less likely to affect other aspects of brain function or change other aspects of sleep organization, producing fewer side effects.
All that said, I strongly advocate cognitive behavioral therapy for insomnia. The American Academy of Sleep Medicine guidelines provide good reasons for using cognitive behavioral therapy as the first line of insomnia treatment. In head-to-head comparisons between cognitive behavioral therapy and medications, in most instances cognitive behavioral therapy does as well as the medications. I would argue in the long term, cognitive behavioral therapy does even better at treating insomnia since it provides the patient with a set of tools that they can use to deal with sleeping difficulties in the future. Cognitive behavioral therapy involves things like restricting the time a patient is in bed, changing the associations about going to bed, etc., and is more than just sleep hygiene.
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