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Daridorexant, an investigational dual orexin receptor antagonist (DORA), met its primary endpoints in treating insomnia, data from the first of two phase III randomized placebo-controlled trials showed.

Compared with placebo, daridorexant at 25 mg and 50 mg significantly improved sleep onset and sleep maintenance from baseline, reported Thomas Roth, PhD, of Henry Ford Health System in Detroit, in a late-breaking presentation at the virtual SLEEP 2020, the joint meeting of the American Academy of Sleep Medicine and the Sleep Research Society.

The drug also improved daytime functioning, an important secondary endpoint, Roth said.

Insomnia is very common, affecting about one in ten adults in the U.S., noted Michael Grandner, PhD, of the University of Arizona College of Medicine in Tucson, who wasn't involved with the study.

"This is significant, since insomnia disorder has been shown to be a major risk factor for mental health problems, and even cardiovascular and metabolic problems as well, in addition to a shorter lifespan," Grandner told 番茄社区app.

Cognitive behavioral therapy for insomnia should come first and "is usually the most effective approach," he said. "Most people do not have access to this treatment and medications are their only option. But most medications have troubling side effects and many people try to avoid these."

The DORA class, however, "seems to be quite effective for insomnia without the same risks you see in more traditional sedative medications," Grandner said.

DORAs inhibit orexin signaling by binding to orexin receptors 1 and 2, dampening orexin activity and affecting sleep/wake function. Two orexin receptor antagonists have been approved to treat insomnia to date: suvorexant (Belsomra) in 2014 and lemborexant (Dayvigo) in 2019.

This multicenter, double-blind used polysomnography to measure wake after sleep onset (WASO) and latency to persistent sleep (LPS), a sleep diary questionnaire to assess subjective total sleep time, and the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), a newly developed instrument, to measure daytime functioning. IDSIQ looked at three domains of the daytime effects of insomnia: alert/cognition, mood, and sleepiness/tiredness.

The researchers randomized 930 adults with insomnia 1:1:1 to 25 mg or 50 mg daridorexant or placebo for 3 months. After 3 months, treatment was discontinued. The groups were mostly female with a mean age of about 56; about 39% in each group were 65 and older.

Daridorexant improved sleep maintenance with a larger decrease in WASO from baseline than placebo. Mean change in minutes from baseline in WASO for placebo, 25 mg, and 50 mg was -6.2, -18.4, and -29.0 at 1 month, and -11.1, -23.0 and -29.4 at 3 months, respectively (all P<0.0001 vs placebo).

The drug also improved sleep onset, showing a larger decrease in LPS from baseline than placebo. Mean LPS change in minutes from baseline for placebo, 25 mg, and 50 mg was -19.9, -28.2 (P=0.0005) and -31.2 (P<0.0001) at 1 month, and -23.1, -30.7 (P=0.0015) and -34.8 (P<0.0001) at 3 months, respectively (P values vs placebo).

Subjective total sleep time also increased more with daridorexant than with placebo. Mean change in minutes from baseline for placebo, 25 mg, and 50 mg was 21.6, 34.2 (P=0.0013), and 43.6 (P<0.0001) at 1 month, and 37.9, 47.8 (P=0.0334), and 57.7 (P<0.0001) at 3 months, respectively (P values vs placebo).

Daytime functioning, measured by the sleepiness/tiredness domain of the patient-reported IDSIQ, was improved with the drug, Roth said. Other domains in the IDSIQ also showed a clear dose-dependent improvement, he added.

Nasopharyngitis was the most frequent adverse event and was balanced among the groups. Headache was reported by 4% of patients on placebo, 5% of patients on daridorexant 25 mg, and 6% of patients on daridorexant 50 mg. Somnolence was reported in 2% patients on placebo, 4% of patients on daridorexant 25 mg, and 2% of patients on daridorexant 50 mg.

There was no evidence of residual sleepiness in the morning. There also was no evidence of rebound insomnia when the drug was stopped or withdrawal symptoms, nor evidence of suicidal ideation or self-injury, Roth said.

Daridorexant is expected to be around the end of 2020, drugmaker Idorsia Pharmaceuticals said. The company's phase III registration program includes two 3-month pivotal trials plus a long-term extension study. Because insomnia often presents later in life, about 40% of the population recruited for the trials was 65 or older.

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