Emmanuel Mignot, MDEmmanuel Mignot, MD
The safety and efficacy of the dual orexin receptor antagonist daridorexant have been confirmed in a second pivotal phase 3 study (NCT03575104) in 924 adults and elderly patients with insomnia.1

The results follow a data readout in April 2020 from Idorsia’s first pivotal phase 3 study of daridorexant (NCT03545191), which also showed promising results.2

The latest data demonstrate a statistically significant improvement in sleep maintenance and subjective total sleep time at months 1 and 3 for patients, nearly 40% of whom were 65 or older, who received the 25-mg dose. The therapy was also associated with positive effects on daytime functioning, as measured daily using the sleepiness domain score from the Insomnia Daytime Symptoms and Impacts Questionnaire, with participants reporting no residual morning sleepiness and no evidence of rebound or withdrawal symptoms after discontinuing treatment.

“For me, the improved daytime functioning seen with daridorexant is most impressive. What is important to patients is not only to improve their night sleep but also how they feel during the day,” said Emmanuel Mignot, MD, professor of psychiatry and behavioral sciences at Stanford University, in a statement.1 “By measuring the benefits of the drug through the day as well as through the night, the program has put patients back at the center of the equation and raised the standard for what we need to see with sleep medications.”
 
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Notably, the positive impact on sleep onset and daytime functioning observed in the 25-mg group, although consistent with what was observed in the previous study, did not reach statistical significance. In addition, numerical improvements across all efficacy measures were observed in the 10-mg group, though none reached statistical significance.

Overall, the results in the 25-mg arm confirm those observed in the previous pivotal study, which evaluated a 25 mg and 50 mg dose in 930 patients with insomnia over a 3-month period. Data from that double-blind, randomized, placebo-controlled, parallel-group, phase 3 polysomnography study showed that treatment with daridorexant significantly improved sleep onset and sleep maintenance as measured objectively in a sleep lab by polysomnography. Self-reported data from daily diaries showed the drug’s significant impact on subjective total sleep time, as well, compared with placebo.

The safety of the drug was consistent across both studies, with treatment-emergent adverse events (TEASs) reported in 38.2% and 39.3% of patients treated with 10 mg or 25 mg daridorexant compared with 32.7% in the placebo group in the latest data. The most common TEAEs were nasopharyngitis, headache, somnolence, and fatigue. Reports of serious adverse events were few (3 patients each in 10- and 25-mg groups; 4 in placebo), and only 1 and 4 patients in the 10- and 25-mg treatment groups reported excessive daytime sleepiness compared with 1 in the placebo group. Notably, no cataplexy-like events or next-morning residual effects were reported, and no suicide or self-injurious behavior was observed.

Idorsia plans to compile a pooled analysis using the data from the 25-mg groups of the 2 pivotal studies to further characterize the effects of daridorexant in patients with insomnia and support a new drug application filing near the end of the year.
REFERENCES
1. Idorsia announces positive results in the second Phase 3 study of daridorexant. News release. Idorsia. July 6, 2020. Accessed July 6, 2020. https://www.globenewswire.com/news-release/2020/07/06/2057679/0/en/Idorsia-announces-positive-results-in-the-second-Phase-3-study-of-daridorexant.html
2. Idorsia announces positive results in the first phase 3 study of daridorexant with improved sleep and daytime performance of patients with insomnia. News release. Idorsia. April 20, 2020. Accessed April 21, 2020. https://www.globenewswire.com/news-release/2020/04/20/2018329/0/en/Idorsia-announces-positive-results-in-the-first-Phase-3-study-of-daridorexant-with-improved-overall-sleep-and-daytime-performance-of-patients-with-insomnia.html