FDA Approves Daridorexant for Insomnia Treatment

Martine Clozel, MD

The FDA has approved Idorsia’s daridorexant, a dual orexin receptor antagonist, for the treatment of insomnia in adults. Marketed under the name Quviviq, the medication, which has been recommended as a controlled substance by the FDA, is expected to be available in May 2022 following scheduling by the US Drug Enforcement Administration.¹

The basis for the decision comes from a clinical program that included 1854 adults across 160 clinical trial sites. Data showed that treatment with daridorexant 25- and 50-mg resulted in significant improvement compared with placebo on objective measures of sleep onset and sleep maintenance, as well as patient reported total sleep time.

"After more than 20 years of research and a progressive understanding of the role of orexin in sleep-wake balance and of the potential of orexin receptor antagonism, we designed daridorexant to help address several issues people with insomnia face," Martine Clozel, MD, chief scientific officer, Idorsia, said in a statement.¹ "Daridorexant properties include a potent inhibition of both orexin receptors, a rapid absorption for sleep onset, and a pharmacokinetic profile such that around 80% of daridorexant has been eliminated after a night of sleep to help minimize residual effects."

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The drug is designed to block the binding of the wake-promoting neuropeptides orexins, addressing overactive wakefulness. The drug showed statistically significant improvement in sleep and daytime functioning, as measured by the Insomnia Daytime Symptoms and Impacts Questionnaire, while keeping a favorable safety profile in adult and elderly patients through 2 phase 3 clinical trials.

Study 1 (NCT03545191) and Study 2 (NCT03575104) were multicenter, randomized, double-blind, parallel-group studies that included 1854 patients with insomnia who were randomly assigned 1:1:1 to daridorexant 25 mg, 50 mg, or placebo in Study 1 (n = 930) and to daridorexant 10 mg, 25 mg, or placebo in Study 2 (n = 924).

Both studies used change from baseline from month 1 and month 3 in Latency to Persistent Sleep (LPS) and Wake After Sleep Onset (WASO), measured objectively by polysomnography, as the primary end point. In Study 1, doses of 25 and 50 mg daridorexant demonstrated statistically significant improvement vs placebo on LPS, WASO, and self-reported total sleep (TST) at months 1 and 3. The drug continued to show similar improvements in WASO and TST in Study 2 at doses of 25 mg; however, a similar effect was not observed in the 10 mg group.

All told, daridorexant dose-dependently increased TST (in minutes) from baseline to month 3 more than placebo (Study 1: 25 mg: 55 [±56]; 50 mg: 61 [±53]; placebo: 40 [±56]; Study 2: 10 mg: 37 [±57]; 25 mg: 50 [±53]; placebo: 35 [±56]). Both trials showed preservation of the sleep stage proportions from baseline to month 3, with no significant changes in any group.²

Both trials also showed consistent time spent in each sleep stage, as measured by percentage of TST, consistent across both treatment groups (N1: 11-13; N2: 55-57; N3: 11-14; REM: 19-20). In Study 1, the change from baseline to month 3 of the percentage of time spent in N1 (25 mg: –0.3 [±4.7]; 50 mg: –0.2 [±5]; placebo: 0.1 [±5]), in N2 (25 mg: 2 [±8]; 50 mg: 1 [±7]; placebo: 1 [±7]), in N3(25 mg: –2 [±6]; 50 mg: –2 [±6]; placebo: –2 [±6]) and in REM (25 mg: 1 [±6]; 50 mg: 1 [±5]; placebo: 1 [±5]) was low and numerically similar across treatments. Consistent results were observed in Study 2.

The most common adverse reactions reported were headache (25 mg: 6%; 50 mg: 7%; placebo: 5%) and somnolence or fatigue (25 mg: 6%; 50 mg: 5%; placebo: 4%)

"As noted in the definition of insomnia, the disorder is not only a problem of the night but affects a patient’s ability to function during the day. Although the personal and societal burden of insomnia is well established, elevating the impact insomnia has on both the night and day remains critical in addressing patients’ needs," Thomas Roth, PhD, director, Sleep Disorder and Research Center, Henry Ford Hospital, said in a statement.¹ “I am encouraged to see a new advanced treatment option for the millions of adults struggling with insomnia."

REFERENCES
1. Idorsia recieves US FDA approval of Quiviviq (daridorexant) 25 and 50 mg for the treatment of adults with insomnia. News release. Idorsia. January 10, 2022. Accessed January 10, 2022. https://www.biospace.com/article/releases/idorsia-receives-us-fda-approval-of-quviviq-daridorexant-25-and-50-mg-for-the-treatment-of-adults-with-insomnia/?s=85
2. Zammit G, Mayleben D, Fietze I, Pain S, Kinter DS, Gimona A, Dauvilliers Y. Daridorexant improves total sleep time (TST) In insomnia patients without altering the proportion of sleep stages Presented at SLEEP 2021 Annual Meeting; June 10-13. Abstract 344.