Daridorexant Shows Efficacy as Insomnia Therapy With Evidence of No Withdrawal Effects

The Idorsia dual orexin receptor antagonist was accepted by the FDA for review in March 2021 and has shown efficacy in a number of SLEEP 2021 poster presentations.

A number of poster presentations at the 2021 SLEEP Virtual Annual Meeting, June 10-13, suggest that daridorexant,an investigational dual orexin receptor antagonist for the treatment of adult patients with insomnia, is effective in a number of facets of treating the sleep disorder.1

One of the posters suggests that at any dose—each more than placebo—treatment with the Idorsia agent increased total sleep time (TST) in a dose-dependent manner lacking any impact on the proportion of all sleep stages in patients with insomnia.2 Another found that the treatment improved objective sleep parameters in patients with mild to moderate obstructive sleep apnea (OSA), also without modifying any sleep architecture,3 while a third suggested that the discontinuation of daridorexant among individuals with insomnia can be completed without withdrawal or rebound symptoms.4

“As a company with a strong scientific core rooted in innovative small molecules, Idorsia aims to transform the horizon of therapeutic options,” Antonio Olivieri, MD, senior vice president, and Head, Global Medical Affairs, Idorisa, said in a statement.1 “We look forward to presenting new data from our phase 3 clinical program and other important new data on daridorexant. This reflects our commitment to advance research for insomnia, a condition that can substantially impact the physical and mental health of patients and remains an area with great unmet need.”

At the end of March 2021, the FDA accepted a new drug application (NDA) for daridorexant, which included data from a comprehensive clinical and nonclinical developmental program demonstrating the efficacy of daridorexant on subjective sleep parameters and an improvement in daytime functioning, while maintaining a favorable safety profile. Idorsia submitted the NDA to the FDA on January 8, 2021, and noted that should it receive approval, daridorexant will launch in the first half of 2022.5

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In the first poster, assessing TST in patients with insomnia, data was included from 2 phase 3 trials, Trial-1 (NCT03545191) and Trial-2 (NCT03575104), totaling more than 1800 patients randomized (1:1:1) to daridorexant 25 mg, 50 mg, or placebo in Trial-1 (n = 930) and to daridorexant 10 mg, 25 mg, or placebo in Trial-2 (n = 924).2

All told, daridorexant dose-dependently increased TST (in minutes) from baseline to month 3, more than placebo, in Trial-1 (25 mg: 55 [±56]; 50 mg: 61 [±53]; placebo: 40 [±56]) and in Trial-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.

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 Trial-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 Trial-2.

The second posted included data on 25 individuals (n =15 with mild/moderate OSA; mean apnea-hypopnea index [AHI]: 16.3 events/h [standard deviation, 8.2]). Compared to those on placebo, daridorexant prolonged mean TST by 38.8 minutes (90% CI, 19.7-57.9), shortened mean latency to persistent sleep (LPS) by 17.2 minutes (90% CI, –35.5 to 1.02), and reduced mean wake after sleep onset (WASO) by 31.0 minutes (90% CI, –47.3 to 14.7). Sleep duration was prolonged in the second part of the night, with the mean and longest duration of awakenings decreasing by a mean of 2.0 minutes (90% CI, –3.1 to 0.9) and 16.3 minutes (90% CI, –24.1 to –8.6), respectively, without treatment difference for the total number of awakenings.3

Finally, the findings presented in the third poster, which also utilized data from Trial-1 and Trial-2, suggested that there was no increase in mean Benzodiazepine Withdrawal Symptom Questionnaire (BSWQ) scores from last assessment to the end of placebo run out in Trial-1 (25 mg: –0.6 [±2.3]; 50 mg: –0.6 [±2.3]; placebo: –0.7 [±2.3]) or in Trial-2 (10 mg: –0.5 [±2.6]; 25 mg: –0.4 [±1.9]; placebo: –0.4 [±1.4]), nor did any patients report a BWSQ score of greater than 20 at the end of the run-out period. Additionally, no adverse events suggestive of withdrawal symptoms were reported.4

The mean WASO and LPS values (in minutes) decreased from baseline to placebo run-out in both Trial-1 (WASO 25 mg: –8.6 [±55.5]; WASO 50 mg: –2.5 [±52.4]; WASO placebo: –20.4 [±45.8]; LPS 25 mg: –17.2 [±56.7]; LPS 50 mg: –15.0 [±55.8]; LPS placebo: –27.8 [±47.2]) and in Trial-2 (WASO 10 mg: –11.6 [±58.3]; WASO 25 mg: –5.1 [±57.9]; WASO placebo: –26.2 [±53.5]; LPS 10 mg: –17.3 [±67.2]; LPS 25 mg: –10.3 [±67.3]; LPS placebo: –18.3 [±63.8]). However, subjective TST values increased in both trials, indicating an absence of rebound effects.

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REFERENCES
1. Idorsia to present new Phase 3 data on daridorexant in insomnia at SLEEP 2021. News release. Idorsia. June 9, 2021. Accessed June 18, 2021. https://www.globenewswire.com/news-release/2021/06/09/2244070/0/en/Idorsia-to-present-new-Phase-3-data-on-daridorexant-in-insomnia-at-SLEEP-2021.html
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.
3. Boof ML, Fietze I, Lederer K, Fuern AS, Lemoine V, Ufer M, Dingmanse J. Daridorexant improves sleep in patients with mild/Moderate obstructive sleep apnea. Presented at SLEEP 2021 Annual Meeting; June 10-13. Abstract 358.
4. Leger D, Fietze I, Pain S, Kinter DS, Flamion B, Mignot E. Absence of withdrawal symptoms and rebound insomnia upon discontinuation of daridorexant in patients with insomnia. Presented at SLEEP 2021 Annual Meeting; June 10-13. Abstract 348.
5. FDA Accepts the new drug application for review of Idorsia’s daridorexant for the treatment of adult patients with insomnia. News release. Idorsia. March 10, 2021. Accessed June 18, 2021. http://www.globenewswire.com/news-release/2021/03/10/2190042/0/en/FDA-accepts-the-new-drug-application-for-review-of-Idorsia-s-daridorexant-for-the-treatment-of-adult-patients-with-insomnia.html