Pooled Phase 3 Data Suggests 50 mg Daridorexant as Most Effective Starting Dose in Insomnia

William McCall, MD

In a new pooled analysis of trials assessing daridorexant (Quviviq; Idorsia), results revealed a favorable benefit-risk profile for both the 25 mg and 50 mg doses; however, greater efficacy and safety was observed in the 50 mg group. Overall, these data support the use of daridorexant 50 mg as the starting dose in patients with insomnia.¹

Presented at the 2024 SLEEP Annual Meeting, held June 1-5, in Houston, Texas, the analysis featured 2153 patients randomized to placebo (n = 678), daridorexant 5 mg (n = 60), 10 mg (n = 365), 25 mg (n = 679), and 50 mg (n = 371) who were included in a phase 2 study and 2 phase 3 studies (NCT03545191; NCT03575104). The 2 phase 3 trials, otherwise known as study 1 and study 2, were randomized, double-blind, parallel-group studies that served as supportive data for the therapy’s approval in January 2022.

Led by William McCall, MD, chairman of psychiatry and health behavior at the Medical College of Georgia, dose-response analyses at 1 month of double-blind treatment were performed using 2 statistical approaches: a linear regression approach based on individual patient data and a 2-stage meta-analysis approach based on aggregated data. The analysis end points such as polysomnography–determined wake after sleep onset (WASO) and latency to persistent sleep (LPS), self-reported total sleep time (TST), and the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) total score.

Daridorexant, a dual orexin receptor antagonist, is designed to block the binding of the wake-promoting neuropeptides orexins, addressing overreactive wakefulness. Using both statistical approaches, investigators observed a significant dose-response across all doses at month 1 for all 4 efficacy end points (P <.01). All dose-response relationships were linear except for LPS, which showed a change in slope after daridorexant 10 mg, without reaching a plateau.

During the first month of treatment with the agent, results showed no significant dose-response relationship for adverse events (AEs), which was consistent across methods (P >.05). AEs corresponding to somnolence/fatigue were low at all doses and relaxing the linear assumption (2-stage meta-analysis) showed no evidence of dose-dependency (P = .369).

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Daridorexant, which carries a controlled substance label, was approved by the FDA based on clinical program data that included 1854 adults across 160 clinical trial sites. Both phase 3 studies used change from baseline from month 1 to month 3 in LPS and 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 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.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 extension of the pivotal phase 3 studies, presented at the 2022 World Sleep Congress, included 804 adults (18-64 years) and elderly (≥65 years) patients with insomnia who were followed for 40 weeks, with an additional 7-day placebo run-out. Patients originally randomized to daridorexant (10 mg: n = 142; 25 mg: n = 270; 50 mg: n = 137) stayed on their respective treatments, while those randomized to placebo were re-randomized to daridorexant 25 mg (n = 127) or placebo (n = 128).³

Improvements on subjective TST and daytime functioning, assessed using Insomnia IDSIQ, were observed at 3 months and sustained until the 12-month time point. The most pronounced improvements were observed in the 50-mg group, represented by mean increases of 67.7 (SD, 68.65), 68.9 (SD, 65.89), and 75.6 (SD, 69.90) minutes in sTST from baseline to months 6, 9, and 12, respectively. For the 25 mg group, these patients saw mean improvements of 58.06 (SD, 58.61), 65.1 (SD, 58.75), and 66 (61.09) minutes, at the 6-, 9-, and 12-month periods, respectively, compared with improvements of 50.3 (SD, 65.73), 59.0 (SD, 62.62), and 62.6 (SD. 72.42) minutes in the placebo group.

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REFERENCES
1. McCall W, Bassetti C, Braunstein G, et al. Dose-response of Daridorexant in Insomnia Disorder: A Meta-analysis of Phase 2 and 3 Studies. Presented at: 2024 SLEEP Annual Meeting; June 1-5; Houston, TX. ABSTRACT 0414.
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. Kunz D, Benes H, Garcia-Borreguero D, et al. Long-term safety and efficacy of daridorexant in patients with insomnia disorder. Presented at SLEEP 2022; March 11-16. Abstract 2145