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Abstract Introduction Daridorexant is a dual orexin receptor antagonist approved for the treatment of insomnia disorder at two dose levels (25 and 50 mg). Dose-efficacy and -safety response relationships were evaluated using data from Phase 2 and 3 studies. Methods Data from one Phase 2 study evaluating daridorexant 5 mg, 10 mg, 25 mg, 50 mg and placebo for 1 month, and two Phase 3 studies investigating daridorexant 10 mg and 25 mg or 25 mg and 50 mg vs placebo for 3 months were used. Dose-response analyses at 1 month of double-blind treatment were performed using two statistical approaches: a linear regression approach based on individual patient data and a two-stage meta-analysis approach based on aggregated data. Efficacy endpoints were polysomnography-determined wake after sleep onset (WASO) and latency to persistent sleep (LPS), self-reported total sleep time and the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) total score (Phase 3 only for the latter endpoint). Safety endpoints were the percentage of patients with at least one adverse event (AE) and at least one AE corresponding to somnolence/fatigue during the first month of the double-blind study periods. Results Pooled efficacy analyses included 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). The dose-response was significant for both statistical approaches in the observed range of 0 to 50 mg at Month 1 for all four efficacy endpoints (p 0.01). All dose-response relationships were linear except for LPS (two-stage meta-analysis) which showed a change in slope after daridorexant 10 mg, without reaching a plateau. No significant dose-response relationship was observed for any AEs during the first month; results were consistent across methods (p0.05). AEs corresponding to somnolence/fatigue were low at all doses and relaxing the linear assumption (two-stage meta-analysis) showed no evidence of dose-dependency (p=0.369). Conclusion The data support a favorable benefit-risk balance for daridorexant 25 mg and 50 mg at 1 month of treatment. The greater efficacy and similar safety at 50 vs 25 mg support the use of daridorexant 50 mg as a starting dose in patients with insomnia disorder. Support (if any) Idorsia Pharmaceuticals Ltd
McCall et al. (Sat,) studied this question.