0460 Efficacy and Safety of Daridorexant in Individuals with Insomnia with Short Sleep Duration and Normal Sleep Duration

Abstract Introduction Insomnia with objective short sleep duration has been identified as a distinctive phenotype notable for increased physiological hyperarousal and cardiometabolic risk. This phenotype has been associated with a suboptimal response to cognitive-behavioral therapy for insomnia (CBTi) in preliminary studies and has been proposed to respond better to pharmacotherapy. Daridorexant, a dual-orexin receptor antagonist, has demonstrated efficacy and safety in pivotal trials (NCT03545191) of individuals with insomnia disorder. This post-hoc analysis from the 301 study examined efficacy and safety of daridorexant in individuals who demonstrated less than 6 hours of objective total sleep time (TST) on baseline polysomnogram (PSG) recording. Methods 930 participants with insomnia disorder received daridorexant 25 mg, 50 mg, or placebo for 3 months in a randomized, placebo-controlled, parallel-group clinical trial with polysomnography. Individuals underwent 2 consecutive nights of PSG at baseline, end of Month 1 and end of Month 3. Efficacy endpoints included changes from baseline in PSG -measured wake after sleep onset (WASO), latency to persistent sleep (LPS) and TST, as well as self-reported Insomnia Severity Index (ISI) and Insomnia Daytime Symptoms and Impact Questionnaire (IDSIQ). Results 688 (74%) subjects demonstrated an average PSG-measured TST lower than 360 minutes at baseline [i.e., Insomnia with Short Sleep Duration (ISSD)]. Mean age was 56.9 years (SD=15.1) and 65% were female. Daridorexant significantly improved WASO [Month 3 difference to placebo, LSM mean of -12.50 (3.52) for daridorexant 25 mg, p 0.0004 and -18.11 (3.59) for daridorexant 50 mg, p< 0.0001] and LPS [-7.70 (2.92), p 0.008 and -11.95 (2.98), p< 0.0001 for 25 and 50 mg, respectively]. At month 3, daridorexant 50 mg - not 25 mg - significantly improved all the domains and the total score of IDSIQ [total score, LSM -7.67 (2.03), p 0.0002]. Similarly, only daridorexant 50 mg significantly improved ISI over 3 months. No significant treatment-related adverse events associated with use of daridorexant were seen. Conclusion Individuals with ISSD benefited from 3 months of continuous treatment with daridorexant 50 mg, both objectively and subjectively. The findings highlight the efficacy and safety of daridorexant for this complex group of insomnia patients. Support (if any) Idorsia Pharmaceuticals