Idorsia Ltd reports positive results from the first pivotal Phase 3 study (evaluating 25 mg and 50 mg doses) of its investigational dual orexin receptor antagonist, daridorexant, in adult and elderly patients with insomnia. Results were presented by Thomas Roth, PhD, at Virtual SLEEP 2020. The study demonstrated efficacy of treatment with daridorexant on objective and subjective sleep parameters, and daytime functioning, with no next-morning residual effect.
The presentation, entitled “Efficacy and safety of daridorexant in adult and elderly patients with insomnia,” is available for on-demand replay for registered participants through August 1, 2021.
Roth, director of the Sleep Disorder and Research Center at Henry Ford Hospital, says in a release, “Daridorexant, a new dual orexin receptor antagonist, has a pharmacokinetic and pharmacodynamic profile optimized for sleep onset and duration of action to improve night-time efficacy, without residual effects. These pharmacological properties led us to hypothesize that daridorexant could also improve the impaired daytime functioning frequently observed in insomnia. A new patient-reported outcome instrument was developed— and validated according to FDA requirements—to specifically assess daytime functioning in patients with insomnia and we included it in the Phase 3 program. The results have been outstanding.”
The Phase 3 trial was designed to measure the impact of daridorexant on objective and subjective sleep parameters as well as on daytime functioning, and to evaluate safety, in patients with moderate to severe insomnia. Sleep variables were assessed using polysomnography for wake after sleep onset (WASO) and latency to persistent sleep (LPS). A sleep diary questionnaire was used to measure subjective total sleep time (sTST). Daytime functioning was assessed using a newly developed and validated patient-reported outcome instrument, the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). The IDSIQ comprises 14 items grouped into three domains that reflect daytime effects of insomnia that are commonly encountered in clinical practice: alert/cognition, mood, and sleepiness/tiredness.
Daridorexant significantly improved sleep maintenance as measured by a larger decrease in WASO from baseline compared to placebo. The mean change from baseline in WASO (minutes) for placebo, 25 mg and 50 mg was -6.2, -18.4, and -29.0 at 1 month and -11.1, -23.0 and -29.4 at 3 Months, respectively (all p values vs. placebo <0.0001).
Daridorexant significantly improved sleep onset as measured by a larger decrease in LPS from baseline compared to placebo. The mean change from baseline in LPS (minutes) for placebo, 25 mg and 50 mg was -19.9, -28.2 (p=0.0005) and -31.2 (p<0.0001) at 1 month and, -23.1, -30.7 (p=0.0015) and -34.8 (p<0.0001) at 3 months, respectively (p-values vs placebo).
Subjective total sleep time assessed daily by patients increased more with daridorexant from baseline compared to placebo. The mean change from baseline in sTST (minutes) for placebo, 25mg and 50mg was 21.6, 34.2 (p=0.0013), and 43.6 (p<0.0001) at 1 month, and 37.9, 47.8 (p=0.0334), 57.7 (p<0.0001) at 3 months, respectively (p-values vs placebo).
Daridorexant improved daytime functioning, as measured in a secondary efficacy endpoint by the sleepiness/tiredness domain of the IDSIQ. For this domain, the improved daytime functioning was demonstrated by a mean score reduction from baseline for placebo, 25mg and 50mg of -2.0, -2.8 (p=0.0547) and -3.8 (p<0.0001) at 1 Month, and of -3.8, -4.8 (p=0.0534) and -5.7 (p=0.0002) at 3 months, respectively (p-values vs placebo). In addition, other efficacy endpoints from the IDSIQ patient-reported outcome instrument, namely the alert/cognition domain, mood domain, and the total IDSIQ scores, consistently showed a dose-dependent improvement, as presented.
The most frequent adverse events, nasopharyngitis and headache, were balanced between arms. Somnolence was reported in 6 (1.9%) patients on placebo, 11 (3.5%) patients on daridorexant 25mg, and 5 (1.6%) of patients on daridorexant 50mg.
The late breaking abstract (LBA 4) is available in the Virtual Sleep 2020 meeting guide.
Roth says, “As hypothesized, the optimized profile of daridorexant not only translated in this study into a dose-dependent improvement on objective and subjective sleep parameters, but also into improved daytime functioning, all of which was sustained over time. Very importantly, safety was comparable with daridorexant 25 mg and 50 mg, with no dose-limiting safety findings, no observed next-morning sleepiness compared to placebo, no signals suggestive of rebound insomnia compared to baseline sleep parameters, and no withdrawal effects. With these results daridorexant addresses important needs of patients with insomnia.”