Abuse potential assessment of the new dual orexin receptor antagonist daridorexant in recreational sedative drug users as compared to suvorexant and zolpidem

Abstract

Study Objectives: Abuse potential properties have been reported for the dual orexin receptor antagonists (DORAs) suvorexant and lemborexant. Daridorexant is a new DORA currently in late-stage clinical development. This randomized, double-blind, double-dummy, placebo- and active-controlled six-period crossover study assessed its abuse potential in healthy recreational sedative drug users (n = 63). Methods: In each study period, a single, oral, morning dose of either daridorexant (50, 100, and 150 mg), placebo, or active control, i.e. suvorexant (150 mg) or zolpidem (30 mg), was administered. Primary pharmacodynamic (PD) endpoint was the Emax of the drug-liking visual analog scale (VAS) assessed over 24 h. Several secondary subjective and objective PD endpoints were also assessed. Results: Study validity was confirmed based on drug-liking of suvorexant and zolpidem greater than placebo applying a predefined 15-point validity margin (p < 0.0001). Drug-liking VAS Emax (mean; 95% confidence interval) of daridorexant at 50 mg (73.2; 69.0-77.5) was significantly lower compared to suvorexant (80.7; 77.0-84.5) and zolpidem (79.9; 76.2-83.5) (p < 0.001), but similar at 100 mg (79.1; 75.0-83.3) and 150 mg (81.3; 77.7, 84.8). Such dose-related patterns were also observed for most secondary endpoints. At each daridorexant dose, Drug-liking VAS scores were greater than placebo. Both control drugs and daridorexant were safe and the pharmacokinetics of daridorexant was consistent with earlier trials indicating quick absorption and elimination. Conclusions: In this large, valid human abuse potential study, daridorexant showed dose-related drug-liking among recreational sedative drug users with lower effects at the highest phase-3 dose, and similar effects at higher doses compared to supratherapeutic doses of suvorexant and zolpidem. Statement of Significance The high prevalence of insomnia and shortcomings of existing therapies highlight a major unmet need for safe, effective, and well-tolerated pharmacological treatments of insomnia. Daridorexant is a new dual orexin receptor antagonist (DORA) with profound, dose-dependent sleep-promoting effects and lack of nextmorning residual effects in adult and elderly insomnia patients. This large, valid human abuse potential study indicates lower abuse potential of daridorexant at the highest phase-3 dose, and similar effects at higher doses compared to supratherapeutic doses of the control drugs suvorexant and zolpidem in recreational sedative drug users. These results together with other preclinical and clinical data regarding abuse and dependence potential are relevant for regulatory decision-making and cross-study comparisons with other DORAs including suvorexant and lemborexant.