Impact of Daridorexant, a Dual Orexin Receptor Antagonist, on Cardiac Repolarization Following Bedtime Dosing: Results from a Thorough QT Study Using Concentration-QT Analysis.

BACKGROUND AND

OBJECTIVE

Daridorexant is a new dual orexin receptor antagonist currently in late-stage clinical development for the treatment of insomnia. This randomized, double-blind, placebo-controlled, four-period crossover study investigated the effect of daridorexant at a therapeutic and supratherapeutic dose on QT interval duration.

METHODS

Thirty-six healthy subjects received single oral doses of daridorexant (50 mg; 200 mg), moxifloxacin (400 mg; open label), and placebo. All treatments were administered at bedtime to mimic therapeutic practice. The primary analysis was based on linear mixed-effects concentration-QT modelling. Triplicate ECG data were extracted from Holter recordings at baseline and until 24 h post dosing at time points matching those for pharmacokinetic sampling. Plasma concentrations of daridorexant were determined over 24 h.

RESULTS

Assay sensitivity was demonstrated based on mean baseline- and placebo-corrected QT interval using Fridericia's formula (ΔΔQTcF) > 5 ms following moxifloxacin administration (p < 0.01). Following daridorexant administration, mean (90% confidence interval, CI) ΔΔQTcF was 1.40 ms (0.48; 2.32 ms) and 1.84 ms (-0.12; 3.79 ms) at the Cmax of 747 ng/mL (50 mg dose) and 1809 ng/mL (200 mg dose), respectively, i.e., the upper bounds of the CIs were < 10 ms defined as threshold of regulatory concern. Lack of relevant QT prolongation was confirmed by secondary by-time point analysis and absence of relevant findings in the categorical outlier analysis. Daridorexant was safe and well tolerated and its pharmacokinetics were consistent with previous data.

CONCLUSION

Daridorexant does not impair cardiac repolarization evidenced by absence of relevant QT prolongation at therapeutic and supratherapeutic doses. Clinical Trials Registration ID: NCT04250506.