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

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Abstract

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.

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Acknowledgements

The authors thank Dr. Jiří Liška and Dr. Luboš Janů (CEPHA s.r.o., Pilsen, Czech Republic) for the clinical conduct of the study, Dr. Susanne Globig and Giancarlo Sabattini (Department of Preclinical Pharmacokinetics and Metabolism, Idorsia Pharmaceuticals Ltd) for the bioanalytical analysis, Dr. Eric Ertel (Department of Pharmacology, Cardiovascular and Pulmonary, Idorsia Pharmaceuticals Ltd) for the preclinical studies, Biotrial (Rennes, France) for the Holter ECG extraction and reading, Kristyna Horakova and Kateřina Mertlíková (Aixial s.r.o., Brno, Czech Republic) for study monitoring, and Martin Wojcik (Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd) for study project management.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland

    Uta Schilling, Andrea Henrich, Clemens Muehlan, Andreas Krause, Jasper Dingemanse & Mike Ufer

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  1. Uta Schilling
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  2. Andrea Henrich
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  3. Clemens Muehlan
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  4. Andreas Krause
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  5. Jasper Dingemanse
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  6. Mike Ufer
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Corresponding author

Correspondence to Jasper Dingemanse.

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Funding

This study was sponsored by Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.

Conflict of interest

All authors were employees and/or shareholders of Idorsia Pharmaceuticals Ltd at the time the research was performed. Daridorexant is currently in clinical development by Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.

Availability of data and material

This study was registered on clinicaltrials.gov (NCT04250506). Data are available upon request from the corresponding author.

Ethics approval

The study protocol was approved by the Czech health authority (SUKL) as well as an Independent Ethics Committee (Ethics Committee of CEPHA s.r.o., Pilsen, Czech Republic). It was conducted in full accordance with the principles of the Declaration of Helsinki and ICH good clinical practice guidelines.

Consent to participate

Each study subject provided written informed consent prior to any treatment and study-related assessment.

Author contributions

US, CM, JD, and MU designed the study. AH and AK performed the concentration-QT modeling. US analyzed the data and drafted the manuscript. All authors reviewed the manuscript and approved its submission.

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Not applicable.

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Schilling, U., Henrich, A., Muehlan, C. et al. Impact of Daridorexant, a Dual Orexin Receptor Antagonist, on Cardiac Repolarization Following Bedtime Dosing: Results from a Thorough QT Study Using Concentration-QT Analysis. Clin Drug Investig 41, 711–721 (2021). https://doi.org/10.1007/s40261-021-01062-1

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