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Clinical Pharmacology of Daridorexant, a Novel Dual Orexin Receptor Antagonist

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Clinical Pharmacology of Daridorexant, a Novel Dual Orexin Receptor Antagonist Clinical pharmacology of daridorexant, a novel dual orexin receptor antagonist Inauguraldissertation zur Erlangung der Würde eines Dr. sc. med. Vorgelegt der Medizinischen Fakultät der Universität Basel Von Clemens Mühlan aus 4055 Basel, Schweiz Basel, 2021 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Genehmigt von der Medizinischen Fakultät auf Antrag von Prof. Dr. Stephan Krähenbühl Prof. Dr. Matthias Liechti Dr. Alexander Jetter Dr. Jasper Dingemanse Basel, 24. Februar 2021 Dekan Prof. Dr. Primo Leo Schär 2 of 118 TABLE OF CONTENTS LIST OF ABBREVIATIONS AND ACRONYMS ............................................................4 ACKNOWLEDGEMENTS .................................................................................................8 SUMMARY .........................................................................................................................9 1 BACKGROUND AND INTRODUCTION ................................................................15 1.1 Insomnia .......................................................................................................15 1.2 The orexin system as a therapeutic target .....................................................18 1.3 Review of orexin receptor antagonists .........................................................20 1.4 Selective vs dual orexin receptor antagonism ..............................................23 1.5 Orexin receptor antagonists available in clinical practice ............................24 1.6 Orexin receptor antagonists in clinical development ...................................33 1.7 Concluding remarks ......................................................................................38 1.8 References ....................................................................................................39 2 AIMS OF THE PROJECT ..........................................................................................49 3 RESULTS ....................................................................................................................51 3.1 Single-dose clinical pharmacology of daridorexant .....................................52 3.2 Multiple-dose clinical pharmacology of daridorexant ..................................61 3.3 Clinical pharmacology of daridorexant in the elderly ..................................73 3.4 Metabolism of daridorexant in humans ........................................................84 3.5 Clinical pharmacology of daridorexant in Japanese vs Caucasian subjects .........................................................................................................98 4 DISCUSSION AND CONCLUSIONS .....................................................................108 4.1 References ..................................................................................................113 5 CURRICULUM VITAE ...........................................................................................116 3 of 118 LIST OF ABBREVIATIONS AND ACRONYMS 14C Carbon 14 (radiocarbon) AA Amino acid AD Alzheimer’s disease ADME Absorption, distribution, metabolism, excretion AE Adverse event AI Accumulation index AIF All ion fragmentation AMS Accelerator mass spectrometry/meter AUC Area under the plasma concentration-time curve AUC0-inf or 0-∞ AUC from zero to infinity AUC0-24 AUC from zero to 24 h BMI Body mass index BCRP Breast cancer resistance protein CBT Cognitive behavioral therapy CHDR Centre for Human Drug Research CI Confidence interval CL Total body clearance Cmax Maximum plasma concentration CNS Central nervous system COPD Chronic obstructive pulmonary disease CV Coefficient of variation CVb Coefficient of inter-subject variation CYP(3A4) Cytochrome P450 (isoenzyme 3A4) DDI Drug-drug interaction DORA Dual orexin receptor antagonist dpm Disintegrations per minute DR Dorsal raphe nucleus DSM-5 Diagnostic and Statistical Manual of Mental Disorders DSST Digit Symbol Substitution Test ECG Electrocardiogram/graphy 4 of 118 EP Extended plasma regions EOS End-of-Study EU European Union F Absolute bioavailability (US) FDA (United States) Food and Drug Administration FIH First in human GABA(A) Gamma-amino butyric acid (type A) GPCR G protein-coupled receptors HPLC High performance liquid chromatography ICU Intensive care unit IDSIQ Insomnia Daytime Symptoms Impacts Questionnaire ISWRD Irregular sleep-wake rhythm disorder i.v. Intravenously KSS Karolinska Sleepiness Scale λz First order rate constant associated with the terminal log-linear portion of the plasma concentration-time curve LC Liquid chromatography LDT/PPT Laterodorsal/pedunculopontine tegmental nucleus LHA Lateral hypothalamic areas LLOQ Lower limit of quantification LOQ Limit of quantification LPS Latency to persistent sleep LSM Least square means MAD Multiple ascending dose MIST Metabolites in safety testing MS Mass spectrometry mSNS Modified Swiss Narcolepsy Scale nCi Nanocurie NIH National Institutes of Health n.k. Not known NREM Non-rapid eye movement 5 of 118 ORA Orexin receptor antagonist OSA Obstructive sleep apnea OxA Orexin A OxB Orexin B OX1R Orexin receptor Type-1 OX2R Orexin receptor Type-2 PD Pharmacodynamic(s) P-gp P-glycoprotein PK Pharmacokinetic(s) PRO Patient reported outcome PSG Polysomnography REM Rapid eye movement SAD Single ascending dose SD Standard deviation SDLP Standard deviation of the lateral position SE Sleep efficiency sLSO Subjective latency to sleep onset SOL Sleep onset latency SPV Saccadic peak velocity SRTT Simple Reaction Time Test sSE Subjective sleep efficiency sTST Subjective total sleep time sWASO Subjective wake after sleep onset t½ Terminal half-life tmax Time to reach maximum plasma concentration TMN Tuberomammillary nucleus TST Total sleep time Vss Volume of distribution at steady-state VAS Visual analog scale VTA Ventral tegmental area WASO Wake after sleep onset 6 of 118 WASO-6 Wake after sleep onset over the first 6 h WHO World Health Organization 7 of 118 ACKNOWLEDGEMENTS First and foremost, I would like to thank my PhD committee, Prof. Stephan Krähenbühl, Prof. Matthias Liechti, Dr. Alexander Jetter, and Dr. Jasper Dingemanse for giving me the opportunity to pursue a PhD at the University of Basel while being based at a biopharmaceutical company (Idorsia Pharmaceuticals Ltd), thereby, combining PhD studies with industry experience. In that context I want to specifically mention my primary adviser at the University of Basel, Prof. Krähenbühl, and my supervisor at work, Dr. Dingemanse. It was Dr. Dingemanse who planted the idea in my head of pursuing a PhD and he also put me in contact with Prof. Krähenbühl. I am grateful to both for their immense trust in my abilities, which motivated me to complete the studies and to write the papers, even during difficult times. I highly appreciated the many interesting scientific discussions, their immense knowledge, and their open-door policy which always allowed spontaneous questions and feedback. I want to express my sincerest gratitude to Dr. Dingemanse for spending countless hours reviewing my work and providing critical feedback. I also wish to thank all my colleagues at the department of Clinical Pharmacology at Idorsia for all the fruitful discussions and the moral support. Furthermore, I would like to thank my family and friends for their patience and understanding regarding my limited time over the last years. Special thanks to Katie Cheadle for proofreading and help with formatting. My deepest appreciation goes to my partner in life, Dr. Souphalone Luangsay, and her daughter Elisabeth. Thank you for always being with me. Basel, February 2021 Clemens Mühlan 8 of 118 SUMMARY Epidemiological studies suggest that sleep problems are highly prevalent in the general population. Symptoms such as prolonged time to fall asleep, sleep disruption, and early morning awakenings associated with daytime functional impairment are consistent with the diagnosis of insomnia disorder. According to current guidelines, psychological and pharmacological therapies are recommended in order to reduce the time to fall asleep and the time spent awake after sleep onset, with subsequent improvements in daytime functioning. Under- or untreated insomnia can lead to severe physical and psychological consequences, such as impairment in cognitive functioning, daytime fatigue, increased accident risk, and increased utilization of medical care. In addition, many studies have shown an association between insomnia and psychiatric disorders, specifically depression and anxiety. Current treatment of insomnia includes sleep hygiene measures and other non- pharmacological therapies, and (short-term)pharmacotherapy. With regards to pharmacotherapy, prescription sleep drugs are associated with unwanted side effects such as morning or next-day hangover, cognitive and motor impairment, and dependence. Thus, novel pharmacological treatment options without these drawbacks are an important step forward, and in particular a long-term option that addresses the most pressing symptoms without negatively impacting next-day functioning is needed. Since accumulating evidence is pointing to the pivotal role of the orexin system in the regulation of wakefulness and arousal, drugs interacting with the orexin system could potentially be part of improved treatment options of insomnia. This thesis discusses the pharmacological characterization of daridorexant (ACT-541468) as evaluated during the early clinical development program. Chapter 1 provides a general introduction to the field
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