Novel Synthetic Drugs in Migraine (Headache)

Published in the series Headache, endorsed by the European Headache Federation, this is the first book on the novel synthetic treatment of migraine with ditans (lasmiditan) and gepants (atogepant, ubrogepant, rimegepant, vazegepant). These drugs will provide additional options for people with migraine put at risk of side effects by other medications or with unsatisfactory response to previous drugs. There is now a sufficient amount of literature published to interest a wide multidisciplinary readership (general physicians, general neurologists, clinical psychologists, neurologists in training, and medical students) facing every day this burdensome disorder in their clinical practice. The book aims therefore at offering an overview of these new drugs for both acute and prophylactic treatments of migraine, covering studies on clinical evidence, tolerability, and the different stages of clinical development. Foreword 6 Preface 7 Contents 9 Chapter 1: Novel Pharmacological Targets of Migraine: An Overview 10 1.1 Introduction 10 1.2 Novel Pharmacological Treatments for Migraine 11 1.3 Acute Treatment for Migraine Beyond Ergots and Triptans 13 1.3.1 5-HT1F Agonists: Ditans 13 1.3.2 CGRP Receptor Antagonists: Gepants 15 1.4 Gepants as Prophylactic Treatment for Migraine 17 1.5 Mechanisms of Action of Ditans and Gepants: Is It a Common Pathway? 17 1.6 Conclusion 19 References 20 Chapter 2: Molecular and Cellular Mechanisms of CGRP Antagonists 27 2.1 Introduction 27 2.1.1 Trigeminovascular System 28 2.2 Neuropeptide Signaling 28 2.2.1 CGRP 28 2.2.2 Amylin 29 2.2.3 Neuropeptide Receptors 29 2.2.4 Downstream Activation 30 2.3 The Blood–Brain Barrier 30 2.4 CGRP Antagonists 31 2.5 Molecular Targets 31 2.6 Cellular Targets 32 2.6.1 Vascular Targets 32 2.6.2 Trigeminal Targets 33 2.6.2.1 Satellite Glial Cells 33 2.6.2.2 Neuronal Targets 33 2.6.2.3 Potential Antagonistic Effect at the Nodes of Ranvier 33 2.7 Non-migraine Targets 34 2.8 Conclusion 35 References 35 Chapter 3: Atogepant 40 3.1 Introduction 40 3.2 Chemical Characteristics, Pharmacodynamics and Pharmacokinetics 41 3.3 Atogepant in Preclinical Studies 42 3.4 Efficacy of Atogepant in Phase II and Phase III Clinical Trials 42 3.5 Safety and Adverse Events 44 3.6 Future Developments 47 3.7 Conclusions 48 References 48 Chapter 4: Ubrogepant 50 4.1 Introduction 50 4.2 Pharmacology 51 4.2.1 Chemistry 51 4.2.2 Pharmacodynamics 51 4.2.3 Pharmacokinetics and Metabolism 51 4.3 Clinical Registered Trials 52 4.3.1 Phase I Trials 52 4.3.2 Phase II Trials 52 4.3.3 Phase III Trials: ACHIEVE I and II and Their Extension Study 53 4.3.4 Post-marketing Studies 54 4.4 Safety and Tolerability 54 4.5 Regulatory Affairs and Clinical Approval 55 4.6 Conclusions 56 References 56 Chapter 5: Rimegepant 58 5.1 Introduction 58 5.2 Introduction to the Compound 59 5.2.1 Chemistry 59 5.2.2 Pharmacodynamics 60 5.2.3 Pharmacokinetics and Metabolism 60 5.2.4 Metabolism 61 5.2.5 Drug Interactions 61 5.3 Clinical Efficacy 62 5.3.1 Phase II Studies 62 5.3.2 Phase III Studies 62 5.4 Safety and Tolerability 68 5.4.1 Phase I Studies 68 5.4.2 Phase II Studies 68 5.4.3 Phase III Studies 70 5.5 Exclusion Criteria 71 5.6 Conclusions 71 References 72 Chapter 6: Zavegepant 74 6.1 Introduction 74 6.2 Preclinical Pharmacology 76 6.3 Clinical Trials 77 6.3.1 Safety and Tolerability 77 6.3.2 Efficacy 77 6.4 Conclusion 78 References 79 Chapter 7: Molecular Mechanisms of 5-HT1F Receptor Agonists 80 7.1 Serotonin (5-HT) and 5-HT Receptors 80 7.2 5-HT1B/D and 5-HT1F Receptors and Migraine Treatment 81 References 85 Chapter 8: Lasmiditan 89 8.1 Introduction 89 8.2 Pharmacological Profile 91 8.3 Preclinical Studies 92 8.4 Clinical Studies 93 8.5 Safety 95 8.6 Drug Interactions 97 8.7 Conclusion 97 References 98 Chapter 9: Update on Old and Current Targets for Antimigraine Therapies 102 9.1 Introduction 102 9.2 Current Drugs for Acute Migraine 103 9.2.1 NSAIDs and Other Analgesics 103 9.2.2 5-Hydroxytryptamine Receptors in Migraine 104 9.2.3 Neurokinin Receptors and Blockers 105 9.2.4 Gepants 106 9.3 Targets for Prophylaxis of Migraine 106 9.3.1 Beta-Adrenoceptor Blockers 106 9.3.2 Angiotensin II AT1 Receptor Antagonists 107 9.3.3 Anticonvulsant Drugs 107 9.3.4 Tricyclic Antidepressant 108 9.3.5 Calcium Channel Antagonists 108 9.3.6 Onabotulinum Toxin A 109 9.4 Conclusion 110 References 110