Calcitonin gene-related peptide-targeting drugs for migraine: how pharmacology might inform treatment decisions

Abstract

Migraine is the second most disabling disorder across all age groups worldwide. Since 2018, two classes of drugs that inhibit the actions of calcitonin gene-related peptide (CGRP), which is implicated in migraine pathophysiology, have become available: gepants (CGRP receptor antagonists) and monoclonal antibodies directed against CGRP or its receptor. Despite phase 3 clinical trials and some real world evidence, knowledge of the pharmacology and related clinical effects of these drugs is low, and trial data are not necessarily generalisable to all populations. Additionally, several pharmacodynamic processes affected by both gepants and monoclonal antibodies to CGRP and its receptor are not fully understood. Sex, body-mass index, age, ethnic background, and other characteristics, which are subject to considerable variation, might affect the pharmacokinetics of these therapies, especially gepants. If studies confirm this possibility, these characteristics could assist clinicians in choosing the optimal treatment for patients with migraine. The choice between a gepant or monoclonal antibody should be made carefully, taking into consideration a patient's comorbidities and preferences. As more becomes known about CGRP-targeted therapies, management based on the characteristics of patients could have a more prominent role in the treatment of migraine.

Conflict of interest statement

Declaration of interests PJG reports, over the past 36 months, personal fees for consulting from AEON BioPharma, Alder Biopharmaceuticals, Allergan, Biohaven Pharmaceuticals, Clexio Biosciences, Dr Reddy's Laboratories, eNeura, Epalex, GlaxoSmithKline, Impel NeuroPharma, Lundbeck, Novartis, Pfizer, Praxis, Santara Therapeutics Biotechnology, Sanofi, Satsuma, and Teva Pharmaceuticals. PJG also reports stock options (no commercial product) and consulting from Trigemina, research grants and personal fees for consulting from Amgen, Eli Lilly and Company, consulting (without fee) for Electrocore LLC, and a research grant from Celgene. In addition, PJG declares a patent magnetic stimulation for headache (No. WO2016090333 A1, issued and licensed) assigned to eNeura without fee and fees for advice through Gerson Lehrman Group and Guidepoint; fees for educational materials from Medery, Medlink, Prime-Ed, UptoDate, and WebMD; and fees for publishing royalties from Oxford University Press, Massachusetts Medical Society, and Wolters Kluwer, and for medicolegal advice in headache. AMVDB has received research grants and consultation fees from Amgen/Novartis, Eli Lilly, Allergan, Teva, and ATI, and reports funding by the Dutch Research Council (Vici grant no 09150181910040). AMVDB reports a board membership at the Dutch Headache Society, European Headache Federation, Dutch Pharmacological Society, and Federation of European Pharmacological Societies (all unpaid). All other authors declare no competing interests.