Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention?

Abstract

Opinion statementMigraine is a very disabling disorder with severe impact on patients’ lives and substantive costs to society in terms of healthcare costs and lost productivity. Prevention is a key component of migraine therapy, and while numerous preventive options exist, each is burdened by either troublesome side effects or insufficient efficacy. All migraine preventives currently in clinical use were licensed for other purposes and, by chance, have efficacy against migraine. As our understanding of migraine has evolved, calcitonin gene-related peptide (CGRP) has moved to the forefront as a neuropeptide central to migraine pathophysiology. Six small molecule CGRP receptor antagonists were shown to be effective for acute treatment of migraine; two were stopped for hepatotoxicity or one for formulation concern issues and one is now in phase III. Monoclonal antibodies against CGRP or the CGRP receptor have a longer duration of action and have been investigated for migraine prevention. Four are in development and three have completed phase II and one phase III trials; every reported study has been positive. Furthermore, no safety issues have arisen to date, including hepatic or cardiovascular effects, and initial tolerability appears to be excellent. Monoclonal antibodies antagonizing the CGRP pathway represent a novel approach to prevention: a mechanism-specific migraine-targeted therapy. While we must await the results of all the phase III trials, cautious excitement seems warranted as we enter a new era of better tolerated, well-understood, bespoke migraine treatment for this common and disabling neurological disorder.

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

“…Happily, to date, there is no evidence for the liver toxicity liability that was seen with early CGRP‐RAs in chronic daily use. The final profiles, however, await the outcome of longer term real‐world open label studies in greater numbers of patients …”

CGRP, Amylin, Immunology, and Headache Medicine

“…11 CGRP by intradermal injection in humans induces persistent local reddening exceeding histamine from a long-lasting local blood flow increase, sometimes with flare but not the wheal of the histaminic triple response of Lewis. All vasculature is innervated by CGRP-containing nerve fibers.…”

Antigens and Antibodies in Disease With Specifics About CGRP Immunology

“…CGRP is a potent vasodilator expressed and released in the perivascular space by trigeminal sensory neurons with a central role in neurogenic inflammation . An additional summary list of abbreviated details of CGRP in migraine includes: CGRP + nerves innervate all pertinent cerebral arteries; released into the jugular venous system during migraine; ictal migraine and inter‐ictal chronic migraine levels are elevated; infusion evokes migraine‐like attacks; levels are reduced in parallel with triptan efficacy; all novel selective antagonists are effective …”

“…CGRP exists in 2 isoforms, α and β, and is a member of the calcitonin family of receptors. CGRP α, β are 37‐amino acid neuropeptides encoded on chromosome 11 . Human αCGRP and βCGRP differ by 3 amino acids, with activities difficult to distinguish .…”

“…αCGRP is widely distributed in the peripheral and central nervous systems, innervating the vasculature . CGRP α is of utmost interest as it is the most abundant dural and trigeminal ganglion peptide, while regulating the cardiovascular system – vasodilation, mediating neurogenic inflammation – mast cell degranulation and modulating nociceptive input – sensory pain signaling …”