Migraine, CGRP, and Antibodies

by | Jul 11, 2021 | Medication

CGRP (Calcitonin Gene-Related Peptide) and Migraine

CGRP (calcitonin gene-related peptide) has been found to play a role in causing migraine.  CGRP is released from cells in the trigeminal ganglia, and migraineurs have an increased level of CGRP in blood serum.  In the brain, CGRP levels are increased in inflammatory conditions.  There is some evidence that at least some migraine sufferers may have inflammatory markers (such as TNF-α) present in their nervous systems during migraine attacks.  CGRP is thought to increase the sensitivity of migraine pain receptors (trigeminal nociceptors).  There is also some evidence that CGRP is implicated in paroxysmal hemicranias.  CGRP may even play a role in hypertension.

Drug development for CGRP blockers has been a long road.  Telcagepant was found to be effective in Phase III trials, but was abandoned after the discovery of concerns about liver toxicity.  Olcegepant, which had undergone Phase II trials, is intravenous, and was not developed further due to adverse effects as well as an intravenous therapy for an acute medication not being the most practical option for many.  Other CGRP antagonist drugs in the gepant class have emerged and more are in development (rimegepant, ubrogepant, atogepant, and vazegepant).  Some gepants are used as acute medications, while others have utility for prevention of migraine.

Another form of CGRP blockade is in the form of monoclonal antibody drugs that either block the CGRP receptor or the CGRP ligand.  There are currently four injectable monoclonal antibody CGRP blockers for migraine prevention:  erenumab, galcanezumab, fremenezumab, and eptinezumab.

References:

1. Durham PL. Calcitonin Gene-Related Peptide (CGRP) and Migraine. Headache. 2006;46(Suppl 1):S3–S8.
2. Hoffmann J, Goadsby PJ. New Agents for Acute Treatment of Migraine: CGRP Receptor Antagonists, iNOS Inhibitors. Curr Treat Options Neurol. 2012;14(1):50–59. doi:10.1007/s11940-011-0155-4.
3. Durham PL, Vause CV. CGRP Receptor Antagonists in the Treatment of Migraine. CNS Drugs. 2010;24(7):539–548. doi:10.2165/11534920-000000000-00000.
4. Goadsby PJ, Edvinsson L. Neuropeptide changes in a case of chronic paroxysmal hemicrania-evidence for trigemino-parasympathetic activation. Cephalalgia. 1996;16:448-450.
5. Tepper, S. J. and Stillman, M. J. (2008), Clinical and Preclinical Rationale for CGRP-Receptor Antagonists in the Treatment of Migraine. Headache: The Journal of Head and Face Pain, 48: 1259–1268. doi: 10.1111/j.1526-4610.2008.01214.
6. Rafaelli, B. Neeb, L. Reuter, U.  Monoclonal Antibodies for the Prevention of Migraine. Expert Opin. Biol. Ther. 2019 Dec; 19(12):1307-1317.