Migraine, CGRP, and Antibodies

CGRP (calcitonin gene-related protein) has been found to play a role in causing migraine. CGRP is released from trigmeninal ganglia cells, 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.

Other CGRP drugs have proven problematic. Telcagepant was found to be effective in Phase III trials, but was abandoned after the discovery of concerns about liver toxicity. Olcegepant, which has undergone Phase II trials, is intravenous, and not the most practical option for many. Other CGRP antagonist drugs are in development.

One potentially interesting twist on this is the efforts of Alder Pharmaceuticals in Bothell, WA. Alder has created an antibody to CGRP, delivered as a monthly injection. They are presently conducting a trial of monthly injections for the prevention of migraine, and are studying people with 4 to 14 migraines a month. Their hope is that this new antibody-based drug will prevent migraines with fewer side effects than existing treatments.

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.x