The Holy Grail of Migraine Medications? (1/3) - CGPR Blockers
With the three newest migraine drugs specifically designed for migraine prevention released this year, is this new class - CGRP blockers the holy grail of migraine medications? We have divided learning about the CGRP blockers into a three-part series. Today we will look at an overview of the CGRP blockers.
Calcitonin-gene-related peptide (CGRP) is a small molecule that is synthesized in our nervous system throughout the brain and other parts of the body to act as a chemical messenger between different cells. Since its discovery in 1982, CGRP has been demonstrated to play an integral role in migraine pathophysiology. The current theory explaining the cause of migraines is the dysfunction of the brain stem, which regulates pain sensations and blood vessel tone.
The activation of the CGRP pathways during a migraine attack causes the amplification of pain sensations and the dilation of blood vessels. The link between CGRP release and migraines has been demonstrated in early studies where researchers saw an increase in plasma concentration of CGRP levels during an acute migraine attack and a decrease in plasma concentration of CGRP levels during migraine abortive treatments. Additionally, when patients who were prone to migraine attacks were given an infusion of CGRP, it triggered migraine-like headaches.
Two kinds of anti-CGRP medications (oral vs mAbs):
Oral anti-CGRP medications called “-gepants” were initially developed and tested in the early 2000s but the discovery of liver toxicity with its use caused many drug companies to stop pursuing this class of drugs.
In clinical studies, gepants demonstrated comparable efficacy to triptans and was found to have minimal adverse cardiovascular symptoms unlike triptans, making gepants a good alternative for those who cannot use triptans for cardiovascular problems. Gepants are still being developed for acute migraine treatment. There are currently three gepants in development: atogepant, ubrogepant, and rimegepant.
With many drug companies halting the development of gepants, the use of monoclonal antibodies (mAbs) to target CGRP molecules and its receptors were developed. Monoclonal antibodies are proteins that uses the immune system to target specific molecules inside your body. Currently, there are four anti-CGRP mAbs that have been developed, galcanezumab, eptinezumab, erenumab, and fremanezumab.
Out of these four, three are now available in the US market under the brand name Aimovig™, Ajovy™, and Emgality™ .
Differences between the anti-CGRP drugs
The second article of this series of three dedicated to the new preventative migraine medications - the anti-CGRPs- will be posted early next week, so stay tuned!
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Mitsikostas DD and Reuter U. Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies. Curr Opin Neurol. 2017;30:000-000. doi: 10.1097/WCO.0000000000000438
Edvinsson L, Hannes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338-350.
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Aimovig™ [package insert]. Thousand Oaks, CA; Amgen; Published May, 2018. https://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/aimovig/aimovig_pi_hcp_english.ashx
Ajovy™ [package insert]. North Wales, PA; Teva Pharmaceutical USA, Inc; Published September, 2018. https://www.ajovyhcp.com/globalassets/ajovy/ajovy-pi.pdf
Villalón CM, Olesen J. The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacol Ther. 2009;124(3):309-323. doi:10.1016/j.pharmthera.2009.09.003
Rosenfeld MG, Mermod JJ, Amara SG, et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature. 1983;304:129-135. doi:10.1038/304129a0
Emgality™ [package insert]. Indianapolis, IN; Eli Lilly and Company; Published September, 2018. http://pi.lilly.com/us/emgality-uspi.pdf