Migraine is the most common neurologic disorder, with an estimated 38 million sufferers in the United States. Symptoms include throbbing, often unilateral head pain along with associated symptoms such as light and/or sound sensitivity, and nausea and/or vomiting. Migraine is often associated with significant functional disability (missed time from work, school, family and social activities). Treatment consists of lifestyle modification, acute therapy such as triptans and non-steroidal anti-inflammatories, and preventives such as topiramate, divalproex sodium, propranolol and amitriptyline, biofeedback, and for chronic migraine only, onobotulinumtoxin A (Botox).
While studies suggest that many more migraineurs should be on preventive therapy then are currently receiving it, a substantial percentage of patients who have tried preventive migraine therapy do not continue, due to either lack of efficacy or intolerable side-effects. Thus there is an unmet need for new effective and well-tolerated preventives. Monoclonal antibodies (MAbs) directed against calcitonin gene related peptide (CGRP) or its receptor appear ideally suited to fill this treatment gap, and are due out in mid-2018.
... a substantial percentage of patients who have tried preventive migraine therapy do not continue, due to either lack of efficacy or intolerable side-effects.
While most primary care providers (PCPs) will not be prescribing CGRP MAbs, migraineurs will soon be bombarded with information overload related to the coming CGRP products, and will flock to PCP offices looking for guidance. Thus a working knowledge of this blockbuster new class of migraine preventives will be essential in the coming months.
CGRP widely expressed
CGRP is the product of a tissue-specific alternative splicing of the CALC1 gene, which also produces calcitonin and the calcium-lowering peptide katacalcin. But CGRP, which exists in both alpha and beta isoforms, plays no role in calcium homeostasis; rather, it has both vasodilatory and nociceptive properties. Present throughout the body, CGRP is widely expressed in both the peripheral and central nervous system (CNS), including important migraine sites, such as the dorsal root ganglia, trigeminal ganglion, and dorsal raphe nuclei. The first CGRP blocking agents used in migraine were not MAbs but rather small molecules. Olcegepant (Boehringer Ingelheim GmbH), an intravenous formulation, and Telcagepant (Merck & Co.), an oral preparation, both demonstrated efficacy in randomized, placebo-controlled trials. However, issues with formulation in the former, and off-site (liver) toxicity in the latter prevented commercialization.
In the early 2000s production of anti-CGRP agents switched from small molecules to MAbs in an effort to avoid off-site toxicity. There is a lot to like about MAbs, including exquisite “lock-and-key” specificity, long half-life (about 4 weeks) and no drug-drug interactions. Currently four anti-CGRP MAbs have completed phase 3 studies and either have applied to the Food and Drug Administration for approval, or will do so in the near future.