Monoclonals and Migraine: What the Primary Care Physician Needs to Know

September 21, 2017

Monoclonal antibodies that inhibit calcitonin gene-related peptide could revolutionize preventive migraine therapy. Here's what you need to know.

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. [[{"type":"media","view_mode":"media_crop","fid":"63450","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_4135590792222","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"8100","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"height: 115px; width: 200px; float: right;","title":"MAbs, in brief (Click to enlarge) ","typeof":"foaf:Image"}}]]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.

Next: The Four MAbs


The four MAbs

The four CGRP MAbs currently competing for FDA approval for migraine are erenumab (co-developed by Amgen and Novartis), fremenezumab (Teva), galcanezumab (Eli Lilly) and eptinezumab (Alder Biopharmaceuticals). Erenumab is a fully human MAb, while the others are humanized. Erenumab is also the only one of the four to bind the CGRP receptor; the others bind the CGRP ligand itself. (See Table; click to enlarge). Erenumab, to be marketed under the brand name Aimovig, has a tentative FDA approval date of May 17, 2018, and the other three will likely follow throughout the summer and fall.

[[{"type":"media","view_mode":"media_crop","fid":"63434","attributes":{"alt":"","class":"media-image media-image-right","height":"140","id":"media_crop_655346553807","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"8096","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image","width":"241"}}]]Fremenezumab, galcanezumab and erenumab will be admistered as monthly intramuscular injections (likely at home), while eptinezumab will be an intravenous injection every three months in a physician’s office or infusion center. All four products appear to work quickly (within a week) to reduce the number of migraine days/month in both episodic migraine (4-14 headache days/month) and chronic migraine (15 or more headache days a month). All products have shown a proportion of “super-responders”: those who have 75% to 100% reduction in migraine days per month, though it remains unclear who these people are.  All four compounds have positive secondary outcome measures such as reduction in migraine-related disability and improvement in migraine-specific quality of life. 

No safety signals, well tolerated
No CGRP MAb significant safety signals have been identified in more than 8000 subjects over a four-year period. Side-effects, generally rated as mild-to-moderate, vary slightly between compounds and include injection site pain and erythema, upper respiratory and urinary tract infections, nausea, dizziness and abdominal pain. Unlike small molecule oral CGRP antagonists, no liver function abnormalities or other off-site safety signals have been detected. Despite CGRP’s vasodilatory properties, no cardio- or cerebrovascular signals have emerged. Importantly, and unlike MAbs directed against components of the immune system, no changes in white blood count have been seen. It is highly unlikely that CGRP MAbs, once approved, will require blood monitoring, have restricted access, or require a REMS program.

While the CGRP MAbs have numerous advantages, it is still early, and questions remain. Safety in long-term use, in pregnancy, and in special populations such as children and the elderly remains unknown. Post-marketing surveillance will be essential. CGRP facilitates wound healing, prevents cellular apoptosis, and increases anti-oxidant enzymes, all of which may theoretically be disrupted by blocking the CGRP ligand or receptor, although complete lack of significant safety signals in human studies are thus far quite reassuring.

Cost could be a barrier

Cost may also prove a roadblock and hinder widespread use of these agents. Although all four companies are tight-lipped on price structure, industry analysts estimate the CGRP MAb price tag will “not be inconsequential.” Given that all four products seem similar in efficacy, payers will likely play one company against the other, extracting deep discounts in price in return for formulary exclusivity. Additionally, payers will almost certainly require step-edits and prior authorizations, an already vexing problem for busy practitioners.

Despite these unanswered questions, CGRP MAbs are on their way. As migraine is the third most prevalent and seventh most disabling medical condition worldwide, new treatments, particularly those that are targeted, safe, fast, and well-tolerated, are welcome. And with an estimated 38 million migraine sufferers in the US alone, there is a massive potential market for CGRP MAbs (estimated at five billion dollars annually), giving biopharmaceutical companies more than ample impetus to push ahead to the finish line. An interesting era is approaching in neurology and headache medicine, harkening back to the heady days of the introduction of triptans a generation ago.

Get ready. The next 12-24 months promise to be an exciting time.


Please click here forthe Patient Care "What's New In Migraine" Special Report POSTEST

For previous articles:

Hormones and Migraine: A Case Study

Pediatric and Adolescent Migraine: Update on Treatment Options

Introduction and Pre-test