New Treatment Options: Anti-CGRP Monoclonal Antibodies for Migraine Prevention

Deborah Friedman, MD, MPH, FAHS


December 06, 2018

Editorial Collaboration

Medscape &

In the rapidly changing landscape of migraine therapeutics, providers are faced with the challenge of navigating unfamiliar waters. Parenteral therapies targeting calcitonin gene-related peptide (CGRP) and neuromodulation devices are available for prescribing. Moreover, a new category of serotonin antagonists (5HT1F), oral agents blocking CGRP, implanted sphenopalatine ganglion stimulators, and other neuromodulation devices are expected to be approved by the US Food and Drug Administration (FDA) within the next year. Improved delivery systems and reformulations of foundational medications to decrease side effects and improve adherence are emerging.

This expanded array of options for acute and preventive migraine treatment creates an opportunity to examine treatment strategies to maximize effectiveness and safety for patients. Here, we highlight the anti-CGRP monoclonal antibodies (Table).

An Overview of Anti-CGRP Monoclonal Antibodies

CGRP, a 37–amino acid peptide, is a potent vasodilator and modulator of nociception. It is present peripherally and centrally in the trigeminovascular system and is implicated in the pathogenesis of both migraine and cluster headache. Monoclonal antibodies targeting CGRP entered the US market in late May 2018. There are three medications available to date: erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality); all are FDA-approved for the prevention of migraine in adults. A fourth, eptinezumab, has completed phase 3 trials, with anticipated FDA approval in early 2020. The currently available therapies are administered by subcutaneous injection. Erenumab blocks the CGRP receptor and the others target the ligand. Erenumab is prescribed as 70 mg or 140 mg monthly. Galcanezumab dosing is 240 mg for the first month and 120 mg monthly thereafter. Fremanezumab is dosed either as 225 mg monthly or 675 mg every 3 months. Eptinezumab is administered intravenously once every 3 months (100 mg and 300 mg studied in clinical trials).

All formulations have been studied in episodic migraine, defined as at least 4 migraine days per month, and in chronic migraine, defined as at least 15 headache days monthly (including at least 8 days meeting criteria for migraine or probable migraine). All have shown statistical superiority in reducing migraine days, reducing headache days, and in 50% responder rates (the percentage of trial patients achieving a 50% reduction in migraine/headache days) compared with placebo. On average, the therapeutic gain in the reduction of monthly migraine days compared with placebo is about 2 days for episodic migraine and 4-6 days for chronic migraine. Benefit may begin as soon as the first day after administration (eptinezumab) and within the first week for the subcutaneous formulations. "Super-responders" are those who achieve a 75%-100% reduction in monthly migraine days after receiving the first dose. The Table below summarizes the published results from the pivotal trials of the medications.[1,2,3,4,5,6,7,8]

The safety profile of the anti-CGRP monoclonal antibodies is excellent and similar to placebo in clinical trials. These trials have demonstrated low dropout rates, with over 90% of enrollees completing the studies. The most common side effect with the subcutaneous formulations is injection-site reactions. Constipation and upper respiratory tract infections may occur. Three-year safety data thus far indicate no serious safety signals[9]; however, the short duration of use in the clinic thus far precludes any statements about the "real world" experience. While there are no contraindications to prescribing the anti-CGRP medications, their safety during pregnancy has not been established and they have not been studied in the pediatric population yet. The average cost for currently available therapies is about $600 a month.

In general, patients with episodic or chronic migraine who have tried two or three oral preventive medications or onabotulinumtoxinA with either (1) lack of effectiveness, (2) intolerable side effects, or (3) incomplete response are candidates for these treatments. These are also treatment options for patients with concomitant medical problems that preclude the use of foundational oral preventives with high levels of evidence (eg, topiramate, beta-blockers, sodium valproate/divalproex sodium, tricyclic antidepressants). As the safety during pregnancy is uncertain, women of childbearing potential should be counseled to use appropriate methods of birth control and delay pregnancy for 5 months after their last dose of these medications (5 half-lives). Pregnancy registries are established to report the experience of females who take the medications during pregnancy.

On the practical side, third-party payers have disparate policies regarding coverage for these medications which, in some cases, have made it nearly impossible for patients to receive them despite their medical need. Limitations that have already surfaced include restrictions regarding who can prescribe the medications. For example, prescribing in a few states is limited to United Council for Neurologic Subspecialties (UCNS)-certified headache specialists. Other restrictions include limiting prescribers to neurologists or physicians.[10]

Additional constraints include the number and type of previous preventive medications tried, and denial of coverage for patients using concurrent onabotulinumtoxinA with benefit but an incomplete response.

OnabotulinumtoxinA was discontinued prior to participation in the clinical trials because its effectiveness tends to wear off in less than 12 weeks, which would confound both the baseline headache frequency and outcome of the studies; there was no medical reason for exclusion. Only time will tell whether these long-awaited treatments will actually reach the millions of patients who could benefit from them.

Table. Results of Pivotal Trials for Anti-CGRP Monoclonal Antibodies published as of November 4, 2018


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