Attacking Migraine: Why CGRP?

The first calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) has received FDA approval and is now available for providers to prescribe. Why should primary care providers consider this novel category of preventive migraine medication for their patients? Which migraine patients are appropriate candidates for a CGRP mAb?

Background

About 40% of migraine sufferers are candidates for prevention but only a small percentage are on a preventive.¹ Lack of efficacy and intolerable side effects are among the top reasons for discontinuation of a preventive treatment.² Even those medications that have an FDA indication for prevention of episodic or chronic migraine were not originally brought to market for migraine. These include topiramate, divalproex, propanolol, timolol, and onabotulinum toxin A.

CGRP, identified as a key player in the pathogenesis of migraine, is a neuropeptide that modulates nociceptive signaling. This signaling occurs through the trigeminal pathway. Activation of this pathway is associated with migraine pathophysiology.

Plasma levels of CGRP sampled from external jugular blood were reported to be higher in migraine patients actively experiencing a headache vs healthy control subjects.³ A follow-up study showed that elevated CGRP levels in external jugular blood returned to baseline following triptan administration.⁴ In addition, a study in which researchers infused CGRP or a placebo in migraine patients showed the development of headache in all patients receiving CGRP. Significantly, intravenous injections of CGRP did not trigger migraine-like attacks in healthy volunteers.^5,6 The exact reason for this difference in susceptibility is unclear.

Next: Erenumab, Now Available

Now Available

Erenumab (Aimovig) was FDA-approved on May 17, 2018 for the prevention of episodic and chronic migraine for adults aged 18 years and over. The recommended dosage is 70 mg given monthly as a subcutaneous injection. In some cases, a dosage of 140 mg monthly may be warranted.⁷ Erenumab is available as a prefilled auto injection and can be injected into the arm, lower abdomen, or thigh. Most patients should be able to self-administer the drug. The most common side effects in clinical trials included injection site pain, injection site reactions (most commonly redness for a few hours), and constipation. There are no absolute contraindications, but insufficient data are available to make any statements in regards to use during pregnancy or breastfeeding.

Erenumab, like the other CGRP mAbs coming to market, is a large monoclonal antibody and does not cross the blood-brain barrior. The drugs work by blocking CGRP activity peripherally. As a result, there are no central nervous system side effects (eg, sedation or dizziness). Also, there are no drug-drug interactions, no effect on the liver or kidney, and CGRP inhibitors are slowly broken down in the body.

Erenumab works by blocking the CGRP receptor. It does not have significant activity at other receptors of the calcitonin receptor family. The other 3 CGRP mAbs contending for FDA approval are fremanezumab, galcanezumab, and eptinezumab. Both fremanezumab and galcanezumab work by selectively binding the CGRP ligand and are expected to receive approval in September 2018. Both will be given as monthly injections with a possible option for quarterly injections. Eptinezumab also targets the CGRP ligand and is being developed as a quarterly infusion delivery and will most likely not be available until 2019.

All of the CGRP mAbs have demonstrated good safety, tolerability, and efficacy in clinical trials. There have been no head-to-head studies comparing them. Whether one may prove to be more effective or better tolerated than another in clinical practice remains to be seen. What is known is that we now have a new option with a targeted mechanism to prevent migraine in our patients with both episodic and chronic migraine.

Migraine patients are increasingly proactive in their migraine treatment and primary care physicians may be among the first to hear questions about this new preventive treatment. The best candidates appear to be those who have failed or been intolerant of at least 2 standard migraine preventives such as an antiepileptic, antidepressant, and/or an antihypertensive agent.

For more information patients and providers may find www.Aimovig.com a useful website to learn more including how to prescribe.

Next: Looking Toward the Future 

The Future

Oral CGRP antagonists including ubrogepant and rimegepant are under development for the acute treatment of migraine attacks. This new category being developed for acute migraine treatment does not have the vasoconstrictive side effects of triptans and as such may be appropriate treatment in our practices in patients for whom the triptans are contraindicated. Another oral CGRP antagonist, atogepant, is in clinical trials for prevention of migraine.

Migraine is a chronic neurologic disease with significant disability affecting 13% of the American adult population. There are significant unmet treatment needs in this population. The new category of CGRP medications including the mAbs for prevention and the oral antagonists for acute treatment are a welcome addition to our treatment options.

References:

1. Shapiro RE. Preventive treatment of migraine. Headache. 2012;52:65-69.
2. Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 2013;53:644-655.
3. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183-187.
4. Juhasz G, Zsombok T, Jakab B, et al. Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia. 2005;25:179-183.
5. Lassen LH, Haderslev PA, Jacobsen VB, et al. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54-61.
6. Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010;30:1179-1186.
7. Aimovig [package insert]. Thousand Oaks, CA: Amgen Inc; 2018