expert roundtables

Targeted Therapies for Migraine

by David W. Dodick, MD; Deborah I. Friedman, MD, MPH, FAAN, FAHS; and Paul G. Mathew, MD, DNBPAS, FAAN, FAHS

Overview

Newer treatments have been developed to target important mechanisms in migraine pathophysiology. Recent arrivals to the migraine prevention space include monoclonal antibodies (mAbs) directed against calcitonin gene-related peptide (CGRP).

Q:

What are the recent developments in targeted therapy for migraine prevention? What has been the experience thus far?

David W. Dodick, MD

Professor, Department of Neurology
Director, Concussion Program
Director, Headache Program
Mayo Clinic
Scottsdale, AZ

The mAbs are effective in a significant percentage of the population, and this is true regardless of which antibody is used. It is also clear that these antibodies work even if patients have failed multiple other preventative treatments.”

David W. Dodick, MD

We now have several mAbs that target CGRP that have been approved by the US Food and Drug Administration (FDA) based on trials showing efficacy in episodic and chronic migraine. All of the trials have demonstrated efficacy in reducing the frequency of monthly migraine days with generally good tolerability. There are 3 mAbs that target the peptide (CGRP) and 1 that targets the receptor.

We have had a biologic in the migraine preventive space with botulinum toxin for approximately a decade, but we have not had these types of biologics (ie, mAbs) until just the last few years. If you look at the totality of current evidence from all of the clinical trials plus at least 4 countries that have reported some real-world evidence (ie, the United States, Germany, Italy, and Australia), overall, the effects appear similar across these antibodies. They are effective in a significant percentage of the population, and this is true regardless of which antibody is used. It is also clear that these antibodies work even if patients have failed multiple other preventative treatments—not just 2 and even not just 4, but some patients who are clearly referring to numerous medications can still respond well to these antibodies. Further, it has been shown that these preventive treatments work in the setting of medication overuse headache, even if a medication continues to be overused. And they also work in patients with significant comorbid illnesses that would have excluded a patient from participating in a clinical trial, such as fibromyalgia or other chronic pain syndromes.

Now, these agents are not for everyone, and there is still much to be learned going forward. For instance, we do not know about their use in children, older adults, and women who are or plan to become pregnant; the long-term risks in these populations are largely unknown. For female patients with migraine who are of childbearing age, in particular, an advantage of an oral formulation over the infusion or injection of an mAb is that it can be stopped quickly, while the other formulations may remain active in the body for a longer duration of time and must be stopped at least 5 months before pregnancy occurs, as a precaution.

Paul G. Mathew, MD, DNBPAS, FAAN, FAHS

Assistant Professor of Neurology
Harvard Medical School
Boston, MA

“In general, among those who have tried mAbs, I would say that the vast majority are quite satisfied. With gepants likely being approved for prevention, patients may be more willing to try these new oral preventatives knowing that they can simply discontinue the pill if they were to experience a side effect that they do not like or if they were to become pregnant.”

Paul G. Mathew, MD, DNBPAS, FAAN, FAHS

Patient preferences can be highly variable. One common sentiment of many patients is that they would prefer to not take a daily oral medication for migraine prevention; rather, they would prefer using a monthly or quarterly injectable treatment.

On the other hand, some patients may be reluctant to consider onabotulinum toxin or mAb therapy due to the route of administration and needle phobia. Fremanezumab was initially only available in a prefilled syringe, which increased the reluctance of some patients to try the medication due to actually seeing the needle. Since the release of the autoinjector, patient acceptance has, in many cases, improved. In addition, the quarterly dosing option of fremanezumab can be convenient for patients who prefer the treatment to be administered by someone else.

Many patients are concerned that if they take an injectable mAb, they will have to endure its potential side effects for a month or longer. I blame social media to a certain extent, as some patients may start out already believing that a certain medication will not work for them or will cause severe side effects. With social media, it is very common for people to post their negative experiences; however, an ineffective treatment for 1 patient with migraine may be very effective for another patient. In general, among those who have tried mAbs, I would say that the vast majority are quite satisfied. 

With gepants likely being approved for prevention, patients may be more willing to try these new oral preventatives knowing that they can simply discontinue the pill if they were to experience a side effect that they do not like or if they were to become pregnant.

Deborah I. Friedman, MD, MPH, FAAN, FAHS

Professor of Neurology and Ophthalmology
University of Texas Southwestern Medical Center
Dallas, TX

It remains to be determined how well the CGRP antagonists will be accepted by patients and third-party payers.”

Deborah I. Friedman, MD, MPH, FAAN, FAHS

Gepants are the latest class of migraine-specific CGRP antagonists to become available for the abortive treatment of migraine, and there may be FDA approvals for preventive treatment in the not-too-distant future. These agents can be administered orally as abortive therapy and have been shown in clinical trials to be especially useful in patients who either had treatment failure or cannot tolerate triptan therapy, as well as in those with significant cardiovascular contraindications to triptans.

Ubrogepant was the first of this class to be approved by the FDA in 2019, and it was followed by rimegepant in 2020. Both drugs are well tolerated, with nausea being the most common adverse effect. Both drugs are currently used only for acute treatment, although rimegepant and a third drug, atogepant, are awaiting FDA approval for preventive migraine treatment.

It remains to be determined how well the CGRP antagonists will be accepted by patients and third-party payers. Many patients are reluctant to take new therapies until their safety and efficacy have been more fully demonstrated through widespread use over longer periods of time. Another challenge of starting new therapies is that many physicians do not have much independence with respect to selecting therapies; third-party payers—not practitioners—often determine which treatments can be administered in each case.

References

Loder EW, Burch RC. Who should try new antibody treatments for migraine? JAMA Neurol. 2018;75(9):1039-1040. doi:10.1001/jamaneurol.2018.1268

Mohanty D, Lippmann S. CGRP inhibitors for migraine. Innov Clin Neurosci. 2020;17(4-6):39-40.

Ohlsson L, Haanes KA, Kronvall E, Xu C, Snellman J, Edvinsson L. Erenumab (AMG 334), a monoclonal antagonist antibody against the canonical CGRP receptor, does not impair vasodilatory or contractile responses to other vasoactive agents in human isolated cranial arteries. Cephalalgia. 2019;39(14):1745-1752. doi:10.1177/0333102419867282

Schuster NM, Rapoport AM. Calcitonin gene-related peptide-targeted therapies for migraine and cluster headache: a review. Clin Neuropharmacol. 2017;40(4):169-174. doi:10.1097/WNF.0000000000000227

Silberstein SD, Cohen JM, Seminerio MJ, Yang R, Ashina S, Katsarava Z. The impact of fremanezumab on medication overuse in patients with chronic migraine: subgroup analysis of the HALO CM study. J Headache Pain. 2020;21(1):114. doi:10.1186/s10194-020-01173-8

Tiseo C, Ornello R, Pistoia F, Sacco S. How to integrate monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor in daily clinical practice. J Headache Pain. 2019;20(1):49. doi:10.1186/s10194-019-1000-5

Urits I, Jones MR, Gress K, et al. CGRP antagonists for the treatment of chronic migraines: a comprehensive review. Curr Pain Headache Rep. 2019;23(5):29. doi:10.1007/s11916-019-0768-y

Wattiez A-S, Sowers LP, Russo AF. Calcitonin gene-related peptide (CGRP): role in migraine pathophysiology and therapeutic targeting. Expert Opin Ther Targets. 2020;24(2):91-100. doi:10.1080/14728222.2020.1724285

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