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The CGRP Antagonists Are Here. Now How Do You Use Them?

The Real-World Experience of Migraine Experts

Lehmann, Christine

doi: 10.1097/01.NT.0000552940.08727.45
For Your Patients
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Migraine experts share their tips and advice for how to prescribe the new anti-calcitonin gene-related peptide therapies based on their real-world (and early) experiences with patients.

Since the US Food and Drug Administration (FDA) approved three calcitonin gene-related peptide (CGRP) antagonists in 2018 — erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality) — neurologists have begun integrating them into their practice. More CGRP drugs that can prevent and treat acute headaches are in the pipeline, with FDA approval expected within two years.

Designed to prevent chronic and episodic migraines, the CGRPs showed rapid, significant, and long-lasting relief of migraines with minimal adverse effects in clinical trials.

Neurology Today interviewed several neurologists specializing in migraines about their recent clinical experience with the drugs, and any concerns that arose. Their experience to date has been mostly positive, they said, but they did offer several caveats, as well as noteworthy observations from early experiences prescribing them.

“This is the first time we have a preventive class of drugs that was created and designed just for the treatment of migraines based on what we now know about migraine pathophysiology,” said Rebecca Erwin Wells, MD, MPH, associate professor of neurology and founder and director of the comprehensive headache program at Wake Forest Baptist Medical Center in Winston-Salem, NC. “So far patients seem to tolerate it well with few side effects, and there's the potential for super responders and increased adherence through infrequent injections.”

“The CGRP drugs more than meet my expectations,” said Stephen D. Silberstein, MD, FAAN, professor of neurology at Thomas Jefferson University and director of the Jefferson Headache Center in Philadelphia, who has been a researcher in CGRP clinical trials. “In clinical trials, people were excluded after failing just two drugs. In clinical practice, these drugs are the last hope for patients who typically have failed on several drugs.”

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Comparison With Other Drugs

“We may have to redefine what we consider treatment success,” said Noah Rosen, MD, director of Northwell Health's headache center and associate professor at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Great Neck, NY. “We have had to settle for 50 percent response rates with other drugs, but now with the CGRPs, more patients are achieving 75 to 100 percent response rates.”

The CGRP drugs have several advantages over some of the older medications typically used for migraines, Dr. Rosen said. For example, the CGRP drugs can be delivered by injection on a monthly or quarterly basis by the patients or their caregivers, he said. “This can increase medication adherence for patients having difficulty taking oral medications, including the inability to tolerate or absorb them due to gastrointestinal issues,” he added.



“These are the first drugs to have worked well for some of my patients who have been refractory to many other preventive medications,” said Deborah I. Friedman, MD, MPH, FAAN, professor of neurology, neurotherapeutics, and ophthalmology at University of Texas Southwestern Medical Center in Dallas and director of its headache and facial pain program.

The CGRP drugs have other advantages, as well: They don't affect the kidney or liver, and they can be started at the therapeutic dose without requiring a gradual dose escalation. “Nonetheless, to determine their effectiveness, a three-to-four-month trial is sometimes necessary with benefits accruing for up to a year,” said Dr. Friedman.

Patients also appear to tolerate the new drugs better than oral medications, with fewer side effects. The most common side effects reported in clinical practice have been injection-site reactions and constipation for erenumab, according to Dr. Silberstein.

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When to Use as Preventive Therapy

Experts offered some caveats to using CGRPs, however. Dr. Friedman cautioned that some patients do not see any benefits with CGRPs, and some obtain better benefits on various oral preventive drugs used in migraine treatment such as antidepressants, antihypertensives, and antiepileptic medications.

In general, the decision to initiate prevention therapy depends on the frequency of migraines, previous treatment response, and the severity of disability, said Dr. Friedman. “The time to start thinking about migraine prevention is when patients have four or more migraine attacks monthly, they are not getting a good response from acute therapy, or their headache-related disability is limiting daily activities or preventing them from performing well at school or their job,” she said.





Dr. Friedman also recommended prevention therapy for patients with unusual migraine types such as those that are hemiplegic or with brainstem aura, regardless of frequency.

Among the CGRPs, clinicians have the most experience with erenumab, which was the first drug to be approved by the FDA. “But if patients don't improve on it, or have side effects, I prescribe fremanezumab or galcanezumab,” said Dr. Silberstein.

Dr. Wells asks her migraine patients to complete headache logs to track their frequency and “directly assess improvements,” she said, “not only for our benefit but also for insurance companies who require this data.”

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Costs and Access

The cost of the CGRP drugs is high — erenumab costs $575 per month, for example. As a result large health insurers, expecting a flood of expensive prescription claims for erenumab, have established requirements that patients document the number of headaches they suffer per month, as well as provide proof they have failed on at least two drugs.

“If it weren't for these drug-failure requirements and [their] cost, the CGRP drugs could be used as a first-line therapy,” said Dr. Friedman. “In addition, practice resources are strained when staff have to spend a lot of time requesting prior authorizations from insurance companies, and when providers must hold peer-to-peer conversations,” she said.

Some commercial insurers also want patients to stop receiving onabotulinumtoxinA (Botox) for four months before starting CGRP drugs, according to Dr. Friedman. “Most patients on onabotulinumtoxinA are getting some benefit, but not enough,” she said. “But to expect them stop the treatment and return to baseline, which by definition is chronic migraine and severe, is a cruel and unusual punishment. A more rational approach is to leave patients on onabotulinumtoxinA while they are starting a CGRP drug, and then depending on their response, titrating them off onabotulinumtoxinA.”

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The Unknowns

“Since we have limited experience prescribing these drugs, we also don't know about their long-term efficacy and the timing of switching between the different CGRPs,” said Dr. Wells.

The long-term safety and side effects of CGRPs are also unknown. Amgen and Novartis, which make and track prescriptions of erenumab, reported that more than 100,000 scripts were written since May without major safety signals, according to Dr. Wells.

Another unknown is whether pregnant women can take CGRPs without risks to their fetuses. “I do not prescribe or recommend this for anyone who is pregnant, and I advise patients that if they become pregnant while on this medication, they stop taking the treatment immediately,” said Dr. Wells.

Before patients of childbearing age start taking CGRPs, Dr. Wells recommends a pregnancy test if there's any uncertainty about their pregnancy status. “If they want to get pregnant in the future, I recommend they stop the drugs and wait about six months before starting to conceive,” she said.

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Next Steps

The migraine specialists agreed that more clinical practice data is needed to better understand the long-term effects and implications of prescribing CGRPs. “We also want to know whether taking these drugs decrease[s] medical utilization such as emergency department visits and hospitalizations associated with migraines,” said Dr. Rosen. “If that's the case, it is very likely that these medications will be covered by insurers.”

Dr. Silberstein would like more clinical studies to investigate why some people don't respond to CGRPs: Is it because there are parallel mechanisms for migraine, or because some people make too much CGRP, which overwhelms the antibody?

In the meantime, more CGRPs are in the pipeline Clinical trials also showed that galcanezumab was effective in preventing episodic cluster headaches, although the data have not been submitted to the FDA yet for this indication. Fremanezumab is also being studied for this possible indication, but the trial data have not been released yet, according to Dr. Silberstein.

Small-molecule oral CGRP receptor antagonists — ubrogepant (MK-1602) and rimegepant (BHV-3000) — have met clinical endpoints in phase 3 studies for the acute treatment of migraine. Atogepant demonstrated efficacy for acute migraine prevention in phase 2b/3 clinical trials, said Dr. Friedman.

“These medications offer a safe acute treatment option for patients with cardiovascular disease who can't take triptans,” she said. “They also do not produce the side effects of triptans, including chest tightness, fatigue, nausea, dizziness, drowsiness, tingling, and asthenia.”

“We will see a lot of advances in headache medicine in the next three to five years, which is exciting. As health care providers, we have a responsibility to help patients navigate these new options and make wise decisions,” said Dr. Rosen.

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Dr. Wells reported no disclosures. Dr. Friedman has received honoraria from Alder Biopharmaceuticals, Allergan, Amgen, Biohaven, Eli Lilly, Teva, Promius, electroCore, and Zosano. Dr. Rosen serves on the advisory boards and receives honoraria and travel expenses for Allergan, Amgen, Avanir, Biohaven, Eli Lilly, Promius, Supernus, and Teva. Dr. Silberstein is a consultant and/or advisory panel member and has received honoraria from Abide Therapeutics; Alder Biopharmaceuticals, Allergan, Amgen, Avanir, Biohaven, Cefaly, Curelator, Dr. Reddy's Laboratories, Egalet Corporation, GlaxoSmithKline Consumer Health Holdings, eNeura, electroCore Medical, Lilly USA, Medscape, NINDS, Satsuma Pharmaceuticals; Supernus, Teva, Theranica, and Trigemina, Inc.

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Link Up for More Information

•. Tepper SJ. Anti-calcitonin gene-related peptide (CGRP) therapies: Update on a previous review after the American Headache Society 60th Scientific Meeting, San Francisco, June 2018 Headache 2018. 58 Suppl 3:276–290.
    •. Silberstein SD, Dodick DW, Bigal ME, et al Fremanezumab for the preventive treatment of chronic migraine N Engl J Med 2017;377:2113–2122.
    © 2019 American Academy of Neurology