Richard Lipton, MDRichard Lipton, MD
New preventative therapies for migraine have been anxiously awaited. Although acute treatments such as triptans have been available since the early 1990s, their use is limited by contrain- dications, side effects, and a lack of efficacy for some patients. At the same time, preventive treatments for migraine are not universally successful, and many patients drop these therapies because of side effects.

In the United States, adherence to oral preventive therapies for migraine is low among patients with chronic migraine (CM) and worsens over time.1,2 A large retrospective study of 8688 patients with CM found adherence rates of 26% to 29% at 6 months, which diminished to 17% to 20% at 12 months (FIGURE).2 “If you look historically at why patients didn’t continue with migraine medications they were prescribed, there are number of reasons,” Amaal J. Starling, MD, assistant professor of neurology and consultant in the department of neurology at the Mayo Clinic in Phoenix, Arizona, told NeurologyLive®. “One was lack of efficacy and another was [adverse] effects, but a third reason was that they didn’t want to be on an antidepressant or an antiseizure medication.”

Recommendations for oral preventive therapies for migraine are currently limited to only a few drugs that show good clinical evidence of efficacy. According to Richard Lipton, MD, the Edwin S. Lowe professor and vice chair of neurology, professor of epidemiology and population health, and of psychiatry and behavioral sciences at the Albert Einstein College of Medicine, and director of the Montefiore Headache Center in New York, New York, it is standard practice to offer oral generic treatments first to patients in need of prevention, including β-blockers (propran- olol and timolol), antiepileptic drugs (topiramate and divalproex sodium), candesartan, memantine and riboflavin, among other medications. “For chronic migraine, onabotulinumtoxin A is very helpful,” he added. “If 2 or more of these agents fail, monoclonal antibodies become an important option.” Preventive therapy, however, should not substitute for acute treatment of migraine. In the CAMEO study,3,4 which Lipton coauthored, patients who halted their acute treatment to start preventive therapy, stopped on recom- mendations from their physician, or due to financial issues, all repre- sented a high level of unmet need, he said.

A 2015 review by Hepp et al2 showed that a perceived lack of efficacy of preventive medications, combined with significant adverse effects (AEs), contributed substantially to low adherence rates, even among patients with CM (>15 days per month). The authors found this surprising, as the increased frequency of migraine would have been expected to make patients more willing to take a daily pill than those with more occasional episodes.

However, the relevancy of those findings is quickly fading, as in less than 2 years, several new drugs have emerged for migraine prevention and acute treatment that address both the efficacy and tolerability concerns patients have had regarding previous therapies.5,6 “Preventive care for patients with migraine has changed drastically since the middle of 2018, where we have the development of multiple preventive therapies for migraine and others in the pipeline,” Starling said. “Since May of 2018, we have had 3 new CGRP [calcitonin gene-related peptides] monoclonal antibodies approved by the FDA [for migraine prevention], including erenumab, galcane- zumab, and fremanezumab, which are clinically available, and 1 that is currently undergoing active approval, eptinezumab.” Most recently, the FDA approved the first anti-CGRP in the gepant class, ubrogepant (Ubrelvy; Allergan), for acute relief.

Anti-CGRP Therapy for Migraine Prevention and Relief

CRGPs are the most abundant neuropeptides found in the trigeminal system, and they are widely distributed throughout the body, where they serve many functions related to migraine pathophysiology.6

Two types of agents with the ability to block the function of CRGP are currently clinically available and in continual develop- ment, including large-molecule monoclonal antibodies (MAbs) used preventively and small-molecule gepants for both acute relief and prevention.6 Treatments that target the CGRP system have demonstrated a much higher efficacy than other therapies that are less specific.5,6 Lipton explained that “treatment starts with a maximally preventive dose. This improves adherence by avoiding complex dose escalation.” Whereas oral generic preventive medications are often discontinued due to side effects, he noted that MAbs have few side effects and show favorable adherence, and because treatment is given only once monthly or quarterly, “it reduces the opportunity to miss doses taken on a daily basis or more than once a day,” he said.

Monoclonal Antibodies

CGRP mAbs are large proteins that have been genetically engineered to not have any effect on the immune system, Starling explained, “and they are highly specific for either the CGRP molecule or CGRP receptor.” Fremanezumab, galcanezumab, and eptinezumab all target the CGRP ligand, whereas erenumab targets the CGRP receptor.6

Novel CRGP mAbs offer multiple advantages to migraine prevention therapy that can be expected to improve adherence, including improvements in efficacy, tolerability, and dosing, with a significantly reduced AE profile. Because CGRP antibodies are not metabolized in the liver or kidney, dosing frequency can be significantly extended to 30 to 90 days, representing a major benefit overcurrent preventive therapies. “Prior to the anti-CGRP drugs coming out, most of our migraine preventive treatments required daily oral dosing, so patients had to remember to take their medications,” said Mia Minen, MD, MPH, assistant professor of neurology and population health, chief of headache research, and director of headache services at NYU Langone Health in New York, New York. “Some patients also say that they don’t like having to take something daily because it is a constant reminder that they have a debilitating chronic condition. The anti-CGRP drugs can be administered less often, which may improve compliance,” she added.

Results from the CAMEO study reported in 2019 stated that the main reasons for discontinuing standard migraine prevention therapies were switching to an over the counter therapy (45.5%), perceived lack of efficacy (28.2%), and safety/tolerability concerns (24.9%).4 “Unfortunately, with the treatment options that we had available before, because they were not disease specific, they had multiple different contraindications, as well as side effects that patients would experience,” Starling said. “These CGRP monoclonal antibodies seem to be very well tolerated by the majority of our patients, and the AE profile is so much better than with the prior medications we had in the past.”

The anti-CGRP medications also expand the range of patients who respond, according to Jessica Ailani, MD, FAHS, FAAN, director of the Medstar Georgetown Headache Center and professor of clinical neurology at Medstar Georgetown University Hospital, in Washington, DC. “Because the CGRP medications are created to specifically target dysfunction in migraine, we are seeing patients who have never responded to any other treatment find improvement in migraine frequency with this novel class.”

“CRGP therapies are the only disease-specific preventive migraine medications available on the market right now,” Starling said. “Other drugs that do work have their place in migraine prevention and they can be effective for many patients, but they are not disease specific, and patients as well as clinicians want to be able to treat people with migraine with something that is designed for migraine.” Another exciting benefit, she reported, is the exceptionally rapid onset of action. “Several of the monoclonal antibodies seem to have a preventive benefit where the placebo and the treatment arm separate in as early as 1 week for galcanezumab and as early as 3 days with fremanezumab. With the infusion, eptinezumab, that has been shown to be effective as early as post-infusion day 1.”

Gepants

Gepants are oral medications that also target the CGRP receptor and were first investigated in an effort to find effective acute therapies for migraine that were not vasoconstrictive, and therefore, would reduce the side effects and contraindications associated with triptan use.7 Unlike CGRP mAbs, they are small molecules that are metabolized and have to be taken on a regular basis, Starling explained; however, 2 investigational therapies, rimegepant and atogepant, have shown promise as possible preventive therapies.

Like the CRGP mAbs studied for prevention, gepants have demonstrated efficacy in several studies. Results from recent studies showed that 31.4%, 32.9%, and 29.7% of patients given doses of rimegepant (75 mg, 150 mg, and 300 mg) were pain free at 2 hours postdose compared with 15% of patients given placebo.7 These efficacy rates were close to those for sumatriptan (35%). In other studies, oral doses of rimegepant were also superior to placebo in freedom from pain and most bothersome symptoms.8 Similar efficacy has been observed in phase 3 trials for ubrogepant, supporting its regulatory approval in December 2019.

The possible benefits of gepants as preventive therapies are also being investigated. For instance, in an abstract presented at the 2019 Annual Scientific Meeting of the American Headache Society,9 David Dodick, MD, professor of neurology at Mayo Clinic, reported that in 834 patients who received atogepant, at least 52% to 62%— depending on the dose—experienced at least a 50% reduction in average monthly headache days compared with 40% of patients who received placebo.

Why Efficacy Trumps Delivery

Most of the anti-CGRP therapies that are currently available are given by subcutaneous injection. Erenumab and galcanezumab are given once monthly via an autoinjector, and fremanezumab is administered once a month via a prefilled syringe, with a higher-dose option available for administration once every 3 months. Ubrogepant is the first oral option approved.5 Notably, the investigational agent eptinezumab is administered via intravenous infusion once every 3 months.5

Although patients being treated for other diseases often avoid injectable therapies when able, the experts agreed that this does not appear to be a disincentive to use anti-CGRP therapies. “Much of migraine treatment depends on patient preference,” Minen said. “For some time now, we have already been offering patients oral versus injectable medications, such as botulinum toxin. I have some patients who would rather take an oral medicine over injections and others who prefer the injections because they are quick and generally don’t interact with other oral medications.”

Starling, who sees mostly patients with high-frequency episodic migraine (10-14 days per month) and CM (15 or more days per month) in her clinic, agreed. “My patient population includes a lot of refractory patients who have tried many different treatment options, and they have never had an issue with the fact that this is an injection,” she told NeurologyLive®.

In a 2019 review of emerging therapies, Chan and Goadsby5 reported that, “During the next years, as experience with monoclonal antibodies grows in clinical practice, we can expect an evolution in migraine management to take shape. Clinicians will be able to offer treatment patients want rather than trying to fit migraineurs into therapeutic boxes for their management.”

This optimistic view of the next steps in migraine therapy appears to be widespread. “The hope is always that we are able to reduce abortive medication use if the disease is well managed with a good preventive—as sometimes, it takes layering of medications to achieve better control for some patients,” Ailani suggested. “Maybe, with newer targeted medications, we can start seeing a reduction in prescription acute medication use, although every patient with migraine should always have something on hand to treat a migraine attack,” she said.

Ailani noted that, like the CGRP mAbs, most studies of gepants have shown limited AEs. “If they are well tolerated, I would imagine it would be easier for patients to treat a migraine at the first sign of symptoms and therefore achieve a higher degree of success in relieving migraine symptoms, allowing a return to function,” she said. “If the day arrives when we have an oral gepant for migraine prevention, I think patients may like the option of taking a pill daily versus monthly or quarterly injections. Every patient is different, so options are the key here.”
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