By Julia Bucklan, DO, and Zubair Ahmed, MD
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This article is slightly adapted from the April 2020 issue of Cleveland Clinic Journal of Medicine (2020;87:211-218). For references, see the original version there.
The cornerstone of preventive migraine treatment has long been drugs intended for other diseases — epilepsy, depression and hypertension. But in 2018, the FDA approved three new drugs — erenumab, galcanezumab and fremanezumab — specifically for decreasing the frequency of migraine attacks. A fourth, eptinezumab, was approved February 22, 2020. These monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptors are the first preventive medications to target the pathophysiology of migraine.
The new drugs represent a long-overdue new frontier in headache medicine. Although they don’t seem to be more effective than current drugs, they have long half-lives, permitting monthly or even quarterly dosing, and fewer adverse effects, which may improve adherence. In addition, they carry no contraindications for patients with liver disease, kidney disease, stroke or coronary artery disease. They also have no known significant drug-drug interactions. Their primary disadvantage is cost (about $700 per month), although insurance may pay for them and the manufacturers offer assistance programs. For an overview of the four FDA-approved CGRP antagonists, see Table 1 here.
A need for more options
Headache disorders, treated as early as 1200 BCE by the ancient Egyptians, affect nearly half of the world’s adult population. In the U.S. alone, migraine affects nearly 40 million people. It is associated with decreased function in an otherwise healthy and productive demographic group and is the leading cause of healthy life-years lost as a result of disability from ages 15 to 49.
Drugs that have long been used in migraine prophylaxis have many adverse effects and need to be taken daily, which can lead to nonadherence; more than 80% of patients stop taking them within one year.
CGRP is a key molecule in migraine
Migraine is a multifactorial disorder with complex interactions between multiple predisposing genetic and modulating nongenetic factors.
Current understanding of migraine is that a wave of neuronal and glial depolarization activates meningeal nociceptors innervated by the trigeminovascular system. When these perivascular afferent fibers are activated, the signal travels through the trigeminal ganglion to neurons in the trigeminocervical complex, using CGRP as the prominent neurotransmitter. This leads to symptoms such as cutaneous allodynia, neck pain, photophobia, phonophobia and osmophobia. Once this signal reaches the visual cortex, it alters visual perception, resulting in double vision, change in color saturation and blurred vision.
The discovery that using a peripherally active biologic, onabotulinumtoxinA, could be effective in migraine prophylaxis led to further investigation of the mechanism of action. It is now understood that onabotulinumtoxinA inhibits CGRP release from peripheral neuronal C fibers and does not cross the blood-brain barrier.
CGRP, discovered in 1982, is a large molecule. It binds two major receptors: calcitonin receptor-like receptor and receptor activity-modifying protein 1. This leads to signaling that can cause vasodilation or release of neurotransmitters or cytokines, in turn causing neurogenic inflammation and increased neuronal excitability.
CGRP receptors are found at all of the known central and peripheral sites involved in migraine pathogenesis, including the hypothalamus and parabrachial nucleus, and CGRP levels are elevated during migraine attacks and lower between attacks. Studies in animals first showed that stimulation of the trigeminal ganglion was associated with increased blood flow and release of CGRP, which could be inhibited by sumatriptan or dihydroergotamine. Studies in humans showed that sumatriptan, in addition to relieving migraine, lowered CGRP levels in the internal jugular vein. CGRP has also been shown to induce migraine-like symptoms after intravenous infusion.
These observations led researchers to develop drugs that target and block either the CGRP ligand itself or the receptors upon which it acts.
CGRP antagonists: a new class of drugs
The first CGRP antagonists to be studied were small molecules, with names ending in the suffix -gepant. These so-called gepants block CGRP receptors, and six were found to be effective in acute treatment of episodic migraine. However, their development was discontinued due to reports of hepatotoxicity.
Next to be developed were monoclonal antibodies targeting CGRP. These agents are metabolized by the reticuloendothelial system and, as a result, bypass hepatic metabolism; to date, no adverse effects on the liver have been reported. Further, the current injectable antibodies are not thought to be contraindicated in patients with coronary artery, cerebrovascular, peripheral vascular or kidney disease.
Efficacy of CGRP antagonists
Clinical trials of the monoclonal antibodies (summarized in Table 2 here) have found them to be superior to placebo and similar in efficacy to current prophylactic treatments for episodic and chronic migraine. (Episodic migraine is defined as having headaches that fulfill diagnostic criteria for migraine on fewer than 15 days per month. Chronic migraine is defined as having headaches on 15 or more days per month for at least three months with a preexisting diagnosis of migraine; of the total headache days, at least 8 days per month should meet migraine criteria). Roughly half of patients receiving these drugs achieved at least a 50% reduction in the number of headache days per month, compared with roughly one-fourth of patients receiving placebo. The new drugs also have aso been shown to be tolerable and safe, with no significant effects on blood pressure or peripheral vasoconstriction.
Erenumab. Unlike galcanezumab and fremanezumab, erenumab targets the canonical CGRP receptor rather than the CGRP ligand itself. It received FDA approval for prevention of migraine in May 2018. There are two available doses, 70 mg and 140 mg, which patients give themselves once a month at home using a preloaded subcutaneous autoinjector.
- Episodic migraine. Three trials looked at 50% responder rates and mean decrease in monthly migraine days with use of erenumab in patients with episodic migraine (Table 2). Results were reliably better with erenumab than with placebo, including in groups with so-called refractory migraine for whom two to four oral preventive therapies had failed.
- Chronic migraine. Results were similar in patients with chronic migraine. Adverse effects included injection-site pain (reported by 4% of patients receiving active treatment), constipation (4% of those on 140 mg) and muscle spasm (4% of those on 140 mg).
Fremanezumab targets the CGRP ligand rather than the receptor. It gained FDA approval for prevention of migraine in September 2018. It can be taken as a monthly subcutaneous injection of 225 mg or as a quarterly injection of 675 mg.
- Episodic migraine. A phase 3 trial in episodic migraine showed a decrease in mean monthly headache days and increases in the 50% and 75% responder rates with either dose compared with placebo (P < 0.0001) (Table 2).
- Chronic migraine. The same trial also compared fremanezumab and placebo in patients with chronic migraine. The number of days with headache of moderate to severe intensity was reduced by 4.2 days in the placebo group and by 6 days in both a group receiving 225 mg monthly and a group receiving 675 mg quarterly. In a separate study, investigators found that patients noted an improvement as early as one week from initiation of therapy with both dose regimens.
Galcanezumab also targets the CGRP ligand and also received FDA approval for prevention of migraine in September 2018. It is given subcutaneously once a month with an autoinjector or prefilled syringe in a recommended monthly dose of 120 mg after an initial loading dose of 240 mg.
- Episodic migraine. Two six-month trials compared monthly injections of galcanezumab 120 mg, galcanezumab 240 mg and placebo (Table 2). Both studies demonstrated a reduction of migraine days and an increase in 50% responder rate superior to placebo. Interestingly, about 17% of patients had a 100% reduction in mean migraine days. This was seen most commonly in the last three months of the trials and represented a statistically significant difference from placebo (P < 0.001).
- Chronic migraine. In a phase 3 trial (Table 2), galcanezumab showed a significant decrease in mean monthly migraine days compared with placebo. Also, differences in the 50% and 75% responder rates were statistically significant in each treatment group compared with placebo (P < 0.001). Similar to the episodic migraine trial, 11.5% of galcanezumab recipients in the chronic migraine trial noted 100% reduction in mean migraine days, which was again seen most commonly in the last three months of the trial (P < 0.001).
Eptinezumab, a monoclonal antibody against the CGRP ligand, is given intravenously, whereas the other CGRP monoclonal antibodies are given subcutaneously. It was approved by the FDA for migraine prevention in February 2020.
- Episodic migraine. In a three-month phase 3 trial (Table 2), quarterly infusions of eptinezumab 300 mg significantly reduced the mean number of monthly migraine days. Secondary end points included the 75% responder rate at week 12 (49.8% in the 100-mg arm, P = 0.0085; and 56.3% in the 300-mg arm, P < 0.0001). The trial also demonstrated rapid onset of effect, with a reduction in the likelihood of migraine within 24 hours of infusion. Before treatment, 58% of participants were likely to have a migraine on any given day. This declined by 27% in the placebo group, 51% in those who received 100 mg and 53% in those who received 300 mg (P < 0.0001 for both doses). At a 300-mg dose given quarterly, the 75% responder rate was maintained for up to one year.
- Chronic migraine. A phase 3 trial showed a significant reduction in mean monthly migraine days compared with placebo at doses of 100 mg and 300 mg (Table 2).
A pragmatic approach to anti-CGRP drug therapy
The approach to migraine management must remain a combination of cost-effective first- and second-line treatments, with CGRP monoclonal antibodies generally reserved for patients for whom these options fail. All pharmacologic treatments should be accompanied by education and specific lifestyle changes for the best possible outcome.
In 2012, the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society reviewed the evidence and ranked the migraine preventive therapies available in the U.S. at that time according to the evidence of their efficacy. Ratings were as follows:
Level A medications (i.e., having “established efficacy):
- The antiepileptic drugs divalproex sodium, sodium valproate and topiramate
- The beta-blockers metoprolol, propranolol and timolol
- The tripan frovatriptan (for short-term prophylaxis)
Level B medications (i.e., “probably effective”):
- The antidepressants amitriptyline and venlafaxine
- The beta-blockers atenolol and nadolol
- The triptans naratriptan and zolmitriptan
Level C medications (i.e., “possibly effective”):
- The angiotensin-converting enzyme inhibitor lisinopril
- The angiotensin II receptor blocker candesartan
- The alpha-agonists clonidine and guanfacine
- The antiepileptic drug carbamazepine
- The beta-blockers nebivolol and pindolol
- The antihistamine cyproheptadine
While no formal guidelines exist for deciding whether anti-CGRP drugs would be appropriate for specific patients, the American Headache Society has offered general recommendations based on the frequency of migraine. These state that CGRP antagonists may be considered in the following patients:
- Those with 4 to 7 migraine days per month who have been unable to tolerate a six-week trial of at least two oral preventive medications with level A or B evidence (see above). In addition, patients should have at least moderate disability on the Migraine Disability Assessment Scale or the Headache Impact Test 6, both of which are used to assess functional impairment secondary to migraine.
- Those with 8 to 14 headaches per month who cannot tolerate a six-week trial of at least two oral preventive drugs with level A or B evidence (no need to demonstrate functional impairment).
- Those with 15 or more headaches per month (i.e., chronic migraine) if at least two preventive medications with level A or B evidence have failed or if onabotulinumtoxinA has produced an inadequate response after at least two administrations or has caused adverse effects precluding further use.
At this time, not enough data exist on the safety of this class of medications in pregnant patients or children.
Findings from clinical trials suggest that if a patient is going to respond to CGRP monoclonal antibody therapy, response should happen within the first three months, and often as early as one month after starting. If migraines continue unabated in this period, it is reasonable to discontinue the medication.
Orally administered gepant medications have been revisited in clinical trials over the past five years for both abortive and preventive treatment. Results are recapped below.
Ubrogepant for acute migraine treatment. A multicenter, randomized, double-blind, placebo-controlled trial of ubrogepant for acute treatment of migraine showed a statistically significant improvement in rates of pain freedom two hours post-dose at 25 mg (P = 0.013), 50 mg (P = 0.020) and 100 mg (P = 0.003). Adverse effects were similar to those with placebo and included dry mouth, nausea, fatigue, dizziness and somnolence. There were no observed liver function test elevations as seen in previous gepant trials. Ubrogepant received FDA approval for the acute treatment of migraine with or without aura on December 23, 2019.
Rimegepant has also been studied for acute treatment of migraine in a double-blind, randomized, placebo-controlled trial. Patients were randomized to receive placebo, sumatriptan or rimegepant. The primary outcome was percentage of patients who were free of pain two hours post-dose. Sumatriptan 100 mg and rimegepant 75 mg, 150 mg and 300 mg were all significantly more effective than placebo (P < 0.007), and rimegepant was as effective as sumatriptan. No chest discomfort or paresthesias were reported with rimegepant as they were with sumatriptan. A multicenter long-term safety study is underway using a prospective open-label design. Rimegepant received FDA approval for acute treatment of migraine on February 27, 2020.
Atogepant has been evaluated for prevention of episodic migraine. In a phase 2b/3 trial, mean headache days were reduced by 4.23 days per month with atogepant 40 mg twice daily, compared with 2.85 days with placebo (P = 0.0034). There was no evidence of hepatotoxicity.
CGRP antagonists for other types of headache
Cluster headache. Episodic cluster headache is defined as cluster headache attacks occurring in periods lasting from seven days to one year, separated by pain-free periods lasting at least three months. Chronic cluster headache, in contrast, is defined as cluster headache attacks occurring for one year or longer without remission, or with remission periods lasting less than three months.
In June 2019, galcanezumab received FDA approval for treatment of episodic cluster headaches. For treatment, galcanezumab 300 mg is administered as three consecutive injections of 100 mg at the onset of a cluster period and then monthly until the end of the cluster period.
In clinical trials, galcanezumab significantly reduced mean cluster attack frequency compared with placebo, with more than 70% of patients experiencing at least a 50% reduction in weekly cluster headache attack frequency by week 3. However, while trials showed galcanezumab to be effective in episodic cluster, this was not true for chronic cluster.
Fremanezumab was also not effective in the prevention of chronic cluster headache compared with placebo.
Persistent posttraumatic headache. Data from rodent models of concussion suggest that cephalic tactile pain hypersensitivity improves with administration of murine CGRP antagonists. Fremanezumab is currently being studied for the prevention of persistent posttraumatic headache.
Medication-overuse headache. Patients with medication-overuse headache may also benefit from anti-CGRP monoclonal antibodies. Both erenumab and fremanezumab have shown efficacy in treating the subgroup of chronic migraine patients with medication-overuse headache. Erenumab 70 mg led to a reduction of 5.2 migraine days per month, and 140 mg yielded a reduction of 5.4 days, compared with a reduction of 3.5 days with placebo in patients with medication-overuse headache (P < 0.001).
For a version of this article with references, see the original Cleveland Clinic Journal of Medicine publication (2020;87:211-218).
Dr. Bucklan is with the Center for General Neurology and Dr. Ahmed is with the Center for Neurological Restoration, both in Cleveland Clinic’s Neurological Institute.