US Pharm. 2020;45(1):21-24.

ABSTRACT: Migraine is a debilitating disorder that affects 37 million people in the United States. Recently, three new calcitonin gene-related peptide (CGRP) receptor antagonists—erenumab, fremanezumab, and galcanezumab—were FDA approved for prophylactic treatment of migraine. In clinical trials, these agents, which have no drug interactions and minimal adverse reactions, reduced headache days per month by as much as 50% in patients experiencing multiple migraine days each month. These new biologics, however, are more expensive for the patient compared with other prophylactic treatments. The patient should discuss with his or her physician whether a CGRP antagonist is the best therapy choice compared with other treatment options for migraine. The knowledgeable pharmacist will have an opportunity to educate patients on proper care and inform providers on appropriate use.

Migraine is a debilitating disorder that affects 37 million people in the United States.1 The addition of new biologics to the array of migraine treatments makes it necessary for pharmacists to learn how these products work and how they differ from existing therapies. It is essential for pharmacists to understand how the new biologics target a different system in order to effectively reduce or treat a patient’s migraines.

Migraine management has significantly evolved over the past year with the release of new biologics. Historically, prophylactic treatment has involved the use of preventive medications, originally designed for different conditions, that do little for chronic or episodic migraine.2 However, new biologics have been developed to target a specific substance in the brain—calcitonin gene-related peptide (CGRP)—that plays a key role in migraine pathophysiology.3 By blocking the receptor function of CGRP, these agents can reduce the total number of headache days per month and limit the need for using multiple medications. Currently, three CGRP antagonists have been approved by the FDA for the preventive treatment of migraine in adults: Aimovig (erenumab-aooe; hereafter shortened to “erenumab”), Ajovy (fremanezumab-vfrm; shortened to “fremanezumab”), and Emgality (galcanezumab-gnlm; shortened to “galcanezumab”). All three agents are injectables that, with proper counseling and guidance, may be administered by the patient at home. TABLE 1 provides a brief overview of each CGRP antagonist. A fourth CGRP antagonist, eptinezumab, is undergoing open-label safety studies and will not be discussed here.

Migraines and Cluster Headaches

The International Headache Society has published a detailed classification of primary headaches, including migraine. Chronic migraine is defined as the occurrence of 15 or more headache days per month, with migraine features present on at least eight of these days. Episodic migraine is the occurrence of 4 to 14 migraine days per month. Cluster headache, which is often misdiagnosed as migraine, is the most common of the primary headache disorders known as trigeminal autonomic cephalalgias; this type of headache derives its name from the fact that the attacks occur in cyclical patterns, or clusters.4

Mechanism of Action

Traditional first-line therapy for migraine includes several medications from multiple drug classes and lacks a definitive treatment algorithm. Patients often present to a physician after unsuccessfully attempting multiple nonprescription therapies.1 Migraine patients have increased levels of CGRP, which has been shown to play an important role in the pathophysiology of migraine.5 This neuropeptide, when bound to its receptor, is responsible for a cascade of events that contribute to neurogenic inflammation, including mast-cell degranulation, vasodilation, and protein extravasation. CGRP antagonists are humanized monoclonal antibodies that bind to the CGRP receptor or ligand and block its binding activity selectively; this is believed to block the aforementioned cascade of events, thus preventing migraine.5 This is the first class of medications designed for the prevention of migraines to work with this mechanism.

Clinical Trials

The efficacy of erenumab, fremanezumab, and galcanezumab for the treatment of migraine has been established in clinical trials.6-8

Erenumab: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III trial assessed the safety and efficacy of the erenumab injection (70 mg and 140 mg) compared with placebo in 955 patients with episodic migraine. The study period was 6 months. From baseline to the final 3 months (months 4-6) of the double-blind treatment phase, the overall reduction in average migraine days per month was 3.2 days in the 70-mg erenumab group and 3.7 days in the 140-mg erenumab group, compared with 1.8 days in the placebo group (both doses vs. placebo, P <.001). A reduction of at least 50% in average migraine days per month from baseline to months 4 through 6 was achieved by 43.3% of patients in the 70-mg erenumab group and 50.0% of patients in the 140-mg erenumab group, compared with 26.6% in the placebo group (both doses vs. placebo, P <.001).9

A randomized, double-blind, placebo-controlled, multicenter, phase II study of erenumab in adults aged 18 to 65 years with chronic migraine evaluated 667 patients taking erenumab (70 mg or 140 mg) versus placebo. Both erenumab doses reduced monthly migraine days versus placebo (–6.6 days for both doses vs. –4.2 days for placebo; total difference of –2.5 for each dose; 95% CI, –3.5 to –1.4; P <.0001), leading to FDA approval for both dosing regimens.10

Fremanezumab: A randomized, double-blind, placebo-controlled, parallel-group study compared fremanezumab (225 mg monthly or 675 mg quarterly) with placebo in 875 patients with episodic migraine. Mean migraine days per month decreased from 8.9 days to 4.9 days in the 225-mg group; from 9.2 days to 5.3 days in the 675-mg group; and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference of –1.5 days for 225-mg-monthly dosing versus placebo (95% CI, –2.01 to –0.93 days; P <.001) and –1.3 days for 675-mg-quarterly dosing versus placebo (95% CI, –1.79 to –0.72 days; P <.001).11

A randomized, double-blind, placebo-controlled, parallel-group trial compared fremanezumab quarterly and fremanezumab monthly versus placebo (1:1:1 ratio) in 1,130 patients with chronic migraine. The mean number of headache days per month was reduced by 4.3 ± 0.3 days in the fremanezumab-quarterly group, 4.6 ± 0.3 days in the fremanezumab-monthly group, and 2.5 ± 0.3 days in the placebo group (P <.001 for both comparisons). Significantly more patients receiving fremanezumab had a reduction of at least 50% in the average number of headache days per month (quarterly regimen, 38%; monthly regimen, 41%) compared with placebo patients (18%; P <.001 for both comparisons).12 As a result, fremanezumab is approved in dosages of both 225 mg monthly and 675 mg quarterly.

Galcanezumab: A global, double-blind, randomized, placebo-controlled trial (EVOLVE-2) investigated the safety and efficacy of galcanezumab (120 mg and 240 mg) versus placebo in 858 patients with episodic migraine over a 6-month period. Treatment with galcanezumab significantly reduced monthly migraine headache days by 4.7 days (120 mg) and 4.6 days (240 mg), respectively, compared with placebo (2.8 days; P <.001 for both comparisons). Substantially more patients receiving galcanezumab had a reduction of more than 50% in mean headache days per month versus placebo (65% for galcanezumab vs. 42% for placebo; P <.001).13,14

REGAIN, a phase III, randomized, double-blind, placebo-controlled study of galcanezumab in 1,113 patients with chronic migraine, evaluated monthly SC injections of placebo, galcanezumab 120 mg (with a 240-mg loading dose), or galcanezumab 240 mg in a 2:1:1 ratio. Both galcanezumab groups demonstrated greater overall mean reductions in number of headache days per month compared with placebo (placebo –2.7, galcanezumab 120 mg –4.8, galcanezumab 240 mg –4.6; P <.001 for each dose vs. placebo).15 The recommended dosage is 240 mg as an initial loading dose, followed by 120 mg monthly.

A randomized, double-blind, placebo-controlled study comparing galcanezumab and placebo in adult patients with cluster headache was conducted over 8 weeks. Galcanezumab reduced the number of weekly cluster headache attacks by an average of 8.7 versus 5.2 with placebo (P = .036 vs. placebo) over weeks 1 to 3.16 As a result, in 2019, galcanezumab became the first drug to be approved by the FDA for treating episodic cluster headache (it was approved for preventive treatment of migraine in 2018).17

Adverse-Reaction and Safety Concerns

Injection-Site Reactions: In clinical trials, the most common adverse events (in >10% of the study population) for all three CGRP antagonists were injection-site reactions and pain. Hypersensitivity reactions, including redness, swelling, pain, or irritation at the injection site, may occur. The patient should notify his or her physician immediately if he or she has serious injection-site irritation or signs of a severe allergic reaction.6-8 In clinical trials, subjects experienced injection-site reactions while taking erenumab (occurring in 3% or more of treated subjects and more often than in those given placebo), fremanezumab (5% or more of subjects and more often than in those given placebo), and galcanezumab (incidence 2% or higher and at least 2% greater than in those given placebo).1-3,8 Subjects taking galcanezumab 240 mg had significantly more injection-site erythema than subjects given placebo.14

Neutralizing Antibodies: Patients taking CGRP antagonists may experience binding antibodies, and neutralizing antibodies may occur. In the erenumab trials, 35 of the 628 patients (5.6%) tested positive for anti–erenumab binding antibodies, and one of them (in the 70-mg erenumab group) tested positive for neutralizing antibodies (0.2%).9,10 In the fremanezumab trials, antidrug antibodies developed in two patients who received fremanezumab quarterly.12 In the galcanezumab trials, treatment-emergent antidrug antibodies occurred in 22 patients and 13 patients had neutralizing antibodies (0.6%, 2.3%, and 1.5% of the placebo, galcanezumab 120-mg, and galcanezumab 240-mg groups, respectively), with a significant difference between galcanezumab 120 mg and placebo (P <.05). Antidrug antibodies had no discernible effect on treatment efficacy or tolerability.15

Erenumab-Specific Adverse Reactions: Constipation occurred in up to 3% of patients in the erenumab trials. Patients in these trials also experienced muscle cramps and spasms.9,10

Drug Interactions: Currently, there are no known significant drug interactions with erenumab, fremanezumab, or galcanezumab.6-8

Guideline Update

Owing to the lack of extensive published data, the American Headache Society (AHS) included in its recent consensus statement information on CGRP receptor antagonists as emerging treatments for migraines.16 These biologics have proven efficacy, safety, and tolerability for the prevention and treatment of both episodic and chronic migraine in phase II and phase III randomized, placebo-controlled clinical trials. The lack of a required dose titration and the rapid effects of treatment demonstrate the potential utility of these medications. Caution must be exercised in patients with long-standing chronic migraine and in those who have failed multiple prior attempts with preventive treatments. The efficacy and tolerability of these medications are patient-driven and may not replicate the endpoints used in clinical trials; however, they may be useful in practice if mean headache days per month are reduced and the patient has minimal side effects with effective results. According to the AHS, because these novel treatment options—unlike other first-line treatments—do not result in constriction of blood vessels, they may be useful in patients with cardiovascular contraindications. The absence of hepatic and renal metabolism and clearance means that there are no drug interactions with concomitant drugs, so these agents may be added to other injectable or oral therapies for the treatment and prevention of migraines. Response to the continuous use of CGRP antagonists is healthcare professional–dependent and should be guided by outcomes of reduction in mean migraine days per month, migraine-related disability, impact on and functional impairment of patients, and use for up to 3 months.16

Cost Comparison

The estimated cost of erenumab, fremanezumab, and galcanezumab is approximately $575 per month, or approximately $5,000 annually. The Institute for Clinical and Economic Review determined that prices for CGRP antagonist treatments align with the value to patients who failed other preventive therapies. Assistance programs for these medications are available through the manufacturer, providing up to a no-cost 1-year supply or out-of-pocket expense assistance for certain patients with commercial insurance. These agents are shown to be cost-effective for the patient in the long term.17 The AHS pointed out that in order to achieve cost-effective care while ensuring access for those patients most appropriate for these treatments, it is important that the indications for initiating treatment with CGRP antagonists are well understood.18


CGRP antagonists appear to significantly improve treatment outcomes in patients who experience episodic or chronic migraines.19 Previously, there were no medications specifically designed for the prophylactic treatment of migraines until the release of these three new monoclonal antibodies. These agents have ushered a new era of migraine therapy. Because this new class of injectable monoclonal antibodies is directed against a new system and these agents are proven efficacious, pharmacists will have an opportunity to not only educate their patients on proper care, but also inform providers on appropriate use. Patients may experience minimal side effects from a very well tolerated therapeutic regimen that could begin improving their headache days within the first month. Although these CGRP antagonists have been shown to prevent and reduce headache days in clinical trials, they may not work for everyone, and not all patients will benefit. Considerations should be made according to the patient’s health and comorbidities. The patient should discuss with his or her physician whether a CGRP antagonist is the best therapy choice compared with other treatment options for migraine.


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