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Drug Forecast

Erenumab (Aimovig)

A First-In-Class CGRP Receptor Antagonist as a Novel Prophylaxis Treatment for Migraine Headaches
Martin Paspe Cruz PharmD, BCGP, BCPP, FASCP

Introduction

Migraine is a common neurological disorder of intense, episodic headache pain affecting approximately 39 million men, women, and children in the United States and 1 billion worldwide. It is sometimes preceded by sensory warning symptoms or auras (the most common type, accounting for more than 80%) and often accompanied by nausea, vomiting, extreme photophobia, and sound sensitivity, resulting in extreme disability among affected individuals. An estimated $36 billion annually in health care and lost productivity costs are associated with migraine in the U.S. The medical cost of treating chronic migraine was more than $5.4 billion in 2015; health care costs are 70% higher for a family affected with a migraine sufferer than a nonmigraine household; and U.S. employers lose more than $13 billion annually as a result of 113 million lost work days due to migraine.1–6

Migraine aura usually develops over five to 20 minutes and can last for an hour, but many people experience migraines lasting for four to 72 hours. The International Headache Society describes chronic migraine as headache occurring on 15 or more days a month for more than three months, which, on at least eight days of the month, has the features of migraine headache. Other common symptoms of migraine include visual disturbances (flashing lights, blind spots, zig-zag patterns), paresthesia, throbbing, and unilateral headache with moderate-to-severe pain that increases with activity. About two-thirds of migraine sufferers are women.7–8

Several treatments are available for migraine, but none has made a more significant impact on acute treatment than triptans, which bind and stimulate serotonin receptors in aborting a migraine attack by inhibiting the activity of the trigeminal nerve and its connections with the brain. Onabotulinum toxin A, popularly known as Botox, is used for chronic migraine prevention, which significantly improved quality of life in most clinical trials. Recently, monoclonal antibody (mAb) products directed at calcitonin gene-related peptide (CGRP) and its receptor have been used for the treatment of migraine and cluster headache.9–11 

CGRP plays an integral role in nociception and the modulation of pain pathways in headache disorders. It is a potent cerebral vasodilator and key molecule in the mediation of pain transmission in the trigeminovascular system as well as the pain pathways between the brainstem, thalamus, and cortex. Elevated CGRP levels have been measured in migraine patients compared to healthy patients, and CGRP infusion can induce migraine attacks in the experimental setting. The motivation for developing drugs targeting CGRP and its receptor has been based on these observations.12–14 Erenumab (Aimovig, Amgen), designated erenumab-aooe by the Food and Drug Administration (FDA) when it was approved in May 2018, is a fully human mAb that inhibits the action of CGRP as a competitive receptor antagonist, and studies have shown its efficacy in the acute and prophylactic treatment of migraine in adults.15–19

Description20,21

Erenumab is a human immunoglobulin G2 mAb produced using recombinant DNA technology in Chinese hamster ovary cells. Erenumab is composed of two heavy chains, each containing 456 amino acids, and two light chains of the lambda subclass, each containing 216 amino acids. The chemical formula of erenumab is C6472H9964N1728O2018S50 with an approximate molecular weight of 150 kDa. Erenumab is available as a sterile, preservative-free, clear-to-opalescent, colorless-to-light-yellow solution for subcutaneous administration in a 1-mL single-dose prefilled autoinjector and single-dose prefilled glass syringe containing 70 mg of erenumab, 1.5 mg of acetate, 0.10 mg of polysorbate 80, and 73 mg of sucrose. The erenumab solution has a pH of 5.2. 

Mechanism of Action20–24

Erenumab binds to a CGRP receptor and antagonizes its function. CGRP and its receptor are expressed throughout the peripheral and central nervous system, with vital roles in cranial nociception, and act as a potent arterial vasodilator. CGRP, released from trigeminal terminals at peripheral synapses, results in vasodilation through the CGRP receptors on the smooth muscle cells of meningeal and cerebral blood vessels. Its vasodilatory effects have been shown to play a vital role in migraine pathophysiology. Moreover, studies have shown that patients suffering from migraine headaches produced elevated CGRP levels during acute migraine attacks but returned to therapeutic ranges after effective suma-
triptan treatments. In addition, intravenous administration of CGRP in healthy subjects induced migraine-like attacks. Erenumab is believed to prevent migraine by blocking the CGRP receptor that transmits signals that can cause incapacitating pain.

Pharmacokinetics20–23

Erenumab exhibits nonlinear kinetics. The mean peak serum concentrations (Cmax) and median area under the curve (AUC) were reached following a single subcutaneous dose of 70 mg or 140 mg of erenumab administered to healthy patients and migraine patients (Table 1). The trough serum concentrations for episodic and chronic migraine patients following subcutaneous administration of 70 mg of erenumab once per month and 140 mg of erenumab once per month represented a less-than-twofold accumulation and attained steady state by three months of dosing (Table 1). The mean Cmax of erenumab was observed in approximately six days, with an estimated absolute bioavailability of 82% after a single subcutaneous dose of 70 mg or 140 mg of erenumab administered to healthy volunteers. The mean volume of distribution after a single 140-mg intravenous dose of erenumab during the terminal phase was estimated to be approximately 3.86 L (standard deviation, 0.77). Erenumab CGRP antibodies demonstrate a low risk for drug–drug interactions and hepatotoxicity because they are predominantly metabolized by degradation into peptides and single amino acids. At low concentrations, the elimination of erenumab occurs predominantly through saturable binding to target (CGRP receptor), while at higher concentrations the elimination of erenumab is mainly through a nonspecific, nonsaturable proteolytic pathway. The maximal nonlinear clearance of erenumab was observed to be about 1.84 L per day, with an effective half-life of approximately 28 days. The protein binding of erenumab has not been established, but it is reported to be capable of 50% to 99% total inhibition of CGRP receptors with dosages of 255 ng/mL and 1,134 ng/mL, respectively. The pharmacokinetics of erenumab were not affected by age, gender, race, subtypes of migraine spectrum (episodic or chronic migraine), renal impairment, and hepatic impairment based on population pharmacokinetics analysis. 

Table 1 Pharmacokinetics of Erenumab From a Single-Dose Study20
Parameter Erenumab 70 mg Monthly (mcg/mL) Erenumab 140 mg Monthly (mcg/mL)
Cmax mean (SD) 6.1 (2.1) 15.8 (4.8)
AUClast mean (SD) 159 (58) day 505 (139) day
Cmin (SD)    
Episodic migraine 5.7 (3.1) 12.8 (6.5)
Chronic migraine 6.2 (2.9) 14.9 (6.5)
AUClast = extrapolating area under the curve from time 0 to last measurable concentration;
Cmax = peak serum concentration; Cmin = trough serum concentration; SD = standard deviation

Pharmacodynamics20

Erenumab had no effect on resting blood pressure following intravenous administration of a single 140-mg dose at the same time as 12 mg of sumatriptan (given as two 6-mg doses separated by one hour) versus sumatriptan alone, based on a randomized, double-blind, placebo-controlled study in healthy volunteers. Erenumab is indicated for subcutaneous use only. 

Clinical Trials20

Three randomized, double-blind, placebo-controlled studies were conducted to establish the efficacy and safety of erenumab as a preventive treatment for migraine headaches in adults. Studies 1 and 2 included patients with episodic migraine (four to 14 migraine days per month), and Study 3 included patients with chronic migraine (15 or more headache days per month with at least eight migraine days per month). Patients with a history of migraine, with or without aura, met the criteria based on International Classification of Headache Disorders (ICHD-III) diagnostic criteria. Migraine medications such as triptans, ergot derivatives, and NSAIDs could be used to treat acute headaches during all the studies conducted. Patients with histories of treatment overuse headache, myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening were not included in the three studies; the third study also excluded patients with concurrent use of migraine preventive treatments.20,25

Episodic Migraine Study 120

A randomized, multicenter, six-month, placebo-controlled, double-blind study (N = 955), Episodic Migraine Study 1, was conducted to evaluate erenumab for the preventive treatment of episodic migraine. Subjects were randomly administered erenumab 70 mg (n = 317), erenumab 140 mg (n = 319), or placebo (n = 319) by subcutaneous injection once monthly for six months. Primary efficacy was evaluated based on the change from baseline in mean monthly migraine days (MMDs) over months 4 to 6. Secondary endpoints included a 50% or greater reduction from baseline in mean MMD over months 4 to 6, the change from baseline in mean monthly acute migraine-specific medication days over months 4 to 6, and the change from baseline in mean Migraine Physical Function Impact Diary (MPFID) scores, the impact of migraine on everyday activities (EA) and physical impairment (PI) documented using a daily electronic diary over months 4 to 6. Including days with and without migraine, the monthly MPFID scores (0 to 100) were averaged over 28 days, with higher scores from baseline indicating worse impact on EA and PI and decreased scores indicating improvement. Table 2 shows statistically significant efficacy improvements with erenumab versus placebo in mean MMD (difference from placebo, –1.4 for erenumab 70 mg and –1.9 for erenumab 140 mg [P < 0.001 for both]); a higher number of 50% or more MMD responders (difference from placebo, 16.7% for erenumab 70 mg and 23.4% for erenumab 140 mg [P < 0.001 for both]); and statistically significant results in mean monthly acute migraine-specific medication day scores (difference from placebo, –0.9 for erenumab 70 mg and –1.4 for erenumab 140 mg [P < 0.001 for both]) averaged over four to six months in patients treated with erenumab 70 mg and 140 mg monthly. 

Table 2 Efficacy Endpoints of Erenumab Over Months 4 to 6 (Study 1)20
Endpoints Erenumab 70 mg Monthly
(n = 312)
Erenumab 140 mg Monthly
(n = 318)
Placebo
(n = 316)
Monthly migraine days (MMDs)
Change from baseline –3.2 –3.7 –1.8
Difference from placebo –1.4 –1.9  
P value < 0.001 < 0.001  
≥ 50% MMD responders
Percentage 43.3% 50.0% 26.6%
Difference from placebo 16.7% 23.4%  
Odds ratio relative to placebo 2.1 2.8  
P value < 0.001 < 0.001  
Monthly acute migraine-specific medication days
Change from baseline –1.1 –1.6 –0.2
Difference from placebo –0.9 –1.4  
P value < 0.001 < 0.001  
Episodic Migraine Study 220

A randomized, multicenter, three-month, placebo-controlled, double-blind study (N = 577), Episodic Migraine Study 2, was conducted to evaluate erenumab for the preventive treatment of episodic migraine among subjects who randomly received monthly subcutaneous injections of either erenumab 70 mg (n = 286) or placebo (n = 291) for three months. Primary efficacy was evaluated based on the change from baseline in MMDs at month 3; secondary endpoints were a 50% or greater reduction from baseline in MMDs (50% or greater MMD responders), the change from baseline in monthly acute migraine-specific medication days at month 3, and the proportion of patients with at least a 5-point score reduction from baseline in MPFID at month 3. Table 3 shows statistically significant efficacy improvements for erenumab versus placebo in mean MMD (difference from placebo, –1.0 [P < 0.001]); no significant reductions from baseline in mean MMD (difference from placebo, 10.2%; odds ratio, 1.6 [P = 0.01); and no statistically significant results in mean monthly acute migraine-specific medication day scores (difference from placebo, –0.6 [P < 0.002]) averaged over three months in patients treated with erenumab 70 mg monthly. 

Table 3 Efficacy Endpoints of Erenumab at Month 3 (Study 2)20
Endpoints Erenumab 70 mg Monthly
(n = 282)
Placebo
(n = 288)
Monthly migraine days (MMDs)
Change from baseline –2.9 –1.8
Difference from placebo –1.0  
P value < 0.001  
≥ 50% MMD responders
Percentage 39.7% 29.5%
Difference from placebo 10.2%  
Odds ratio relative to placebo 1.6  
P value 0.010  
Monthly acute migraine-specific medication days
Change from baseline –1.2 –0.6
Difference from placebo –0.6  
P value 0.002  
Chronic Migraine Study 320

A randomized, multicenter, three-month, placebo-controlled, double-blind study (N = 667), Chronic Migraine Study 3, was conducted to evaluate erenumab for the preventive treatment of chronic migraine among patients, with or without aura, who were randomized to receive monthly subcutaneous injections for three months of erenumab 70 mg (n = 191), erenumab 140 mg (n = 190), or placebo (n = 286). The change from baseline in MMD at month 3 was used as the primary efficacy endpoint, while a 50% or greater reduction from baseline in MMDs (50% or greater MMD responders) and change from baseline in monthly acute migraine-specific medication days at month 3 were used as secondary endpoints. Table 4 shows statistically significant efficacy improvements for erenumab versus placebo in mean MMDs (difference from placebo, –2.5 for erenumab 70 mg and –2.5 for erenumab 140 mg [P < 0.001 for both]); greater reductions from baseline in mean MMDs; a greater number of 50% or more MMD responders (difference from placebo, 16.7% for erenumab 70 mg and 23.4% for erenumab 140 mg [P < 0.001 for both]); and statistically significant results in mean monthly acute migraine-specific medication day scores (difference from placebo, –1.9 for erenumab 70 mg and –2.6 for erenumab 140 mg [P < 0.001 for both) averaged over three months in chronic migraine patients treated with erenumab 70 mg and 140 mg monthly.

Table 4 Efficacy Endpoints of Erenumab in Chronic Migraine Patients at Month 3 (Study 3)20
Endpoints Erenumab 70 mg Monthly
(n = 188)
Erenumab 140 mg Monthly
(n = 187)
Placebo
(n = 281)
Monthly migraine days (MMDs)
Change from baseline –6.6 –6.6 –4.2
Difference from placebo –2.5 –2.5  
P value < 0.001 < 0.001  
≥ 50% MMD responders
Percentage 39.9% 41.2% 23.5%
Difference from placebo 16.4% 17.7%  
Odds ratio relative to placebo 2.2 2.3  
P value < 0.001 < 0.001  
Monthly acute migraine-specific medication days
Change from baseline –3.5 –4.1 –1.6
Difference from placebo –1.9 –2.6  
P value < 0.001 < 0.001  

Safety Profile

Adverse Events20

The most common adverse reactions with erenumab in clinical trials (3% or more of erenumab-treated patients versus placebo) were injection-site reactions (pain, erythema, pruritus) and constipation based on placebo-controlled studies in which 2,184 subjects (84% female; 91% white; mean age, 42 years) were treated with erenumab 70 mg once per month (n = 787), 140 mg once per month (n = 507), and placebo (n = 890) during three or six months of double-blind treatment. Cramps and muscle spasms were also reported (Table 5). 

Table 5 Adverse Effects of Erenumab Within 3 Months of Migraine Studies20
Adverse Effects Erenumab 70 mg Monthly
(n = 787)
Erenumab 140 mg Monthly
(n = 507)
Placebo
(n = 890)
Injection site reactions 6% 5% 3%
Constipation 1% 3% 1%
Cramps, muscle spasms <1% 2% <1%
Immunogenicity20

Due to its potential for immunogenicity, erenumab was evaluated using an immunoassay screening for anti-erenumab antibodies, as well as subsequent in vitro assay for detection of neutralizing antibodies in subjects who tested positive during the screening immunoassay. Controlled studies demonstrated an incidence of anti-erenumab antibody development of 6.2% (48/778) and 2.6% (13/504) among subjects who received erenumab 70 mg once monthly (two had in vitro neutralizing activity) and erenumab 140 mg once monthly (none had in vitro neutralizing activity), respectively. Despite the lack of clinical effects of neutralizing anti-erenumab antibody development rates on the efficacy or tolerability of erenumab among subjects during migraine prevention studies, the data available were too limited to make definitive conclusions.

Contraindications20

Erenumab has no contraindications for its use in the prevention of migraine headaches in adults. 

Carcinogenesis, Mutagenesis, and Impairment of Fertility20

Carcinogenic potential, genetic toxicology, and fertility impairment studies were not conducted during the clinical trials of erenumab for migraine prevention. There were no reported histopathological changes in the male or female reproductive organs in monkeys following subcutaneous administration of erenumab (0, 25, or 150 mg/kg) twice weekly for up to six months during clinical trials. 

Drug–Drug Interactions20 

Since erenumab is not metabolized by cytochrome P450 enzymes, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely. The pharmacokinetics of combined ethinyl estradiol and norgestimate oral contraceptive were unaffected following subcutaneous administration of a single 140-mg dose of erenumab based on an open-label drug interaction study in healthy females. Additionally, concomitant administration of erenumab with sumatriptan had no effect on the pharmacokinetics of suma­triptan based on a clinical trial in healthy volunteers. 

Use in Specific Populations 

Pregnancy and Lactation20 

No adequate data are available regarding erenumab-induced fetal developmental risks. Although serum erenumab (AUC) levels in animals were approximately 20 times that in humans at a dose of 140 mg once per month during trials, no adverse side effects were reported on offspring in pregnant monkeys given subcutaneous erenumab (0 or 50 mg/kg) twice per week throughout pregnancy. The excretion of erenumab in human milk, its effects on the breastfed infant, and the effects on milk production are unknown. 

Geriatric and Pediatric Use20 

The safety and efficacy of erenumab injection in geriatric and pediatric patients have not been studied. A lower dosage of erenumab may be recommended in patients 65 years of age and older since they are more likely to have decreased hepatic, renal, or cardiac function; to have concomitant disease; or to use other drugs that may interact with erenumab.

Renal and Hepatic Impairment20 

The pharmacokinetics of erenumab in patients with renal or hepatic impairment have not been established, and the manufacturer did not provide any dosage adjustment in such patients. 

DOSAGE & ADMINISTRATION20

The recommended dose of erenumab for migraine prevention is 70 mg once monthly via subcutaneous administration in the abdomen, thigh, or upper arm, although some patients may benefit from 140 mg once monthly (given as two injections of 70 mg). Individuals with sensitivity to latex may experience an allergic reaction because the needle shield within the white cap (prefilled autoinjector) and gray needle cap (prefilled syringe) of erenumab injections contains a latex derivative. Special instructions during preparation include storing the erenumab injection solutions at 2° C to 8° C, keeping it at room temperature for at least 30 minutes prior to administration, discarding it when left at room temperature after seven days, protecting it from direct sunlight, not warming it up using hot water or a microwave, and not shaking the product. 

Conclusion 

Migraine is associated with pain, disability, decreased quality of life, and economic burden, and it has been listed as one of the top 10 causes of years lived with disability among adults by the World Health Organization. Current evidence-based treatment guidelines from the American Academy of Neurology and the American Headache Society state that anticonvulsants, such as divalproex sodium and topiramate, as well as beta blockers, including propranolol and metoprolol, offer pharmacological migraine prophylaxis with established efficacy. On the other hand, CGRP has long been implicated in the etiology of migraine. Decades of research established the development of CGRP mAbs as a long-awaited breakthrough in migraine prevention. Erenumab is the first FDA-approved treatment to block the CGRP receptor, which is essential to migraine. Erenumab has established its safety and efficacy in more than 3,000 patients and a five-year open-label extension study is continuing. Aimovig (branded erenumab) has a listed average wholesale price of $690 for a 70-mg or 140-mg single-use prefilled SureClick autoinjector, or $8,280 annually. The cost of erenumab may reflect the value it brings to patients and society considering its improvements in the quality of life for patients suffering with migraine. It is a promising alternative treatment, but accessibility, inconvenience during administration, nonoral formulation, cost, and perhaps the need for a headache specialist or headache specialty center during in-office administration, may be of concern. Injection site-reactions and constipation have been reported as the most common adverse effects of erenumab, but its long-term safety and efficacy await further evaluation, including among special populations with comorbid disease states.6,24,26,27

Disclosure: The authors report no commercial or financial interest in regard to this article.

Author bio: 

Dr. Cruz is a Clinical Assistant Professor at Virginia Commonwealth University School of Pharmacy in Richmond, Virginia, and Hampton University School of Pharmacy in Hampton, Virginia; Assistant Professor of Clinical Psychiatry at Eastern Virginia Medical School in Norfolk, Virginia; and a Clinical Pharmacy Specialist at the Hampton Veterans Affairs Medical Center in Hampton, Virginia. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi and Associates in New York, New York.

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