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A New Breakthrough in Migraine Treatment – Aimovig (erenumab)

Friday, April 19, 2019  
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Allison Tempo, Doctor of Pharmacy Candidate Duquesne University School of Pharmacy

David E. Zimmerman, PharmD, BCPS, BCCCP Associate Professor of Pharmacy at Duquesne University

Migraines are a recurrent type of headache characterized by severe throbbing, one-sided head pain, and occasionally symptoms such as nausea, weakness, and sensitivity to light and sound. Migraines tend to be more common in females. There is currently no cure for migraines, only medications to relieve symptoms and prevent recurrent attacks.1 In May of 2018 the FDA approved the newest treatment for prevention of episodic migraine, Aimovigä (erenumab). Erenumab is administered as a subcutaneous, self-administered injection into the abdomen, thigh, or upper arm (upper arm administration requires administration by a caregiver). Erenumab is recommended at a dosage of 70 mg once a month, but some patients may benefit from 140 mg once a month.2  Erenumab is a fully human monoclonal antibody which binds to calcitonin gene related peptide (CGRP) to block the protein’s activation. It has been shown that serum levels of CGRP increase during a migraine.3 Likewise, decreased jugular venous CGRP levels correspond to migraine termination.4 Erenumab is the first of its kind in the newest class of medications targeting CGRP receptors to specifically target migraines.

The STRIVE trial provided the FDA with the safety and efficacy of erenumab needed for the drug’s approval. STRIVE was a prospective study compared to placebo lasting approximately fourteen months and enrolling patients with four to fifteen migraine days per month and less than fifteen headache days per month reported in the three months prior to beginning the trial. Participants were between the ages of 18 to 65 with the majority of participants being female and Caucasian. There were four phases to the STRIVE trail.  The initial phase, in which patients were screened for up to 3 weeks and then underwent a 4 week baseline phase to monitor adherence.  The initial phase was followed by a 24 week double blind treatment phase.  Participants were randomly assigned in a 1:1:1 ratio to receive 70 mg, 140 mg, or placebo injections each month.  Following the double blind treatment phase, participants were then randomized into a 28 week active treatment phase and received either the 70mg or the 140mg monthly injection.  Lastly, participants underwent a 12 week safety/follow-up period.  During the entire trial participants were required to electronically track their migraine days per month and medication usage and the patients who could not achieve 80% adherence to documenting during the lead in phase were excluded from the trial. Initially 1,492 patients were screened for trial eligibility but only 858 completed the 24 week double blind treatment phase. With a planned enrollment of 284 patients per treatment group this study provided a power of ≥ 90%. The primary endpoint of this study was to compare erenumab with placebo in regard to the change in mean number of migraine days per month from baseline to the final three months of the double blind treatment phase. The primary endpoint was analyzed with the use of a linear mixed effects model without any imputation of missing data and the change in baseline of migraine days over the last three months of the double blind treatment phase showed statistical significance between both erenumab groups and the placebo group. The placebo group showed a 1.8 day reduction, the erenumab 70mg group showed a 3.2 day reduction, and the erenumab 140mg group showed a 3.7 day reduction in monthly migraine days over the last three months of therapy (p < 0.001, 95% CI).  Secondary endpoints of the trial included: at least a 50% reduction in the mean number of migraine days per month and a change in the baseline number of days of acute migraines specific medicaition.5 A linear mixed effects model without any imputation of was used to analyze the change in monthly acute migraine-specific medication treatment days during the 24 week double blind treatment phase while a Cochran-Mantel-Haenszel test was used to analyze for at least a 50% reduction in the mean number of monthly migraine days.5 Changes from baseline in mean monthly acute migraine specific medication use over the last 3 months of the double blind treatment phase between both erenumab doses and placebo also proved to be statistically significant.  Patients reduced the monthly migraine specific medication usage by 0.2 days with placebo, 1.1 days with erenumab 70mg, and 1.6 days with erenumab 140mg (p < 0.001, 95% CI) .6 At least a 50% reduction in monthly migraine days during the last 3 months of the double blind phase was achieved in 43.3% of patients receiving 70 mg of erenumab, 50.0% of patients receiving 140 mg erenumab, and only 26.6% of patients receiving placebo (p < 0.001, 95% CI). This proved statistical significance for the rate of a 50% or greater reduction from baseline in migraine days per month with erenumab as opposed to placebo.5 Overall, erenumab proved to be an effective treatment option in lowering monthly migraine days and monthly migraine medication use in patients with episodic migraine.

Despite the noted benefits of erenumab in patients with episodic migraine, during clinical trials the medication was not tested for safety and efficacy for certain patient-specific situations and therefore there is no evidence supporting the use of erenumab in patients who:

  • Had no therapeutic response in migraine prevention after an adequate trial of more than two of the following medications:
    • Divalproex sodium, sodium valproate
    • Topiramate
    • Beta blockers
    • TCAs
    • Serotonin-norepinephrine reuptake inhibitors
    • Flunarizine, verapamilLisinopril, candesartan
  • Take certain medications or who have had certain procedures for migraine prevention:
    • Botulinum toxin (face/neck region) within 4 months before starting therapy
    • Ergotamine derivatives, steroids, triptans within 2 months before starting therapy
    • Other devices and procedures for migraine prophylaxis
    • Patients taking investigational medications or using investigational devices during treatment or within 90 days of therapy
  • Were taking two or more of these medications concomitantly for migraine prevention within two months before starting erenumab therapy:
    • Divalproex sodium, sodium valproate, topiramate, carbamazepine, gabapentin
    • Beta blockers
    • TCAs
    • Venlafaxine, desvenlafaxine, duloxetine, milnacipran
    • Flunarizine, verapamil, lomerizine
    • Lisinopril, candesartan
    • Clonidine, guanfacine
    • Cyproheptadine
    • Methysergide
    • Pizotifen
    • Butterbur, feverfew, ≥ 600 mg/day magnesium, ≥ 100 mg/day riboflavin6

Despite these exclusions, there were limited side effects reported during this trial. Most adverse effects reported were similar between the placebo and erenumab groups. Numerically, more patients experienced injection site reactions with the 70 mg dose than the 140 mg dose. Approximately 5% of participants developed anti-erenumab antibodies during the trial period.  The formation of said antibodies would neutralize the effects of erenumab in these patients, therefore the drug would have little to no effect.  This medication was not clinically tested in patients whose migraines developed after the age of 50 or in patients with a history of hemiplegic or cluster headaches.5 There is no adequate data on the developmental risk with the use of erenumab in pregnant women. An animal study in pregnant female monkeys showed no adverse effects on offspring even with serum levels approximately 20 times that of serum levels in humans receiving the highest monthly dose (140mg) of erenumab. There is no evidence on the presence of erenumab in breast milk, its effects on breastfed infants, or effects on milk production. Erenumab was not studied in patients < 18 years old, so the medication’s safety and effectiveness has not been established for the pediatric patients.  Pharmacokinetic analysis of data from clinical trial of erenumab did not reveal a difference in the pharmacokinetic actions of erenumab in patients with mild to moderate renal impairment compared to patients with normal renal impairment. Patients with severe renal impairment (eGFR < 30 mL/min/1.73m2) have not been studied. It is not expected that renal or hepatic impairment will effect, but no clinical studies have been done to directly evaluate the effect of renal or hepatic impairment on the pharmacokinetics of erenumab.2

Recently, the LIBERTY trial evaluated the effectiveness of erenumab in treating patients with episodic migraine in whom two to four previous migraine prevention treatments were unsuccessful. This trial shows that  erenumab is a great second-line therapy in the treatment of episodic migraine for patients who are not well controlled on other migraine prophylaxis medications.7 Migraine is a public health issue, affecting not only the patient, but increasing health care costs and resulting in productivity losses. Acute migraine medications costs on average $60 per month per person and on average patients lose $208 per missed work days due to migraines.8 Erenumab may help to reduce health care costs and costs due to lost productivity, but a cost-analysis study is needed to prove a correlation. The average wholesale price of erenumab 70 mg is $345 and the average wholesale price of erenumab 140 mg is $690.9 Erenumab is an effective and safe medication for the treatment of episodic migraine, but due to the cost and lack of data for certain populations, erenumab is best for patients with episodic migraine who have not found relief with other migraine-specific medications.

 

References

  1. National Institutes of Health. MedlinePlus. Migraine. https://medlineplus.gov/migraine.html, Accessed December 22, 2018.
  2. Aimovigä [package insert]. Thousand Oaks, CA: Amgen Inc.; 2018.
  3. Erenumab (Aimovig) for Migraine. Med Lett Drugs Ther. 2018;60(1549):101-103. https://secure.medicalletter.org/article-share?a=1549b&p=tml&title=Erenumab%20(Aimovig)%20for%20Migraine%20Prevention&cannotaccesstitle=1. Accessed October 30, 2018.
  4. Taylor FR, CGRP, Amylin, Immunology, and Headache Medicine. Headache. 2018;59(1):131-150.
  5. Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123-2132.
  6. Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine [supplementary appendix]. N Engl J Med. 2017;377:2123-2132.
  7. Reuter U, Goadsby PJ, Lanteri-Minte M, et al. Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventative treatments were unsuccessful: a randomized, double-blind, placebo-controlled, phase 3b study. Lancet. 2018;392(10161):2280-2287.
  8. Porter JK, Di Tanna GL, Lipton RB, Sapra S, Villa G. Costs of acute headache medication use and productivity losses among patients with migraine: insights from three randomized controlled trials. Pharmacoecon Open. 2018. doi: 10.1007/s41669-018-0105-0.
  9. Active Ingredient: Erenumab-aooe. RED BOOK Online. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Truven Health Analytics; 2019. Accessed March 6, 2019.

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