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Recent Medications Approved for Preventing Migraine Headaches

Brittany L. Spindler PharmD Candidate ,

Melody Ryan PharmD, MPH

PII: S0002-9343(20)30143-1
DOI: https://doi.org/10.1016/j.amjmed.2020.01.031
Reference: AJM 15612

To appear in: The American Journal of Medicine

Please cite this article as: Brittany L. Spindler PharmD Candidate , Melody Ryan PharmD, MPH , Re-
cent Medications Approved for Preventing Migraine Headaches, The American Journal of Medicine
(2020), doi: https://doi.org/10.1016/j.amjmed.2020.01.031

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© 2020 Published by Elsevier Inc.

 Recent Medications Approved for Preventing Migraine Headaches

Brittany L. Spindler, PharmD Candidate;1 Melody Ryan, PharmD, MPH1

1
University of Kentucky College of Pharmacy, 789 S. Limestone St., Lexington, KY 40536-

0596, USA; Blsp227@uky.edu; melody.ryan@uky.edu

Corresponding author: Melody Ryan, PharmD, MPH

University of Kentucky College of Pharmacy

789 S. Limestone St.

Lexington, KY 40536-0596 USA

01-859-257-8790

melody.ryan@uky.edu

Manuscript type: Review

Keywords: migraine, headache, CGRP, calcitonin gene-related peptide

Funding sources related to this manuscript: none

All authors had access to the data and a role in writing the manuscript

Running head: Migraine Prevention

Abstract:

Migraine is the third most prevalent disease in the world and affects approximately 39 million

individuals in the United States alone. Migraine occurs in nearly one in seven individuals

between 15 and 49 years of age and is three times more frequent in women than in men. The

FDA recently approved three new humanized monoclonal antibodies that target calcitonin gene-

related peptide (CGRP): erenumab , fremanezumab, and galcanezumab. The agents either bind to

the CGRP receptor (erenumab) or bind to the CGRP ligand (fremanezumab and galcanezumab)

and block its binding to the receptor. All three products are indicated for preventative treatment

of episodic or chronic migraine in adults. The available studies to date document that these

agents reduce migraine attacks. The CGRP monoclonal antibodies offer patients new options

once they have exhausted other treatments.

Introduction:

Migraine is the third most prevalent disease in the world and affects approximately 39

million individuals in the United States alone. Migraine occurs in nearly one in seven individuals

between 15 and 49 years of age and is three times more frequent in women than in men.1

A migraine is a complex neurobiologic disorder featuring a unilateral headache with a

throbbing quality. There may also be associated symptoms such as nausea, photophobia, and

phonophobia.1 The two most common types of migraine are migraine without and with aura,

which affect 80% and 20% of migraine patients, respectively.1 Aura symptoms including visual,

sensory, speech, motor, brainstem, and/or retinal changes precede the headache, spread

gradually, and last 5 to 60 minutes.2 While migraine attacks can be debilitating, there are

abortive3 and prophylactic4 treatments available that stop or prevent attacks.

 The neurobiology pathophysiology theory of migraine posits that migraines are due to

changes in the activity of the locus coeruleus which can cause neuronal excitation in the

trigeminal nucleus (Figure 1). This nucleus releases vasoactive substances; in particular,

calcitonin gene-related peptide (CGRP), nitric oxide, and substance P. Three major effects of

CGRP with regard to migraine are arterial dilation, inflammation, and pain. During migraine

attacks, CGRP binds to receptors on the smooth muscle cells within the artery walls which

causes dilation of intracranial arteries.5 CGRP also causes inflammation that makes the neurons

in the brain hyper-excitable.5,6 As CGRP binds to the receptor, post-synaptic neuron firing is

increased, which results in the exaggerated pain signals being sent to the brain. The new

migraine pharmacotherapies either reduce CGRP release or block its action.

CGRP Products

The FDA recently approved three new humanized monoclonal antibodies that target

CGRP: erenumab (Aimovig®), fremanezumab (Ajovy®), and galcanezumab (Emgality®). The

agents either bind to the CGRP receptor (erenumab) or bind to the CGRP ligand (fremanezumab

and galcanezumab) and block its binding to the receptor. All three products are indicated for

preventative treatment of episodic or chronic migraine in adults. Galcanezumab is also approved

for abortive treatment of cluster headache in adults.

Efficacy

The available studies to date of erenumab, fremanezumab, and galcanezumab document

that these agents reduce migraine attacks. All these products are periodically self-administered

subcutaneous injections once monthly or every three months (Table 1). These new CGRP
monoclonal antibodies are effective in patients who have failed prior treatments as well as those

who are concurrently taking oral preventative and abortive therapies. Throughout phase 2 and

phase 3 randomized, placebo-controlled trials, these agents demonstrated efficacy, safety and

tolerance for the preventative treatment of episodic and chronic migraine. Erenumab reduced

monthly migraine days by 6.6 days compared with 4.2 days for placebo (mean treatment

difference −2.5, p < 0.001).7 Another study showed fremanezumab reduced the mean migraine

headache days for both FDA approved dosages compared to placebo [fremanezumab 225 mg

(−6.27 versus −3.46 days, p < 0.0001) and fremanezumab 675 mg (−6.09 versus

−3.46 days, p < 0.0001)].8 Galcanezumab had a greater mean change in migraine headache days

compared to placebo (−4.2 versus −3.0 days, respectively; p< 0.0030).8

All three of the new monoclonal antibodies are well tolerated with very few adverse

reactions. The most common adverse event in clinical trials was injection-site reactions. Some

recent studies have shown that erenumab may cause constipation as well.9 These products are not

metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications

that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.10 Because

these products are newly introduced to practice, they will require long-term studies to determine

how safe and efficacious they are in large populations with a variety of comorbidities.

Advice to Clinicians

With three new monoclonal antibodies, the potential to change the lives of patients

suffering with episodic and chronic migraine is greater than ever.9 Due to cost, the monoclonal

agents should not be considered first-line options, however they should be considered in patients

who have failed or did not tolerate traditional treatment options.

 Clinicians should perform a thorough medication history to determine what medications

the patient is taking and/or has already tried and failed. All patients should continue to have

abortive therapy available, if needed. Providers may initiate CRGP prophylaxis as the sole

therapy for prophylaxis or as an add-on to an established medication.8 Dual therapy is usually

considered in patients that exhaust single treatment options. After the initial use of a CGRP

monoclonal antibody, the clinicians should evaluate how effective the medication was during a

3-month treatment period.12 CGRP monoclonal antibody treatment can be considered successful

when either of the following are met:

 Reduction in mean monthly headache days of >50% compared to the pretreatment

baseline number of headache days;

 A clinically meaningful improvement in any of the following validated migraine-

specific patient-reported outcomes measures (Migraine Disability Assessment

[MIDAS], Migraine Physical Function Impact Diary [MPFID], Headache Impact

Test [HIT])

o MIDAS – Reduce > 5 points when baseline is 11-20 and/or reduce > 30%

when baseline score is > 20

o MPFID – Reduction of > 5 points

o HIT – Reduction of > 5 points.

Determining the effectiveness of a biologic is important to assess further treatment and

evaluating the cost-effectiveness to the patient (i.e., how much will treatment cost versus how

much benefit will the patient receive for relief of migraine pain) is also important.

Conclusions
 Migraine is a prevalent disease with an unmet need for diagnosing and treating the

condition. The CGRP monoclonal antibodies offer patients new options once they have

exhausted other treatments. With providers appropriately identifying patients, these therapies can

have a significant effect for patients that suffer from migraine.

References:

1. About Migraine. Migraine Research Foundation, 2019,

https://migraineresearchfoundation.org/about-migraine/migraine-facts/ Accessed

November 20, 2019.

2. Migraine Aura. Mayo Clinic, Mayo Foundation for Medical Education and Research, 26

June 2019, www.mayoclinic.org/diseases-conditions/migraine-with-

aura/multimedia/migraine-aura/vid-20084707. Accessed November 20, 2019.

3. Gilmore B, Michael M. Treatment of acute migraine headache. Am Fam Physician

2011;83:271-280.

4. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update:

pharmacologic treatment for episodic migraine prevention in adults: report of the Quality

Standards Subcommittee of the American Academy of Neurology and the American

Headache Society. Neurology 2012;78:1337-1345. doi:10.1212/WNL.0b013e3182535d20.

5. Iyengar S, Johnson KW, Ossipov MH, Aurora SK. CGRP and the trigeminal system in

migraine. Headache 2019;59:659-681. doi: 10.1111/head.13529.

6. Deen M, Correnti E, Kamm K, et al. Blocking CGRP in migraine patients – a review of

pros and cons. J Headache Pain 2017;18:96. doi: 10.1186/s10194-017-0807-1.

7. Lipton RB, Tepper SJ, Reuter U, et al. Erenumab in chronic migraine: patient-reported

outcomes in a randomized double-blind study. Neurology 2019;92:e2250-E2260. doi:

10.1212/WNL.0000000000007452.

8. Tso AR, Goadsby PJ. Anti-CGRP monoclonal antibodies: the next era of migraine

prevention? Curr Treat Options Neurol 2017;19:27. doi: 10.1007/s11940-017-0463-4.

9. American Migraine Foundation. Migraine and the new anti-CGRP treatments: what to

know about fremanezumab (AJOVY™), the second anti-CGRP treatment for migraine.

October 1, 2018. https://americanmigrainefoundation.org/resource-library/migraine-and-

the-new-anti-cgrp-treatments/. Accessed November 20, 2019.

10. Scuteri D, Adornetto A, Rombolà L, et al. New trends in migraine pharmacology:

targeting calcitonin gene-related peptide (CGRP) with monoclonal antibodies. Front

Pharmacol 2019;10:363. doi: 10.3389/fphar.2019.00363.

11. Lexicomp Online, Anti-CGRP Monoclonal Antibody Medications Lexi-Drugs Online,

Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2018; November 20,

2019.

12. Levin M, Silberstein SD, Gilbert R, et al. Basic considerations for the use of monoclonal

antibodies in migraine. Headache 2018;58:1689-1696. doi: 10.1111/head.13439.

Figure 1. Mechanisms of action of triptans and monoclonal antibodies targeting the Calcitonin-

Gene Related Peptide (CGRP) or the CGRP receptor.

CGRP is released from the trigeminal nerve to activate its receptor. Activating this receptor leads to

relaxation of smooth muscles including those of the vasculature, which results in vasodilation of blood

vessels. The new monoclonal antibodies target either CGRP or the CGRP receptors. The anti-CGRP

antibodies, fremanezumab and galcanezumab, bind directly to CGRP after it is released from the

trigeminal nerve. Erenumab, the anti-CGRP receptor antibody, binds directly to the CGRP receptor

which blocks the CGRP molecule binding. Triptans work through a different mechanism of action by

blocking 5-HT1B or 5-HT1D.5,6

Table 1: Characteristics of CGRP Monoclonal Antibodies11

Erenumab Frenemanezumab Galcanezumab

Dosing 70 mg injected SQ once 225 mg monthly, or 240 mg loading dose,

monthly 675 mg every 3 months, followed by monthly

which is administered as doses of 120 mg

three consecutive SQ

injection of 225 mg each

Half-life 28 days 31 days 27 days

Monitoring Number of MMD, Number of MMD, MIDAS, Number of MMD,

MIDAS, MPFID, HIT MPFID, HIT MIDAS, MPFID, HIT

Metabolism A non-specific, non- Degraded by enzymatic Degraded into small

saturable proteolytic proteolysis into small peptides and amino

pathway peptides and amino acids acids via catabolic

pathways

Cost Auto-injector: Prefilled syringe: Prefilled syringes:

70 mg/mL: $690 225 mg/1.5mL: $460 100 mg/mL: $575

140 mg/mL: $690 120 mg/mL: $690

Auto-injector:

120 mg/mL: $690

MMD - monthly migraine days; MIDAS - Migraine Disability Assessment; MPFID - Migraine

Physical Function Impact Diary; HIT - Headache Impact Test

Clinical Significance
 The FDA recently approved three new humanized monoclonal antibodies that target calcitonin
gene-related peptide (CGRP): erenumab, fremanezumab, and galcanezumab.
 All three products are indicated for preventative treatment of episodic or chronic migraine in
adults.
 The available studies to date document that these agents reduce migraine attacks.
 Although more expensive than other prophylactic treatments, the CGRP monoclonal antibodies
offer patients new options once they have exhausted other treatments.