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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 5  |  Issue : 2  |  Page : 100-104

A novel treatment option for patients suffering from migraine: Erenumab


1 Department of Cardiothoracic and Vascular Surgery, SMS Medical College and Hospital, Jaipur, Rajasthan, India
2 Department of Pharmaology, SMS Medical College and Hospital, Jaipur, Rajasthan, India
3 Department of Anatomy, SMS Medical College and Hospital, Jaipur, Rajasthan, India
4 Department of Medicine, SMS Medical College and Hospital, Jaipur, Rajasthan, India

Date of Submission29-Aug-2018
Date of Decision02-Jan-2019
Date of Acceptance21-Feb-2019
Date of Web Publication29-Aug-2019

Correspondence Address:
Dr. Neha Sharma
Department of Pharmaology, SMS Medical College, Jaipur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJAM.IJAM_42_18

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  Abstract 


Migraine is one of the common disabling neurological disorders. It is conventionally treated by antihypertensives, antidepressants, and antiepileptics for prophylaxis. In spite of all these treatment options available, physicians were always in search of an ideal drug molecule with more target-specific drug action with lesser side effects and which may improve patient compliance. This exhaustive search led to the discovery of a new molecule in the pathophysiology of migraine that is calcitonin gene-related peptide (CGRP) and which in turn led to discovery of specific CGRP antagonists such as gepants and monoclonal antibodies such as erenumab. A systematic literature search was carried out on the internet using databases such as PubMed, Cochrane Reviews, Google Scholar, and Wikipedia using keywords such as migraine, erenumab, and CGRP receptor. Detailed information about pathophysiology of migraine, CGRP, and erenumab was gathered. Erenumab is the first human monoclonal antibody approved by the Food and Drug Administration in May 2018. It is marketed under the trade name “Aimovig.” It acts as an antagonist of CGRP receptors, which plays a key role in the pathophysiology of migraine. In spite of being macromolecular human monoclonal antibodies, it has very few side effects as compared to gepants. Erenumab may offer promising role in the preventive treatment of episodic and chronic migraine. The present study describes the mechanism of action, efficacy, and side effects as documented in three completed clinical trial findings of erenumab.
The following core competencies are addressed in this article: Medical knowledge, Patient care and procedural skills.

Keywords: Calcitonin gene-related peptide, clinical trial, erenumab, migraine, monoclonal antibodies


How to cite this article:
Sharma D, Sharma N, Advani U, Sharma P, Prakash R. A novel treatment option for patients suffering from migraine: Erenumab. Int J Acad Med 2019;5:100-4

How to cite this URL:
Sharma D, Sharma N, Advani U, Sharma P, Prakash R. A novel treatment option for patients suffering from migraine: Erenumab. Int J Acad Med [serial online] 2019 [cited 2019 Sep 23];5:100-4. Available from: http://www.ijam-web.org/text.asp?2019/5/2/100/265679




  Introduction Top


Migraine is one of the common disabling neurological disorders, which particularly focuses on cranium.[1] It is typically characterized by episodic attacks of headache with associated symptoms.[2],[3],[4] Both episodic and chronic migraine combinely affects 14% of the population and 18% of women.[3],[4]

Calcitonin gene-related peptide (CGRP) acts on an unusual type of receptor which has two parts, a calcitonin receptor-like receptor and a receptor-activity modifying protein which is required for the receptor to function. CGRP is a potent vasodilator which acts via adenylyl cyclase. When given intravenously, it causes hypotension, tachycardia, and dilatation of arteries specially coronaries.[5],[6]

CGRP has been documented in the literature to play an integral role in the pathophysiology of migraine. When the trigeminal nerves are activated, they cause release of CGRP from the perivascular nerve endings and dilate peripheral and cerebral nerves. Perivascular trigeminal sensory nerve fibers are then mechanically activated by dilated blood vessels which in turn causes a pain response which is conveyed to the brainstem.[5] CGRP receptor antagonists prevent neurogenic inflammation and vasodilatation and play an integral role in the prevention of migraine.[7]

Although migraine has an immense socioeconomic impact, still it has inadequate available treatment options.[8] Antihypertensives, antidepressants, and antiepileptics are included in the current treatment options of migraine for its prophylaxis. Topiramate has also shown promising role in the preventive treatment of episodic migraine.[9] These drugs affect patients' emotional, social, and occupational functioning and impose financial burden to them. However, unfortunately, none of these proved to be satisfactory by the physicians in treating migraine. Erenumab is given as once a month subcutaneous injection. Hence, it may offer a promising role in the treatment of migraine and may compel physicians to offer its use in migraine.

A systematic literature search was carried out on the internet using databases such as PubMed, Cochrane Reviews, Google Scholar, and Wikipedia using keywords such as migraine, erenumab, and CGRP receptor. Detailed information about pathophysiology of migraine, CGRP, and erenumab was gathered.


  What is Erenumab? Top


Aimovig (erenumab-aooe) was approved by the U.S. Food and Drug Administration on May 17, 2018, for the preventive treatment of migraine in adults. This monoclonal antibody is given by once-monthly subcutaneous self-injections. This fully human injectable monoclonal antibody is marketed under the trade name “Aimovig” and is jointly developed by Novartis and Amgen. It is a human immunoglobulin G2 monoclonal antibody with an atomic weight of approximately 150 kDa. It is composed of two heavy chains and developed by recombinant DNA technology.[10],[11],[12]


  Mechanism of Action of Erenumab Top


Action of CGRP can be blocked by either small molecule CGRP receptor antagonists (gepants) or monoclonal antibodies which can either directly target CGRP or can block the CGRP receptor.[9]

Erenumab acts by inhibiting the binding of CGRP to the human CGRP receptor. This action of erenumab is 20 times more potent than oral peptide telcagepant.[13] It has been reported in previously donein vitro studies that erenumab binds to human CGRP receptors with high affinity (dissociation equilibrium constant KD = 20 pM) and potency (IC50=2.3 nM) in a competitive and reversible manner.[14],[15]


  Efficacy of Erenumab in Preventing Episodic Migraine Top


The efficacy and safety have been evaluated on three previously done randomized, double-blind, placebo-controlled, multicenter trials in which Aimovig 70 and 140 mg versus placebo were compared in the treatment of migraine. A total of 2199 subjects participated in these three completed trials. Till date, seven clinical trials have been registered with erenumab for treating migraine, out of which three studies have been completed and rest are yet recruiting subjects for trial.[16] Details about the completed clinical trials are summarized in [Table 1].
Table 1: Details about the three completed clinical trials of erenumab

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  Efficacy of Erenumab Top


It was found that patients receiving erenumab experienced −2.9 days change in monthly migraine days, compared with −1.8 days for placebo, least-squares mean (95% confidence interval [CI]) treatment difference of −1.0 (−1.6, −0.5) (P< 0.001) as documented by Dodick et al., 2018.[17]

However, Goadsby et al., 2017[8] mentioned in their study that mean number of migraine days per month at baseline was reduced from 8.3 to 3.2 in the 70-mg erenumab group and to 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (P< 0.001 for each dose vs. placebo).

Tepper et al., 2017[18] found that erenumab 70 and 140 mg reduced monthly migraine days versus placebo (both doses −6.6 days and placebo −4.2 days; difference −2.5, 95% CI −3.5, −1.4, P < 0.0001).


  Pharmacokinetic and Pharmacodynamic Studies of Erenumab Top


Validated biomarker that is used to evaluate the target engagement of potential CGRP-blocking therapeutics for migraine is capsaicin-induced dermal blood flow.[14]

The absorption half-life was found to be 1.6 days and bioavailability was 74% when given subcutaneously. Maximum inhibition of CGRP produced by erenumab in a study by Vu et al., 2017 was 89% (95% CI: 87%–91%).


  Side Effects of Erenumab Top


Monoclonal antibodies are found to be safer than gepants.[9] The advantage of erenumab over other older drugs is that it specifically antagonizes CGRP receptors, so there are lesser chances of systemic side effects. This newer purely human monoclonal antibody can prove to be a milestone in treating migraine.

Most frequent adverse events of erenumab as reported by Dodick et al., 2018[17] were upper respiratory tract infection, injection site pain, and nasopharyngitis, while other studies also reported similar rates of adverse events between erenumab and placebo.[8] However, animal studies have suggested that blocking CGRP may cause constipation, affect the homeostatic functions of the pituitary hormones, or attenuate wound healing, but these effects have not yet been reported in human studies.[9] Details about adverse effects caused by different agents that block CGRP are elaborated in [Table 2].
Table 2: Adverse effects caused by different agents that blocks calcitonin gene-related peptide

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  Current Status of Erenumab Top


It is not available in India till date. The price of Aimovig in the U.S. is $575 for once monthly 70 or 140 mg single-use prefilled SureClick ® autoinjectors or $6,900 annually.


  Ongoing Trials Top


After the convincing results of three completed clinical trials that have been documented combinely by Amgen and Novartis Pharmaceuticals, the results of four other multicenter similar arms trials are also eagerly awaited. Results of one of these trials are also awaited which is in phase 2 of clinical trial (ClinicalTrials.gov Identifier: NCT02174861).[16] This study enrolled 609 participants and tested 70 and 140 mg erenumab subcutaneously for 52 weeks. Others are in the initial stages of recruiting subjects for trial.[16] Apart from erenumab, other monoclonal antibodies targeting CGRP such as eptinezumab, fremanezumab, and galcanezumabare also under trial for treating migraine.[9]


  Economic Impact of Migraine Top


There is a considerable impact of migraine on healthcare system and patients.[19] In the United States, 18% of women and 6% of men suffer from migraine.[19] The financial burden of migraine on society includes direct costs that are associated with medical care and indirect costs which are caused by absence from work and reduced productivity.[20] Migraine accounts for approximately $14 billion in direct and indirect costs annually.[19] However, another study confirms that the estimated worldwide annual cost of migraine is $20 billion, relating to healthcare, procedures, and loss of productivity.[21]

Sussman et al., 2018 assessed the cost-effectiveness of erenumab 140 mg (”erenumab”) for the prophylactic treatment of episodic migraine and chronic migraine. It was found in the study that the use of erenumab may be a cost-effective approach to preventing monthly migraine days among patients with chronic migraine but is less likely to offer good value for money for those with episodic migraine, unless lost productivity costs are considered. A plausible reason to this may be the annual drug price of erenumab of $6900.[22] Further economic evaluation of other new upcoming drugs is the need of the hour.


  Conclusion Top


Erenumab might become a potential blockbuster tool against migraine. It may result in improved patient compliance because of its minimized side effects. However, its price might overweigh its benefits in migraine in a low socioeconomic country like India. CGRP being a ubiquitous peptide, apart from migraine, it is also involved in several physiological processes and in homeostatic responses during pathophysiological conditions. Hence, long-term clinical trials are warranted to see its efficacy and side effects. It has been published in previous literature that over a period of time, neutralizing antibodies are formed against the monoclonal antibody that is used to treat a disease. Hence, further long-term studies are also needed to investigate the problems created by neutralizing antidrug antibodies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Ethical conduct of research

This manuscript represents a literature review. Because this project involved no experimental design, the Institutional Review Board approval was not required. Applicable EQUATOR Network (http://www.equator-network.org) guidelines were followed.



 
  References Top

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Goadsby PJ. Pathophysiology of migraine. Ann Indian Acad Neurol 2012;15:S15-22.  Back to cited text no. 1
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Gürsoy AE, Ertaş M. Prophylactic treatment of migraine. Noro Psikiyatr Ars 2013;50:S30-5.  Back to cited text no. 2
    
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Stovner Lj, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, et al. The global burden of headache: A documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27:193-210.  Back to cited text no. 4
    
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Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache 2006;46 Suppl 1:S3-8.  Back to cited text no. 5
    
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Tripathi KD. Nitric oxide and vasoactive peptide signal molecules. In: Essentials of Medical Pharmacology. 8th ed. New Delhi: Jaypee Brothers Medical Publishers; 2018. p. 555.  Back to cited text no. 6
    
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Durham PL. CGRP receptor antagonists: A new choice for acute treatment of migraine? Curr Opin Investig Drugs 2004;5:731-5.  Back to cited text no. 7
    
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Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med 2017;377:2123-32.  Back to cited text no. 8
    
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Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltrán E, et al. Blocking CGRP in migraine patients - A review of pros and cons. J Headache Pain 2017;18:96.  Back to cited text no. 9
    
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Erenumab - Drug Bank. Available from: https://www.drugbank.ca/drugs/DB14039. [Last accessed on 2018 Aug 11].  Back to cited text no. 10
    
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FDA Approves Novel Preventive Treatment for Migraine. Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm608120.htm. [Last accessed on 2018 Aug 10].  Back to cited text no. 11
    
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Novartis and Amgen Announce FDA Approval of Aimovig (TM) (Erenumab), a Novel Treatment Developed Specifically for Migraine Prevention. Available from: https://www.novartis.com/news/media-releases/novartis-and-amgen-announce- fda-approval-aimovigtm-erenumab- novel-treatment-developed- specifically-migraine- prevention. [Last accessed on 2018 Aug 13].  Back to cited text no. 12
    
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Giamberardino MA, Affaitati G, Costantini R, Cipollone F, Martelletti P. Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: Current evidence and safety profile of erenumab. J Pain Res 2017;10:2751-60.  Back to cited text no. 13
    
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Vu T, Ma P, Chen JS, de Hoon J, Van Hecken A, Yan L, et al. Pharmacokinetic-pharmacodynamic relationship of erenumab (AMG 334) and capsaicin-induced dermal blood flow in healthy and migraine subjects. Pharm Res 2017;34:1784-95.  Back to cited text no. 14
    
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Shi L, Lehto SG, Zhu DX, Sun H, Zhang J, Smith BP, et al. Pharmacologic characterization of AMG 334, a potent and selective human monoclonal antibody against the calcitonin gene-related peptide receptor. J Pharmacol Exp Ther 2016;356:223-31.  Back to cited text no. 15
    
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Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia 2018;38:1026-37.  Back to cited text no. 17
    
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Tepper S, Ashina M, Reuter U, Brandes JL, Doležil D, Silberstein S, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: A randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2017;16:425-34.  Back to cited text no. 18
    
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Bonafede M, Cai Q, Cappell K, Kim G, Sapra SJ, Shah N, et al. Factors associated with direct health care costs among patients with migraine. J Manag Care Spec Pharm 2017;23:1169-76.  Back to cited text no. 19
    
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Castle D, Robertson NP. Monoclonal antibodies for migraine: An update. J Neurol 2018;265:1491-2.  Back to cited text no. 21
    
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Sussman M, Benner J, Neumann P, Menzin J. Cost-effectiveness analysis of erenumab for the preventive treatment of episodic and chronic migraine: Results from the US societal and payer perspectives. Cephalalgia 2018;38:1644-57.  Back to cited text no. 22
    



 
 
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  In this article
Abstract
Introduction
What is Erenumab?
Mechanism of Act...
Efficacy of Eren...
Efficacy of Erenumab
Pharmacokinetic ...
Side Effects of ...
Current Status o...
Ongoing Trials
Economic Impact ...
Conclusion
References
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