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Current Treatment Options in Neurology
Published in: Current Treatment Options in Neurology 8/2017

Open Access 01-08-2017 | Headache (JR Couch, Section Editor)

Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention?

Authors: Amy R. Tso, MD, Peter J. Goadsby, MD PhD

Published in: Current Treatment Options in Neurology | Issue 8/2017

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Opinion statement

Migraine is a very disabling disorder with severe impact on patients’ lives and substantive costs to society in terms of healthcare costs and lost productivity. Prevention is a key component of migraine therapy, and while numerous preventive options exist, each is burdened by either troublesome side effects or insufficient efficacy. All migraine preventives currently in clinical use were licensed for other purposes and, by chance, have efficacy against migraine. As our understanding of migraine has evolved, calcitonin gene-related peptide (CGRP) has moved to the forefront as a neuropeptide central to migraine pathophysiology. Six small molecule CGRP receptor antagonists were shown to be effective for acute treatment of migraine; two were stopped for hepatotoxicity or one for formulation concern issues and one is now in phase III. Monoclonal antibodies against CGRP or the CGRP receptor have a longer duration of action and have been investigated for migraine prevention. Four are in development and three have completed phase II and one phase III trials; every reported study has been positive. Furthermore, no safety issues have arisen to date, including hepatic or cardiovascular effects, and initial tolerability appears to be excellent. Monoclonal antibodies antagonizing the CGRP pathway represent a novel approach to prevention: a mechanism-specific migraine-targeted therapy. While we must await the results of all the phase III trials, cautious excitement seems warranted as we enter a new era of better tolerated, well-understood, bespoke migraine treatment for this common and disabling neurological disorder.
Literature
1.
Goadsby PJ, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N Engl J Med. 2002;346:257–70.CrossRefPubMed
2.
Goadsby PJ, Sprenger T. Current practice and future directions in the management of migraine: acute and preventive. Lancet Neurol. 2010;9:285–98.CrossRefPubMed
3.
Humphrey PPA, Feniuk W, Perren MJ, Beresford IJM, Skingle M, Whalley ET. Serotonin and migraine. Ann N Y Acad Sci. 1990;600:587–98.CrossRefPubMed
4.
Graham JR, Wolff HG. Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatr. 1938;39:737–63.CrossRef
5.
•• Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine—a disorder of sensory processing. Physiol Rev. 2017;97:553–622. Comprehensive review of migraine pathophysiology.CrossRefPubMed
6.
Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545–602.CrossRef
7.
Raval AD, Shah A. National trends in direct health care expenditures among US adults with migraine: 2004 to 2013. J Pain. 2017;18:96–107.CrossRefPubMed
8.
Munakata J, Hazard E, Serrano D, Klingman D, Rupnow MF, Tierce J, et al. Economic burden of transformed migraine: results from the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2009;49:498–508.CrossRefPubMed
9.
Blumenfeld AM, Bloudek LM, Becker WJ, Buse DC, Varon SF, Maglinte GA, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 2013;53(4):644–55.CrossRefPubMed
10.
Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478–88.CrossRefPubMed
11.
12.
Goadsby PJ. Bench to Bedside Advances in the twenty-first Century for primary headache disorders—migraine treatments for migraine patients. Brain. 2016;139:2571–7.CrossRefPubMed
13.
Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982;298:240–4.CrossRefPubMed
14.
Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue specific RNA processing. Nature. 1983;304:129–35.CrossRefPubMed
15.
•• Edvinsson L. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br J Clin Pharmacol. 2015;80:193–9. Comprehensive review of CGRP pharmacology.CrossRefPubMedPubMedCentral
16.
Eftekhari S, Edvinsson L. Possible sites of action of the new calcitonin gene-related peptide receptor antagonists. Ther Adv Neurol Disord. 2010;3:369–78.CrossRefPubMedPubMedCentral
17.
Hou M, Kanje M, Longmore J, Tajti J, Uddman R, Edvinsson L. 5-HT1B and 5-HT1D receptors in the human trigeminal ganglion: co-localization with calitonin gene-related peptide, substance P and nitric oxide synthase. Brain Res. 2001;909:112–20.CrossRefPubMed
18.
Van Rossum D, Hanisch UK, Quirion R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev. 1997;21:649–78.CrossRefPubMed
19.
Tschopp FA, Henke H, Petermann JB, Tobler PH, Janzer R, Hokfelt T, et al. Calcitonin gene-related peptide and its binding sites in the human central nervous system and pituitary. Proc Natl Acad Sci U S A. 1985;82:248–52.CrossRefPubMedPubMedCentral
20.
McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature. 1998;393:333–9.CrossRefPubMed
21.
Wimalawansa SJ. Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocr Rev. 1996;17:533–85.CrossRefPubMed
22.
Edvinsson L, Ekman R, Jansen I, McCulloch J, Uddman R. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J Cereb Blood Flow Metab. 1987;7:720–8.CrossRefPubMed
23.
Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183–7.CrossRefPubMed
24.
Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33:48–56.CrossRefPubMed
25.
Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G. Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia. 2005;25:179–83.CrossRefPubMed
26.
Cernuda-Morollon E, Larrosa D, Ramon C, Vega J, Martinez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81:1191–6.CrossRefPubMed
27.
Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54–61.CrossRefPubMed
28.
Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010;30:1179–86.CrossRefPubMed
29.
Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009;73:970–7.CrossRefPubMedPubMedCentral
30.
Diener H-C, Barbanti P, Dahlof C, Reuter U, Habeck J, Podhorna J. BI 44370 TA, an oral CGRP antagonist for the acute treatment of migraine attacks: results from a phase II study. Cephalalgia. 2011;31:573–84.CrossRefPubMed
31.
Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge J, Bachman R, et al. Randomized controlled trial of the CGRP receptor antagonist, MK-3207, in the acute treatment of migraine. Cephalalgia. 2011;31:712–22.CrossRefPubMed
32.
Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34:114–25.CrossRefPubMed
33.
Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350:1104–10.CrossRefPubMed
34.
Voss T, Lipton RB, Dodick DW, Dupre N, Ge JY, Bachman R, et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia. 2016;36:887–98.CrossRefPubMed
35.
Ho TW, Connor KM, Zhang Y, Pearlman E, Koppenhaver J, Fan X, et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology (Minneap). 2014;83:958–66.CrossRef
36.
Foltz IN, Karow M, Wasserman SM. Evolution and emergence of therapeutic monoclonal antibodies: what cardiologists need to know. Circulation. 2013;127(22):2222–30.CrossRefPubMed
37.
Lutterotti A, Martin R. Getting specific: monoclonal antibodies in multiple sclerosis. Lancet Neurol. 2008;7(6):538–47.CrossRefPubMed
38.
Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. CGRP monoclonal antibody LY2951742 for the prevention of migraine: a phase 2, randomized, double-blind, placebo-controlled study. Lancet Neurol. 2014;13:885–92.CrossRefPubMed
39.
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. Randomized, double-blind, placebo-controlled, phase II trial of ALD403, an anti-CGRP peptide antibody in the prevention of frequent episodic migraine. Lancet Neurol. 2014;13:1100–7.CrossRefPubMed
40.
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomized, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14:1081–90.CrossRefPubMed
41.
Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings ELH, Diener H-C, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomized, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14:1091–100.CrossRefPubMed
42.
Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, et al. A randomised, double-blind, placebo-controlled, phase 2 study to evaluate the efficacy and safety of AMG 334 for the prevention of episodic migraine. Lancet Neurol. 2016;15:382–90.CrossRefPubMed
43.
Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099–142.CrossRefPubMedPubMedCentral
44.
• MaassenVanDenBrink A, Meijer J, Villalon CM, Ferrari MD. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci. 2016;37(9):779–88. Summary of cardiovascular and cerebrovascular effects of CGRP.CrossRefPubMed
45.
Bigal ME, Dodick DW, Krymchantowski AV, VanderPluym JH, Tepper SJ, Aycardi E, et al. TEV-48125 for the preventive treatment of chronic migraine—efficacy at early time points. Neurology (Minneap). 2016;87:41–8.CrossRef
46.
Felgenhauer K. Protein size and cerebrospinal fluid composition. Klin Wochenschr. 1974;52(24):1158–64.CrossRefPubMed
47.
Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, Lucchinetti CF, et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 2013;12(6):554–62.CrossRefPubMed
Metadata
Title
Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention?
Authors
Amy R. Tso, MD
Peter J. Goadsby, MD PhD
Publication date
01-08-2017
Publisher
Springer US
Published in
Current Treatment Options in Neurology / Issue 8/2017
Print ISSN: 1092-8480
Electronic ISSN: 1534-3138
DOI
https://doi.org/10.1007/s11940-017-0463-4