Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
The Journal of Headache and Pain
Published in: The Journal of Headache and Pain 1/2017

Open Access 01-12-2017 | Research article

The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis

Authors: Min Hou, Haiyan Xing, Yongqing Cai, Bin Li, Xianfeng Wang, Pan Li, Xiaolin Hu, Jianhong Chen

Published in: The Journal of Headache and Pain | Issue 1/2017

Login to get access

Abstract

Background

Migraine has been recognized as one of the leading causes of disability in the 2013 Global Burden of Disease Study and seriously affects the quality of patients’ life, current treatment options are not ideal. Monoclonal antibodies to calcitonin gene-related peptide and its receptor (CGRP-mAbs) appear more promising for migraine because of considerably better effect and safety profiles. The objective of this study is to systematically assess the clinical efficacy and safety of CGRP-mAbs for migraine therapy.

Methods

A systematic literature search in PubMed, Cochrane Library and Baidu Scholar was performed to identify randomized controlled trials (RCTs), which compared the effect and safety of CGRP-mAbs with placebo on migraine. Regarding the efficacy, the reduction of monthly migraine days from baseline to weeks 1–4, 5–8, and 9–12; responder rates were extracted as the outcome measures of the effects of CGRP-mAbs. Regarding the safety, total adverse events, the main adverse events, and other adverse events were evaluated.

Results

We found significant reduction of monthly migraine days in CGRP-mAbs vs. placebo (weeks 1–4: SMD −0.49, 95% CI −0.61 to −0.36; weeks 5–8: SMD −0.43, 95% CI −0.56 to −0.30; weeks 9–12: SMD −0.37, 95% CI −0.49 to −0.24). 50% and 75% responder rates (OR 2.59, 95% CI 1.99 to 3.37; and OR 2.91, 95% CI 2.06 to 4.10) were significantly increased compared with placebo. There was no significant difference in total adverse events (OR 1.17, 95% CI 0.91 to 1.51), and the main adverse events including upper respiratory tract infection (OR 1.44, 95% CI 0.82 to 2.55), nasopharyngitis (OR 0.59, 95% CI 0.30 to 1.16), nausea (OR 0.61, 95% CI 0.29 to 1.32), injection-site pain (OR 1.73, 95% CI 0.95 to 3.16) and back pain (OR 0.97, 95% CI 0.49 to 1.90) were not obviously changed compared with placebo control, but the results showed significant increase of dizziness in CGRP-mAbs vs. placebo (OR 3.22, 95% CI 1.09 to 9.45).

Conclusions

This meta-analysis suggests that CGRP-mAbs are effective in anti-migraine therapy with few adverse reactions, but more and larger sample-size RCTs are required to verify the current findings.
Literature
1.
2.
Tfelthansen P (2012) Clinical pharmacology of current and future drugs for the acute treatment of migraine: a review and an update. Curr Clin Pharmacol 7:66–72CrossRef
3.
David Dodick MD, Lipton RB, Vincent Martin MD, Vasilios Papademetriou MD, Rosamond W, Maassenvandenbrink A, Hassan Loutfi MD, Welch KM, PhD PJGM, Steven Hahn MD (2004) Consensus statement: cardiovascular safety profile of triptans (5-HT 1B/1D agonists) in the acute treatment of migraine. Headache 44:414–425CrossRefPubMed
4.
Fozard JR, Kalkman HO (1994) 5-Hydroxytryptamine (5-HT) and the initiation of migraine: new perspectives. Naunyn Schmiedeberg’s Arch Pharmacol 350:225–229CrossRef
5.
Silberstei SD (2005) Serotonin (5‐HT) and Migraine. Headache 34:408–417CrossRef
6.
7.
Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (2002) CGRP may play a causative role in migraine. Cephalalgia 22:54–61CrossRefPubMed
8.
Villalon CM, Olesen J (2009) The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacol Ther 124:309–323CrossRefPubMed
9.
Akerman S, Goadsby PJ (2007) Dopamine and migraine: biology and clinical implications. Cephalalgia 27:1308–1314CrossRefPubMed
10.
de Sousa SC, Karwautz A, Wöber C, Wagner G, Breen G, Zesch HE, Konrad A, Zormann A, Wanner C, Kienbacher C (2007) A dopamine D4 receptor exon 3 VNTR allele protecting against migraine without aura. Ann Neurol 61:574–578CrossRefPubMed
11.
Del ZM, Cherchi A, Palmas MA, Ponti M, Bocchetta A, Gessa GL, Piccardi MP (1998) Association between dopamine receptor genes and migraine without aura in a Sardinian sample. Neurology 51:781–786CrossRef
12.
Ferrari MD, Roon KI, Lipton RB, Goadsby PJ (2001) Oral triptans (serotonin 5-HT 1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 358:1668–1675CrossRefPubMed
13.
Tfelthansen P, Saxena PR, Dahlöf C, Pascual J, Láinez M, Henry P, Diener H, Schoenen J, Ferrari MD, Goadsby PJ (2000) Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 123(Pt 1):9–18CrossRef
14.
Vasilios Papademetriou MD (2004) Cardiovascular risk assessment and triptans. Headache 44:S31–S39CrossRefPubMed
15.
Bigal ME, Walter S (2014) Monoclonal antibodies for migraine: preventing calcitonin gene-related peptide activity. CNS Drugs 28:389–399CrossRefPubMed
16.
Connor KM, Aurora SK, Loeys T, Messoud Ashina MD, Christopher Jones BA, Giezek H, Massaad R, Angela Williams-Diaz BS, Lines C, Ho TW (2010) Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. Headache 51:73–84CrossRefPubMed
17.
Han TH, Blanchard RL, Palcza J, Mccrea JB, Laethem T, Willson K, Xu Y, Ermlich S, Boyle J, Lines C (2010) Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults. J Clin Pharmacol 50:1367–1376CrossRefPubMed
18.
Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ, Bachman R, Taraborelli D, Fan X, Assaid C, Lines C (2011) Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia 31:712–722CrossRefPubMed
19.
Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM (2008) Randomized controlled trial of an horal CGRP antagonist, MK-0974, in acute treatment of migraine. Neurology 70:1304–1312CrossRefPubMed
20.
Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C, Lines C (2008) Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet 372:2115CrossRefPubMed
21.
22.
23.
Elvidge S (2014) Anti-CGRP antibodies for migraine turn industry heads. Nat Biotechnol 32:707–707CrossRefPubMed
24.
Giamberardino MA, Affaitati G, Curto M, Negro A, Costantini R, Martelletti P (2016) Anti-CGRP monoclonal antibodies in migraine: current perspectives. Internal & Emergency Medicine 11:1045–1057
25.
Olesen J (2006) International Classification of Headache Disorders, Second Edition (ICHD-2): current status and future revisions. Cephalalgia 26:1409–1410CrossRefPubMed
26.
Olesen J, Goadsby P, Steiner T (2004) The international classification of headache disorders: 2nd edition. Cephalalgia 24:9–160CrossRef
27.
Society HCCOH (2013) The International Classification of Headache Disorders, 3rd edition (beta version). AASM 33:629–808
28.
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928–d5928CrossRefPubMedPubMedCentral
29.
30.
Higgins JP, Green S (2009) Cochrane handbook for systematic reviews of interventions., p 5
31.
Tang Q, Li G, Liu T, Wang A, Feng S, Liao X, Jin Y, Guo Z, He B, Mcclure MA (2015) Modulation of interhemispheric activation balance in motor-related areas of stroke patients with motor recovery: systematic review and meta-analysis of fMRI studies. Neurosci Biobehav Rev 57:392–400CrossRefPubMed
32.
Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558CrossRefPubMed
33.
Tufanaru C, Munn Z, Stephenson M, Aromataris E (2015) Fixed or random effects meta-analysis? Common methodological issues in systematic reviews of effectiveness. Int J Evid Based Healthc 13:196–207CrossRefPubMed
34.
Sedgwick P (2013) Meta-analyses: how to read a funnel plot. BMJ 346:f1342–f1342CrossRef
35.
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, Loupe PS, Burstein R, Newman LC, Lipton RB (2015) Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 14:1081–1090CrossRefPubMed
36.
Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings ELH, Diener H-C, Burstein R, Loupe PS, Ma Y, Yang R, Silberstein SD (2015) Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 14:1091–1100CrossRefPubMed
37.
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS (2014) Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 13:885–892CrossRefPubMed
38.
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B (2014) Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 13:1100–1107CrossRefPubMed
39.
Hong S, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, Saper J, Cady R, Yun C, Dietrich J (2016) Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 15:382–390CrossRef
40.
Buzzi MG, Carter WB, Shimizu T, Iii HH, Moskowitz MA (1991) Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion. Neuropharmacology 30:1193–1200CrossRefPubMed
41.
Knyihár-Csillik E, Tajti J, Samsam M, Sáry G, Buzás P, Vécsei L (1998) Depletion of calcitonin gene-related peptide from the caudal trigeminal nucleus of the rat after electrical stimulation of the Gasserian ganglion. Exp Brain Res 118:111–114CrossRefPubMed
42.
Zagami AS, Goadsby PJ, Edvinsson L (1990) Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides 16:69–75CrossRefPubMed
43.
Ashkenazi A, Silberstein SD (2004) Botulinum toxin and other new approaches to migraine therapy. Annu Rev Med 55:505–518CrossRefPubMed
44.
Silberstein SD (2005) Review of botulinum toxin type A and its clinical applications in migraine headache. Expert Opin Pharmacother 2:1649–1654CrossRef
45.
Cernudamorollón E, Larrosa D, Ramón C, Vega J, Martínezcamblor P, Pascual J (2013) Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 81:1191–1196CrossRef
46.
Edvinsson L, Goadsby PJ (1994) Neuropeptides in migraine and cluster headache. Cephalalgia 14:320–327CrossRefPubMed
47.
Fusayasu E, Kowa H, Takeshima T, Nakaso K, Nakashima K (2007) Increased plasma substance P and CGRP levels, and high ACE activity in migraineurs during headache-free periods. Pain 128:209–214CrossRefPubMed
48.
Shao YF, Zhang Y, Zhao P, Yan WJ, Kong XP, Fan LL, Hou YP (2013) Botulinum toxin type a therapy in migraine: preclinical and clinical trials. Iranian Red Crescent Med J 15:e7704CrossRef
49.
Knight YE, Edvinsson L, Goadsby PJ (1999) Blockade of calcitonin gene-related peptide release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122,288. Neuropeptides 33:41–46CrossRefPubMed
50.
Knight YE, Edvinsson L, Goadsby PJ (2001) 4991 W93 inhibits release of calcitonin gene-related peptide in the cat but only at doses with 5HT 1B/1D receptor agonist activity? ☆. Neuropharmacology 40:520–525CrossRefPubMed
51.
Hou M, Tang Q, Xue Q, Zhang X, Liu Y, Yang S, Chen L, Xu X (2016) Pharmacodynamic action and mechanism of Du Liang soft capsule, a traditional Chinese medicine capsule, on treating nitroglycerin-induced migraine. J Ethnopharmacol 195:231–237
52.
Diener HC, Barbanti P, Dahlöf C, Reuter U, Habeck J, Podhorna J (2011) BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia 31:573–584CrossRefPubMed
53.
Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W (2000) Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol 129:420–423CrossRefPubMedPubMedCentral
54.
Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ (2013) BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 34:114–125CrossRefPubMed
55.
Negro A, Curto M, Lionetto L, Giamberardino MA, Martelletti P (2016) Chronic migraine treatment: from OnabotulinumtoxinA onwards. Expert Rev Neurother 16:1217CrossRefPubMed
56.
Dossantos MF, Holandaafonso RC, Lima RL, Dasilva AF, Mouraneto V (2014) The role of the blood–brain barrier in the development and treatment of migraine and other pain disorders. Front Cell Neurosci 8:302–302CrossRefPubMedPubMedCentral
57.
Edvinsson L, Tfelthansen P (2008) The blood–brain barrier in migraine treatment. Cephalalgia 28:1245–1258CrossRefPubMed
58.
Vermeersch S, De HJ, De SB, Derdelinckx I, Serdons K, Bormans G, Reynders T, Declercq R, De LI, Kennedy W (2013) PET imaging in healthy subjects and migraineurs suggests CGRP receptor antagonists do not have to act centrally to achieve clinical efficacy. J Headache Pain 14:1–1CrossRef
59.
Tfelthansen P, Olesen J (2011) Possible site of action of CGRP antagonists in migraine. Cephalalgia 31:748–750CrossRef
60.
Hirsch S, Corradini L, Just S, Arndt K, Doods H (2013) The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats. Pain 154:700–707CrossRefPubMed
61.
Bigal ME, Escandon R, Bronson M, Walter S, Sudworth M, Huggins JP, Garzone P (2013) Safety and tolerability of LBR-101, a humanized monoclonal antibody that blocks the binding of CGRP to its receptor: results of the phase 1 program. Cephalalgia 34:483–492CrossRefPubMed
62.
Hoon JD, Hecken AV, Yan L, Smith B, Chen J, Bautista E, Hamilton L, Waksman J, Vu T, Vargas G (2015) Phase 1, randomized, double-blind, placebo-controlled, single-dose and multiple dose studies of AMG334 in healthy subjects and migraine patients. Cephalalgia 35:45–46
Metadata
Title
The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis
Authors
Min Hou
Haiyan Xing
Yongqing Cai
Bin Li
Xianfeng Wang
Pan Li
Xiaolin Hu
Jianhong Chen
Publication date
01-12-2017
Publisher
Springer Milan
Published in
The Journal of Headache and Pain / Issue 1/2017
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-017-0750-1

Other articles of this Issue 1/2017

The Journal of Headache and Pain 1/2017 Go to the issue

Review article

Sphenopalatine ganglion: block, radiofrequency ablation and neurostimulation - a systematic review

Research article

Assessment of gray and white matter structural alterations in migraineurs without aura

Research article

Therapeutical approaches to paroxysmal hemicrania, hemicrania continua and short lasting unilateral neuralgiform headache attacks: a critical appraisal

Research article

Copeptin for risk stratification in non-traumatic headache in the emergency setting: a prospective multicenter observational cohort study

Research article

Disrupted functional connectivity of periaqueductal gray subregions in episodic migraine

Research article

The NO-cGMP-PKG signal transduction pathway is involved in the analgesic effect of early hyperbaric oxygen treatment of neuropathic pain