Skip to main content

Advertisement

SpringerLink
Log in

CGRP Mechanism Antagonists and Migraine Management

  • Headache (RB Halker, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Migraine is a complex disorder of the brain that is common and highly disabling. As understanding of the neural pathways has advanced, and it has become clear that the vascular hypothesis does not explain the disorder, new therapeutic avenues have arisen. One such target is calcitonin gene-related peptide (CGRP)-based mechanisms. CGRP is found within the trigeminovascular nociceptive system widely from the trigeminal ganglion to second-order and third-order neurons and in regulatory areas in the brainstem. Studies have shown CGRP is released during severe migraine attacks and the reversal of the attack with effective triptan treatment normalizes those levels. CGRP administration triggers migraine in patients, and CGRP receptor antagonists have been shown to abort migraine. Here, we review the current state of CGRP mechanism antagonist therapy as its research and development is increasing in migraine therapeutics. We discuss several recent trials, highlighting the evidence base behind these novel drugs, and their potential future contribution to migraine management.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Amara SG, Jonas V, Rosenfeld MG, et al. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982;298(5871):240–4.

    Article  CAS  PubMed  Google Scholar 

  2. Mulderry PK, Ghatei MA, Spokes RA, et al. Differential expression of alpha-CGRP and beta-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience. 1988;25(1):195–205.

    Article  CAS  PubMed  Google Scholar 

  3. Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol. 2010;6:573–82. An important review discussing the role of CGRP in migraine.

    Article  CAS  PubMed  Google Scholar 

  4. Moore EL, Salvatore CA. Targeting a family B GPCR/RAMP receptor complex: CGRP receptor antagonists and migraine. Br J Pharmacol. 2012;166(1):66–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. 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(5):649–78.

    Article  PubMed  Google Scholar 

  6. Unger JW, Lange W. Immunohistochemical mapping of neurophysins and calcitonin gene-related peptide in the human brainstem and cervical spinal cord. J Chem Neuroanat. 1991;4(4):299–309.

    Article  CAS  PubMed  Google Scholar 

  7. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol. 1988;23(2):193–6.

    Article  CAS  PubMed  Google Scholar 

  8. Zagami AS, Goadsby PJ, Edvinsson L. Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides. 1990;16(2):69–75.

    Article  CAS  PubMed  Google Scholar 

  9. Goadsby EE. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183–87.

    Article  CAS  PubMed  Google Scholar 

  10. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterising cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33:48–56.

    Article  CAS  PubMed  Google Scholar 

  11. Cernuda-Morollon E, Larrosa D, Ramon C, et al. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81(14):1191–6.

    Article  CAS  PubMed  Google Scholar 

  12. 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(10):1179–86.

    Article  PubMed  Google Scholar 

  13. Sprenger T, Goadsby PJ. What has functional neuroimaging done for primary headache … and for the clinical neurologist? J Clin Neurosci: Off J Neurosurg Soc Australas. 2010;17(5):547–53.

    Article  Google Scholar 

  14. Afridi SK, Matharu MS, Lee L, et al. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain. 2005;128:932–39.

    Article  CAS  PubMed  Google Scholar 

  15. Maniyar FH, Sprenger T, Monteith T, et al. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain. 2014;137(Pt 1):232–41.

  16. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurol. 2011;12:570–84. A review of the role of the brainstem in mediating the neuronal circuitry mechanism in migraine, current ideas regarding the pathophysiology of the condition and areas of the brain and circuitry that could be targeted with anti-migraine agents.

    Article  CAS  Google Scholar 

  17. Edvinsson L, Ekman R, Jansen I, et al. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J Cereb blood flow Metab: Off J Int Soc Cereb Blood Flow Metab. 1987;7(6):720–8.

    Article  CAS  Google Scholar 

  18. Arimura A. Pituitary adenylate cyclase activating polypeptide (PACAP): discovery and current status of research. Regul Pept. 1992;37(3):287–303.

    CAS  PubMed  Google Scholar 

  19. Tuka B, Helyes Z, Markovics A, et al. Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia. 2013;33(13):1085–95.

    Article  PubMed  Google Scholar 

  20. Zagami AS, Edvinsson L, Goadsby PJ. Pituitary adenylate cyclase activating polypeptide (PACAP) and Migraine. Ann Clin Transl Neurol. 2014. in press.

  21. Lundberg JM, Franco-Cereceda A, Hua X, et al. Co-existence of substance P and calcitonin gene-related peptide-like immunoreactivities in sensory nerves in relation to cardiovascular and bronchoconstrictor effects of capsaicin. Eur J Pharmacol. 1985;108(3):315–9.

    Article  CAS  PubMed  Google Scholar 

  22. Uddman R, Edvinsson L, Ekman R, et al. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett. 1985;62(1):131–6.

    Article  CAS  PubMed  Google Scholar 

  23. Goadsby PJ. Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med. 2007;13(1):39–44.

    Article  CAS  PubMed  Google Scholar 

  24. Evans BN, Rosenblatt MI, Mnayer LO, et al. CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J Biol Chem. 2000;275(40):31438–43.

    Article  CAS  PubMed  Google Scholar 

  25. Maniyar FH, Sprenger T, Schankin C, Goadsby PJ. Photic hypersensitivity in the premonitory phase of migraine- a positron emission topography study. Eur J Neurol. 2014;21:1178–83.

    Article  CAS  PubMed  Google Scholar 

  26. Eftekhari S, Edvinsson L. Possible sites of action of the new calcitonin gene-related peptide receptor antagonists. Ther Adv Neurol Disord. 2010;3(6):369–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Lennerz JK, Ruhle V, Ceppa EP, et al. Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. J Comp Neurol. 2008;507(3):1277–99.

    Article  CAS  PubMed  Google Scholar 

  28. Liu Y, Broman J, Zhang M, Edvinsson L. Brainstem and thalamic projections from a craniovascular sensory nervous centre in the rostral cervical spinal dorsal horn of rats. Cephalalgia. 2009;29(9):935–48.

    Article  CAS  PubMed  Google Scholar 

  29. Smith D, Hill RG, Edvinsson L, Longmore J. An immunocytochemical investigation of human trigeminal nucleus caudalis: CGRP, substance P and 5-HT1D-receptor immunoreactivities are expressed by trigeminal sensory fibres. Cephalalgia. 2002;22(6):424–31.

    Article  CAS  PubMed  Google Scholar 

  30. Strata P, Thach WT, Ottersen OP. New insights in cerebellar function. Introduction. Neuroscience. 2009;162(3):545–8.

    Article  CAS  PubMed  Google Scholar 

  31. Kawai Y, Takami K, Shiosaka S, et al. Topographic localization of calcitonin gene-related peptide in the rat brain: an immunohistochemical analysis. Neuroscience. 1985;15(3):747–63.

    Article  CAS  PubMed  Google Scholar 

  32. Brighina F, Palermo A, Panetta ML, et al. Reduced cerebellar inhibition in migraine with aura: a TMS study. Cerebellum (Lond, Engl). 2009;8(3):260–6.

    Article  Google Scholar 

  33. Bahra A, Matharu MS, Buchel C, et al. Brainstem activation specific to migraine headache. Lancet. 2001;357(9261):1016–7.

    Article  CAS  PubMed  Google Scholar 

  34. Eftekhari S, Salvatore CA, Calamari A, et al. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010;169(2):683–96.

    Article  CAS  PubMed  Google Scholar 

  35. Edvinsson L. Calcitonin gene-related peptide (CGRP) and the pathophysiology of headache: therapeutic implications. CNS Drugs. 2001;15(10):745–53.

    Article  CAS  PubMed  Google Scholar 

  36. Lynch Jr JJ, Regan CP, Edvinsson L, et al. Comparison of the vasoconstrictor effects of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) and zolmitriptan in human isolated coronary arteries. J Cardiovasc Pharmacol. 2010;55(5):518–21.

    Article  CAS  PubMed  Google Scholar 

  37. Bigal ME, Walter S. Monoclonal antibodies for migraine: preventing calcitonin gene-related peptide activity. CNS Drugs. 2014;28(5):389–99.

    Article  CAS  PubMed  Google Scholar 

  38. Doods H, Hallermayer G, Wu D, et al. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol. 2000;129(3):420–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Olesen J, Diener HC, Husstedt IW, et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350(11):1104–10.

    Article  CAS  PubMed  Google Scholar 

  40. Mallee JJ, Salvatore CA, LeBourdelles B, et al. Receptor activity-modifying protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists. J Biol Chem. 2002;277(16):14294–8.

    Article  CAS  PubMed  Google Scholar 

  41. Just S, Arndt K, Doods H. The role of CGRP and nicotinic receptors in centrally evoked facial blood flow changes. Neurosci Lett. 2005;381(1–2):120–4.

    Article  CAS  PubMed  Google Scholar 

  42. Petersen KA, Birk S, Lassen LH, et al. The CGRP-antagonist, BIBN4096BS does not affect cerebral or systemic haemodynamics in healthy volunteers. Cephalalgia. 2005;25(2):139–47.

    Article  CAS  PubMed  Google Scholar 

  43. Edvinsson L, Linde M. New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet. 2010;376(9741):645–55.

    Article  CAS  PubMed  Google Scholar 

  44. Ho TW, Ferrari MD, Dodick DW, et al. 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. 2008;372(9656):2115–23.

    Article  CAS  PubMed  Google Scholar 

  45. Ho TW, Connor KM, Zhang Y, et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology. 2014;83(11):958–66.

    Article  CAS  PubMed  Google Scholar 

  46. Ho TW, Ho AP, Chaitman BR, et al. Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease. Headache. 2012;52(2):224–35.

    Article  PubMed  Google Scholar 

  47. Connor KM, Shapiro RE, Diener HC, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009;73(12):970–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Han TH, Blanchard RL, Palcza J, et al. Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults. J Clin Pharmacol. 2010;50(12):1367–76.

    Article  CAS  PubMed  Google Scholar 

  49. Ho AP, Dahlof CG, Silberstein SD, et al. Randomized, controlled trial of telcagepant over four migraine attacks. Cephalalgia. 2010;30(12):1443–57.

    Article  PubMed  Google Scholar 

  50. Connor KM, Aurora SK, Loeys T, et al. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. Headache. 2011;51(1):73–84.

    Article  PubMed  Google Scholar 

  51. Hewitt DJ, Aurora SK, Dodick DW, et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia. 2011;31(6):712–22.

    Article  PubMed  Google Scholar 

  52. Diener HC, Barbanti P, Dahlof C, et al. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia. 2011;31(5):573–84.

    Article  PubMed  Google Scholar 

  53. Luo G, Chen L, Conway CM, et al. Discovery of BMS-846372, a potent and orally active human CGRP receptor antagonist for the treatment of migraine. ACS Med Chem Lett. 2012;3(4):337–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Marcus R, Goadsby PJ, Dodick D, et al. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo-controlled, dose-ranging trial. Cephalalgia. 2014;34(2):114–25.

    Article  PubMed  Google Scholar 

  55. Merck Sharp, Bohme Corp. A pharmacokinetic study of MK-1602 in the treatment of acute migraine (MK-1602-007) NCT01657370. https://clinicaltrials.gov/ct2/show/NCT01657370. Accessed 14 Mar 2015.

  56. Merck Sharp, Bohme Corp. A dose-finding study of MK-1602 in the treatment of acute migraine (MK-1602-006) NCT01613248. https://clinicaltrials.gov/ct2/show/NCT01613248. Accessed 14 Mar 2015.

  57. Edvinsson L. CGRP blockers in migraine therapy: where do they act? Br J Pharmacol. 2008;155(7):967–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Hostetler ED, Joshi AD, Sanabria-Bohorquez S, et al. In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232. J Pharmacol Exp Ther. 2013;347(2):478–86.

    Article  CAS  PubMed  Google Scholar 

  59. Baumann A. Early development of therapeutic biologics—pharmacokinetics. Curr Drug Metab. 2006;7(1):15–21.

    Article  CAS  PubMed  Google Scholar 

  60. Bigal ME, Walter S, Rapoport AM. Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development. Headache. 2013;53(8):1230–44. An up to date current review on the anti-CGRP agents in migraine management, with a particular focus on the monoclonal antibodies.

    Article  PubMed  Google Scholar 

  61. Descotes J. Immunotoxicity of monoclonal antibodies. mAbs. 2009;1(2):104–11.

    Article  PubMed Central  PubMed  Google Scholar 

  62. Feuerstein G, Willette R, Aiyar N. Clinical perspectives of calcitonin gene related peptide pharmacology. Can J Physiol Pharmacol. 1995;73(7):1070–4.

    Article  CAS  PubMed  Google Scholar 

  63. Zeller J, Poulsen KT, Sutton JE, et al. CGRP function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure in the rat. Br J Pharmacol. 2008;155(7):1093–103.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Alder biopharmaceuticals Inc. Safety tolerability and pharmacokinetics of ALD403 NCT01579383. https://clinicaltrials.gov/ct2/show/NCT01579383. Accessed 14 Mar 2015.

  65. Dodick DW, Goadsby PJ, Silberstein SD, et al. 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. 2014;13(11):1100–7.

    Article  CAS  PubMed  Google Scholar 

  66. Dodick DW, Goadsby PJ, Spierings EL, et al. 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. 2014;13(9):885–92.

    Article  CAS  PubMed  Google Scholar 

  67. Amgen. Ascending multiple-doses of AMG 334 in healthy subjects and in migraine patients NCT01723514. https://clinicaltrials.gov/ct2/show/NCT01723514. Accessed 14 Mar 2014.

  68. Amgen. Ascending single doses of AMG 334 in healthy subjects and migraine patients NCT01688739. https://www.clinicaltrials.gov/ct2/show/NCT01688739. Accessed 14 Mar 2015.

  69. Amgen. A phase 2 study to evaluate the efficacy and safety of AMG 334 in migraine prevention NCT01952574. https://clinicaltrials.gov/ct2/show/NCT01952574. Accessed 14 Mar 2015.

  70. Amgen. A study to assess the long-term safety and efficacy of AMG 334 in chronic migraine prevention NCT02174861. https://clinicaltrials.gov/ct2/show/NCT02174861. Accessed 14 Mar 2015.

  71. Bigal ME, Escandon R, Bronson M, et al. 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. 2013;34(7):483–92.

    Article  PubMed  Google Scholar 

  72. Teva Pharmaceutical Industries. A multicenter assessment of LBR-101 in high frequency episodic migraine NCT02025556. https://clinicaltrials.gov/ct2/show/NCT02025556. Accessed 14 Mar 2015.

  73. Teva Pharmaceutical Industries. Assessment of LBR-101 In chronic migraine NCT02021773. https://clinicaltrials.gov/ct2/show/NCT02021773. Accessed 14 Mar 2015.

  74. Walter S, Alibhoy A, Escandon R, Bigal ME. Evaluation of cardiovascular parameters in cynomolgus monkeys following IV administration of LBR-101, a monoclonal antibody against calcitonin gene-related peptide. mAbs. 2014;6(4):871–8.

    Article  PubMed  Google Scholar 

  75. Bigal ME, Walter S, Bronson M, et al. Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP. Cephalalgia 2014.

  76. Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain. 1994;117(Pt 3):427–34.

    Article  PubMed  Google Scholar 

  77. Goadsby PJ, Sprenger T. Current practice and future directions in the prevention and acute management of migraine. Lancet Neurol. 2010;9(3):285–98.

    Article  PubMed  Google Scholar 

  78. Dodick D, Lipton RB, Martin V, et al. Consensus statement: cardiovascular safety profile of triptans (5-HT agonists) in the acute treatment of migraine. Headache. 2004;44(5):414–25.

    Article  PubMed  Google Scholar 

  79. Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Nazia Karsan declares no conflict of interest.

Peter J. Goadsby reports grants and personal fees from Allergan, grants and personal fees from eNeura, personal fees from Autonomic Technologies Inc, grants and personal fees from Amgen, personal fees from BristolMyerSquibb, personal fees from AlderBio, personal fees from Pfizer, personal fees from Zogenix, personal fees from Nevrocorp, personal fees from Impax, personal fees from DrReddy, personal fees from Zosano, personal fees from Colucid, personal fees from Eli Lilly, personal fees from Medtronic, personal fees from Avanir, personal fees from Gore, personal fees from Ethicon, personal fees from Heptares, personal fees from Nupathe, personal fees from Ajinomoto and personal fees from Teva outside the submitted work. Amgen, AlderBio, Lilly and Teva are currently developing CGRP antibodies as CGRP preventive agents.

Human and Animal Rights and Informed Consent

This article does not contain any new studies with human or animal subjects performed by any of the authors, although such studies are reviewed and have been performed by the authors.

Author information

Authors and Affiliations

  1. Headache Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Nazia Karsan

  2. NIHR-Wellcome Trust Clinical Research Facility, Wellcome Foundation Building, King’s College Hospital, London, SE5 9PJ, UK

    Peter J. Goadsby

Authors
  1. Nazia Karsan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter J. Goadsby
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter J. Goadsby.

Additional information

This article is part of the Topical Collection on Headache

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karsan, N., Goadsby, P.J. CGRP Mechanism Antagonists and Migraine Management. Curr Neurol Neurosci Rep 15, 25 (2015). https://doi.org/10.1007/s11910-015-0547-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-015-0547-z

Keywords

Search

Navigation