Skip to main content
Log in

Calcitonin Gene-Related Peptide Targeted Immunotherapy for Migraine: Progress and Challenges in Treating Headache

  • Leading Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

A role for calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine has been established over the past 25 years. There have now been at least five different small-molecule CGRP antagonists that have demonstrated statistical proof of efficacy in the acute treatment of migraine. At present, multiple clinical trials are underway that are assessing the ability of long-acting antibodies against CGRP to prevent frequent migraine attacks. This review summarizes the existing data concerning the role of CGRP in migraine and attempts to highlight some possible outcomes from the ongoing anti-CGRP antibody trials.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. 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.

    Article  CAS  PubMed  Google Scholar 

  2. 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 

  3. Goadsby P, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28(2):183–7.

    Article  CAS  PubMed  Google Scholar 

  4. Gallai V, Sarchielli P, Floridi A, Franceschini M, Codini M, Glioti G, Trequattrini A, Palumbo R. Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia. 1995;15:384–90.

    Article  CAS  PubMed  Google Scholar 

  5. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33(1):48–56.

    Article  CAS  PubMed  Google Scholar 

  6. Sarchielli P, Alberti A, Codini M, Floridi A, Gallai V. Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia. 2000;20(10):907–18.

    Article  CAS  PubMed  Google Scholar 

  7. Cady RK, Vause CV, Ho TW, Bigal ME, Durham PL. Elevated saliva calcitonin gene-related peptide levels during acute migraine predict therapeutic response to rizatriptan. Headache. 2009;49(9):1258–66.

    Article  PubMed  Google Scholar 

  8. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  9. Olesen J, Diener H-C, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM. 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 

  10. Doenicke A, Brand J, Perrin VL. Possible benefit of GR43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine. Lancet. 1988;1(8598):1309–11.

    Article  CAS  PubMed  Google Scholar 

  11. Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70:1304–12.

    Article  CAS  PubMed  Google Scholar 

  12. Connor KM, Shapiro RE, Diener H-CC, Lucas S, Kost J, Fan X, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009;73:970–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, 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;372:2115–23.

    Article  CAS  PubMed  Google Scholar 

  14. MK0974 for migraine prophylaxis in patients with episodic migraine. 2013 [ClinicalTrials.gov identifier NCT00797667]. http://clinicaltrials.gov. Accessed 19 Jan 2014.

  15. Merck. Merck announces second quarter 2011 financial results. Merck Newsroom, 2011. http://www.mercknewsroom.com/press-release/financial-news/merck-announces-second-quarter-2011-financial-results. Accessed 19 Jan 2014.

  16. Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ, 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.

    Article  PubMed  Google Scholar 

  17. Diener H-C, Barbanti P, Dahlöf C, Reuter U, Habeck J, Podhorna J. 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 

  18. 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(2):114–25.

    Google Scholar 

  19. Negro A, Lionetto L, Simmaco M, Martelletti P. CGRP receptor antagonists: an expanding drug class for acute migraine? Expert Opin Investig Drugs. 2012;21(6):807–18.

    Article  CAS  PubMed  Google Scholar 

  20. Lionetto L, Negro A, Palmisani S, Gentile G, Del Fiore MR, Mercieri M, et al. Emerging treatment for chronic migraine and refractory chronic migraine. Expert Opin Emerg Drugs. 2012;17(3):393–406.

    Article  CAS  PubMed  Google Scholar 

  21. deHoon J, Montieth D, Vermeersch S, Van Hecken A, Abu-Raddad E. Safety, pharmacokinetics, and pharmacodynamics of LY2951742: a monoclonal antibody targeting CGRP [abstract]. Cephalalgia. 2013;33(8 Suppl):247–248.

    Google Scholar 

  22. Bigal ME, Escandon R, Bronson M, Walter S, Sudworth M, Huggins JP, Garzone P. 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.

  23. Oh-hashi Y, Shindo T, Kurihara Y, Imai T, Wang YH, Morita H, et al. Elevated sympathetic nervous activity in mice deficient in CGRP. Circ Res. 2001;89(11):983–90.

    Article  CAS  PubMed  Google Scholar 

  24. Kurihara H, Kuwaki T. Targeted disruption of adrenomedullin and alphaCGRP genes reveals their distinct biological roles. Hypertens Res. 2003;26 Suppl:S105–8.

    Google Scholar 

  25. Bowers MC, Katki KA, Rao A, Koehler M, Patel P, Spiekerman A, et al. Role of calcitonin gene-related peptide in hypertension-induced renal damage. Hypertension. 2005;46(1):51–7.

    Google Scholar 

  26. Supowit SC, Rao A, Bowers MC, Zhao H, Fink G, Steficek B, et al. Calcitonin gene-related peptide protects against hypertension-induced heart and kidney damage. Hypertension. 2005;45(1):109–14.

    Google Scholar 

  27. Mishima T, Ito Y, Hosono K, Tamura Y, Uchida Y, Hirata M, et al. Calcitonin gene-related peptide facilitates revascularization during hindlimb ischemia in mice. Am J Physiol Heart Circ Physiol. 2011;300(10):H431–9.

    Article  CAS  PubMed  Google Scholar 

  28. Walker CS, Li X, Whiting L, Glyn-Jones S, Zhang S, Hickey AJ, et al. Mice lacking the neuropeptide alpha-calcitonin gene-related peptide are protected against diet-induced obesity. Endocrinology. 2010;151(9):4257–69.

    Google Scholar 

  29. Kroeger I, Erhardt A, Abt D, Fischer M, Biburger M, Rau T, et al. The neuropeptide calcitonin gene-related peptide (CGRP) prevents inflammatory liver injury in mice. J Hepatol. 2009;51:342–53.

    Article  CAS  PubMed  Google Scholar 

  30. Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Iinuma N, Kawate H, Yoshizawa T, et al. Endogenous alpha-calcitonin gene-related peptide mitigates liver fibrosis in chronic hepatitis induced by repeated administration of concanavalin A. Liver Int. 2009;29:642–9.

    Article  CAS  PubMed  Google Scholar 

  31. Ohno T, Hattori Y, Komine R, Ae T, Mizuguchi S, Arai K, et al. Roles of calcitonin gene-related peptide in maintenance of gastric mucosal integrity and in enhancement of ulcer healing and angiogenesis. Gastroenterology. 2008;134:215–25.

    Article  CAS  PubMed  Google Scholar 

  32. Toda M, Suzuki T, Hosono K, Hayashi I, Hashiba S, Onuma Y, et al. Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide. Proc Natl Acad Sci U S A. 2008;105:13550–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Majima M, Mishima T, Toda M, Suzuki T, Ito Y, Ohno T, et al. Roles of calcitonin gene-related peptide in enhancement of angiogenesis. Inflamm Regen. 2011;31:146–50.

    Article  CAS  Google Scholar 

  34. Mikami N, Matsushita H, Kato T, Kawasaki R, Sawazaki T, Kishimoto T, et al. Calcitonin gene-related peptide is an important regulator of cutaneous immunity: effect on dendritic cell and T cell functions. J Immunol. 2011;186(12):6886–93.

    Article  CAS  PubMed  Google Scholar 

  35. Odar-Cederlöf I, Theodorsson E, Eriksson CG, Kjellstrand CM. Plasma concentrations of calcitonin gene-related peptide increase during haemodialysis: relation to blood pressure. J Intern Med. 1989;226:177–82.

    Article  PubMed  Google Scholar 

  36. Odar-Cederlöf I, Theodorsson E, Ericsson F, Kjellstrand CM. Plasma concentrations of calcitonin gene-related peptide in fluid overload. Lancet. 1991;338:411–2.

    Article  PubMed  Google Scholar 

  37. Wyon Y, Frisk J, Lundeberg T, Theodorsson E, Hammar M. Postmenopausal women with vasomotor symptoms have increased urinary excretion of calcitonin gene-related peptide. Maturitas. 1998;30:289–94.

    Article  CAS  PubMed  Google Scholar 

  38. Wyon YA, Spetz AC, Theodorsson GE, Hammar ML. Concentrations of calcitonin gene-related peptide and neuropeptide Y in plasma increase during flushes in postmenopausal women. Menopause. 2000;7(1):25–30.

    Google Scholar 

  39. Wyon Y, Spetz AC, Hammar M, Theodorsson E, Varenhorst E. Urinary excretion of calcitonin gene-related peptide in males with hot flushes after castration for carcinoma of the prostate. Scand J Urol Nephrol. 2001;35:92–6.

    Article  CAS  PubMed  Google Scholar 

  40. Onuoha GN, Alpar EK. Calcitonin gene-related peptide and other neuropeptides in the plasma of patients with soft tissue injury. Life Sci. 1999;65:1351–8.

    Article  CAS  PubMed  Google Scholar 

  41. Takeuchi H, Kawaguchi S, Ohwada O, Kobayashi H, Hayakawa M, Takebayashi T, et al. Plasma neuropeptides in patients undergoing lumbar discectomy. Spine (Phila. Pa. 1976). 2007;32:E79–E84.

    Google Scholar 

  42. Onuoha GN, Alpar EK. Elevation of plasma CGRP and SP levels in orthopedic patients with fracture neck of femur. Neuropeptides. 2000;34:116–20.

    Article  CAS  PubMed  Google Scholar 

  43. Onuoha GN. Circulating sensory peptide levels within 24 h of human bone fracture. Peptides. 2001;22:1107–10.

    Article  CAS  PubMed  Google Scholar 

  44. Onuoha GN, Alpar EK. Levels of vasodilators (SP, CGRP) and vasoconstrictor (NPY) peptides in early human burns. Eur J Clin Invest. 2001;31:253–7.

    Article  CAS  PubMed  Google Scholar 

  45. Wiśnicka B, Szepietowski JC, Orda A, Reich A. Histamine, substance P and calcitonin gene-related peptide plasma concentration and pruritus in patients. Dermatol Psychosom. 2004;5:73–8.

    Article  Google Scholar 

  46. Reich A, Orda A, Wiśnicka B, Szepietowski JC. Plasma concentration of selected neuropeptides in patients suffering from psoriasis. Exp Dermatol. 2007;16:421–8.

    Article  CAS  PubMed  Google Scholar 

  47. Reich A, Orda A, Wiśnicka B, Szepietowski JC. Plasma neuropeptides and perception of pruritus in psoriasis. Acta Derm Venereol. 2007;87:299–304.

    Article  CAS  PubMed  Google Scholar 

  48. Zelissen PM, Koppeschaar HP, Lips CJ, Hackeng WH. Calcitonin gene-related peptide in human obesity. Peptides. 1991;12:861–3.

    Article  CAS  PubMed  Google Scholar 

  49. Peterlin BL, Rapoport AM, Kurth T. Migraine and obesity: epidemiology, mechanisms, and implications. Headache. 2010;50:631–48.

    Article  PubMed Central  PubMed  Google Scholar 

  50. Evans RW, Williams MA, Rapoport AM, Peterlin BL. The association of obesity with episodic and chronic migraine. Headache. 2012;52(4):663–71.

    Article  PubMed Central  PubMed  Google Scholar 

  51. Bigal M, Rapoport A. Obesity and chronic daily headache. Curr Pain Headache Rep. 2012;16:101–9.

    Article  PubMed  Google Scholar 

  52. Peterlin BL, Rosso AL, Williams MA, Rosenberg JR, Haythornthwaite JA, Merikangas KR, et al. Episodic migraine and obesity and the influence of age, race, and sex. Neurology. 2013;81(15):1314–21.

    Article  PubMed  Google Scholar 

  53. Juhasz G, Modosa EA, Olajosb S, Jakabc B, Nemeth J, Szolcsanyi J, et al. NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain. 2003;106(3):461–70.

    Google Scholar 

  54. Jang M-U, Park J-W, Kho H-S, Chung S-C, Chung J-W. Plasma and saliva levels of nerve growth factor and neuropeptides in chronic migraine patients. Oral Dis. 2011;17(2):187–93.

    Article  PubMed  Google Scholar 

  55. Cernuda-Morollón E, Larrosa D, Ramón C, Vega J, Martínez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81(14):1191–6.

    Article  PubMed  Google Scholar 

  56. Wang Z, Guo J, Wang X, Zhao Y, Hou L. The relationship between serum calcitonin gene-related peptide, sex hormone, homocysteine and coronary artery disease in postmenopausal women. Zhonghua Nei Ke Za Zhi. 2004;43:679–81.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments and Disclosures

The author thanks Mary Ellen Peroutka for her editorial assistance. The author has no conflicts of interest that are directly relevant to the content of this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen J. Peroutka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peroutka, S.J. Calcitonin Gene-Related Peptide Targeted Immunotherapy for Migraine: Progress and Challenges in Treating Headache. BioDrugs 28, 237–244 (2014). https://doi.org/10.1007/s40259-014-0083-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40259-014-0083-4

Keywords

Navigation