Neurological Sciences

, Volume 38, Supplement 1, pp 31–35 | Cite as

The role of anti-CGRP antibodies in the pathophysiology of primary headaches

  • Piero Barbanti
  • Cinzia Aurilia
  • Luisa Fofi
  • Gabriella Egeo
  • Patrizia Ferroni
NEUROBIOLOGY OF HEADACHE

Abstract

Calcitonin gene-related peptide (CGRP), a potent vasodilator and pain-signaling neuropeptide, is a validated therapeutic target for migraine and cluster headache. Four anti-CGRP monoclonal antibodies (mAbs) have been developed, representing the first specific, mechanism-based, migraine prophylactic treatment. CGRP mAbs demonstrated good efficacy coupled to excellent tolerability and safety in 5 phase II clinical trials. Notably, CGRP mAbs induced complete migraine remission in a patients’ subset. To date, more than 20 phase III trials using CGRP mAbs for of episodic and chronic migraine and cluster headache prevention are ongoing. Future investigations will shed light on migraine endophenotypes predictive of good CGRP mAbs responsiveness and provide answers on their long-term cardiovascular safety.

Keywords

CGRP Monoclonal CGRP antibodies Migraine Headache Treatment 

Notes

Compliance with ethical standards

Conflict of interest

The authors certify that there is no actual or potential conflict of interest in relation to this article.

References

  1. 1.
    Edvinsson L (2015) The journey to establish CGRP as a migraine target: a retrospective view. Headache 55(9):1249–1255CrossRefPubMedGoogle Scholar
  2. 2.
    Edvinsson L (2015) CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br J Clin Pharmacol 80(2):193–199CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Schuster NM, Rapoport AM (2016) New strategies for the treatment and prevention of primary headache disorders. Nat Rev Neurol 12(11):635–650CrossRefPubMedGoogle Scholar
  4. 4.
    Russell FA, King R, Smillie SJ et al (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 94(4):1099–1142CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    van Rossum D, Hanisch UK, Quirion R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21(5):649–678CrossRefPubMedGoogle Scholar
  6. 6.
    Dussor G, Yan J, Xie JY, Ossipov MH et al (2014) Targeting TRP channels for novel migraine therapeutics. ACS Chem Neurosci 5(11):1085–1096CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Riera C, Huising MO, Follett P et al (2014) TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell 157(5):1023–1036CrossRefPubMedGoogle Scholar
  8. 8.
    Edvinsson L, Fredholm BB, Hamel E (1985) Perivascular peptides relax cerebral arteries concomitant with stimulation of cyclic adenosine monophosphate accumulation of release of an endothelium derived relaxing factor in the cat. Neurosci Lett 58:213–217CrossRefPubMedGoogle Scholar
  9. 9.
    Yu Y, Lundeberg T, Yu LC (2002) Role of calcitonin gene-related peptide and its antagonist on the evoked discharge frequency of wide dynamic range neurons in the dorsal horn of the spinal cord in rats. Regul Pept 103:23–27CrossRefPubMedGoogle Scholar
  10. 10.
    Di Angelantonio S, Giniatullin R, Costa V (2003) Modulation of neuronal nicotinic receptor function by the neuropeptides CGRP and substance P on autonomic nerve cells. Br J Pharmacol 139:1061–1075CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Giniatullin R, Nistri A, Fabbretti E (2008) Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol Neurobiol 37:83–90CrossRefPubMedGoogle Scholar
  12. 12.
    Ho TW, Edvinsson L, Goadsby PJ (2010) CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol 6(10):573–582CrossRefPubMedGoogle Scholar
  13. 13.
    Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28(2):183–187CrossRefPubMedGoogle Scholar
  14. 14.
    Bellamy JL, Cady RK, Durham PL (2006) Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients. Headache 46(1):24–33CrossRefPubMedGoogle Scholar
  15. 15.
    Tfelt-Hansen P, Le H (2009) Calcitonin gene-related peptide in blood: is it increased in the external jugular vein during migraine and cluster headache? A review. J Headache Pain 10:137–143CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cernuda-Morollón E, Larrosa D, Ramón C et al (2013) Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 81:1191–1196CrossRefPubMedGoogle Scholar
  17. 17.
    Goadsby PJ, Edvinsson L (1994) Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 117(Pt 3):427–434CrossRefPubMedGoogle Scholar
  18. 18.
    Neeb L, Anders L, Euskirchen P et al (2015) Corticosteroids alter CGRP and melatonin release in cluster headache episodes. Cephalalgia 35(4):317–326CrossRefPubMedGoogle Scholar
  19. 19.
    Lassen LH, Haderslev PA, Jacobsen VB et al (2002) CGRP may play a causative role in migraine. Cephalalgia 22(1):54–61CrossRefPubMedGoogle Scholar
  20. 20.
    Hansen JM, Hauge AW, Olesen J, Ashina M (2010) Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30(10):1179–1186CrossRefPubMedGoogle Scholar
  21. 21.
    Hansen JM, Thomsen LL, Olesen J et al (2011) Calcitonin gene-related peptide does not cause migraine attacks in patients with familial hemiplegic migraine. Headache 51:544–553CrossRefPubMedGoogle Scholar
  22. 22.
    Cui XP, Ye JX, Lin H et al (2015) Efficacy, safety, and tolerability of telcagepant in the treatment of acute migraine: a meta-analysis. Pain Pract 15(2):124–131CrossRefPubMedGoogle Scholar
  23. 23.
    Olesen J, Diener HC, Husstedt IW et al (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350(11):1104–1110CrossRefPubMedGoogle Scholar
  24. 24.
    Hewitt D, Aurora SK, Dodick DW et al (2011) Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia 31(6):712–722CrossRefPubMedGoogle Scholar
  25. 25.
    Diener HC, Barbanti P, Dahlöf C et al (2011) BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia 31(5):573–584CrossRefPubMedGoogle Scholar
  26. 26.
    Marcus R, Goadsby PJ, Dodick D et al (2014) BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 34(2):114–125CrossRefPubMedGoogle Scholar
  27. 27.
    Voss T, Lipton RB, Dodick DW et al (2016) A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 36(9):887–898CrossRefPubMedGoogle Scholar
  28. 28.
    Dodick DW, Goadsby PJ, Silberstein SD et al (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(11):1100–1107CrossRefPubMedGoogle Scholar
  29. 29.
    Dodick DW, Goadsby PJ, Spierings EL et al (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(9):885–892CrossRefPubMedGoogle Scholar
  30. 30.
    Sun H, Dodick DW, Silberstein S et al (2016) Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 15(4):382–390CrossRefPubMedGoogle Scholar
  31. 31.
    Bigal ME, Edvinsson L, Rapoport AM et al (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(11):1091–1100CrossRefPubMedGoogle Scholar
  32. 32.
    Bigal ME, Dodick DW, Rapoport AM et al (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(11):1081–1090CrossRefPubMedGoogle Scholar
  33. 33.
    Barbanti P, Egeo G (2015) Pharmacological trials in migraine: it’s time to reappraise where the headache is and what the pain is like. Headache 55(3):439–441CrossRefPubMedGoogle Scholar
  34. 34.
    Palmirotta R, Barbanti P, Ludovici G et al (2013) Establishment of a biorepository for migraine research: the experience of Interinstitutional Multidisciplinary BioBank (BioBIM). Neurol Sci 34:1659–1663CrossRefPubMedGoogle Scholar
  35. 35.
    MaassenVanDenBrink A, Meijer J, Villalón CM, Ferrari MD (2016) Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci 37(9):779–788CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2017

Authors and Affiliations

  • Piero Barbanti
    • 1
  • Cinzia Aurilia
    • 1
  • Luisa Fofi
    • 1
  • Gabriella Egeo
    • 1
  • Patrizia Ferroni
    • 2
  1. 1.Headache and Pain Unit, Department of Neurological, Motor and Sensorial SciencesIRCCS San Raffaele PisanaRomeItaly
  2. 2.Department of Human Sciences and Quality of Life PromotionSan Raffaele Roma Open UniversityRomeItaly

Personalised recommendations