CGRP Antagonists for the Treatment of Chronic Migraines: a Comprehensive Review

Abstract

Purpose of Review

The purpose of the following review is to summarize the most recent understanding of migraine pathophysiology, as well as of basic and clinical science pharmacologic literature regarding the development of calcitonin gene receptor peptide (CGRP) antagonists as a novel therapeutic modality for the treatment of migraine headaches. A review is provided of erenumab, the first of its class FDA approved CGRP antagonist.

Recent Findings

Despite its high prevalence, the occurrence and treatment of migraine headaches is poorly understood. Erenumab and CGRP antagonists as a whole significantly reduce the average number of migraine days experienced in migraine sufferers.

Summary

CGRP antagonists appear to significantly improve treatment outcomes in patients who suffer from episodic and chronic migraines. Erenumab is the first CGRP antagonist to be FDA approved for public use; however, further development of biologics in this class is underway.

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References

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

  1. 1.

    Bajwa ZH, Wootton RJ, Wippold FJ II. Evaluation of headache in adults. UpToDate. 2018.

  2. 2.

    Society IH. The International Classification of Headache Disorders, 3rd edn. 2018.

  3. 3.

    Cutrer FM, Bajwa ZH. Pathophysiology, clinical manifestations, and diagnosis of migraine in adults. UpToDate. 2017.

  4. 4.

    Russo A. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533–52.

    CAS  Article  Google Scholar 

  5. 5.

    Giffin N, Lipton R, Silberstein J, Olesen S, Goadsby P. The migraine postdrome: an electronic diary study. Neurology. 2016;87:309–13.

    Article  Google Scholar 

  6. 6.

    Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98:4687–92.

    CAS  Article  Google Scholar 

  7. 7.

    Gursoy-Ozdemir Y, Qiu J, Matsuoka N, Bolay H, Bermpohl D, Jin H, et al. Cortical spreading depression activates and upregulates MMP-9. J Clin Invest. 2004;113:1447–55.

    CAS  Article  Google Scholar 

  8. 8.

    Karatas H, Erdener S, Gursoy-Ozdemir Y, Lule S, Eren-Koçak E, Sen Z, et al. Spreading depression triggers headache by activating neuronal Panx1 channels. Science. 2013;339:1092–5.

    CAS  Article  Google Scholar 

  9. 9.

    Lipton R, Stewart W, Diamond S, Diamond M, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41:646–57.

    CAS  Article  Google Scholar 

  10. 10.

    Lipton R, Bigal M, Diamond M, Freitag F, Reed M, Stewart W, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343–9.

    CAS  Article  Google Scholar 

  11. 11.

    Stewart W, Wood C, Reed M, Roy J, Lipton R, Group AA. Cumulative lifetime migraine incidence in women and men. Cephalagia. 2008;28:1170–8.

    CAS  Article  Google Scholar 

  12. 12.

    Martin V, Behbehani M. Toward a rational understanding of migraine trigger factors. Med Clin North Am. 2001;85:911–41.

    CAS  Article  Google Scholar 

  13. 13.

    Kelman L. The triggers or precipitants of the acute migraine attack. Cephalagia. 2007;27:394–402.

    CAS  Article  Google Scholar 

  14. 14.

    Bajwa ZH, Smith JH. Preventive treatment of migraine in adults. UpToDate. 2018.

  15. 15.

    Goadsby P, Lipton R, Ferrari M. Migraine—current understanding and treatment. N Engl J Med. 2002;346:257–70.

    CAS  Article  Google Scholar 

  16. 16.

    Bajwa ZH, Smith JH. A cute treatment of migraine in adults. UpToDate. 2018.

  17. 17.

    Breeze A, Harvey T, Bazzo R, Campbell I. Solution structure of human calcitonin gene-related peptide by 1H NMR and distance geometry with restrained molecular dynamics. Biochemistry. 1991;30:575–82.

    CAS  Article  Google Scholar 

  18. 18.

    Sexton P, Christopoulos G, Christopoulos A, Nylen E, Snider R Jr, Becker K. Procalcitonin has bioactivity at calcitonin receptor family complexes: potential mediator implications in sepsis. Crit Care Med. 2008;36:1637–40.

    CAS  Article  Google Scholar 

  19. 19.

    Muddhrry PK, Ghatki MA, Spokks RA, Jonhs PM, Pierson AM, Hamid Q, et al. Differential expression of α-CGRP and β-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience. 1988;25:195–205.

    Article  Google Scholar 

  20. 20.

    Poyner D, Sexton P, Marshall I, Smith D, Quirion R, Born W, et al. International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharm Rev. 2002;54:233–46.

    CAS  Article  Google Scholar 

  21. 21.

    Zhang Z, Winborn C, Marquez de Prado B, Russo A. Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J Neurosci. 2007;27:2693–703.

    CAS  Article  Google Scholar 

  22. 22.

    Archbold J, Flanagan J, Watkins H, Gingell J, Hay D. Structural insights into RAMP modification of secretin family G protein-coupled receptors: implications for drug development. Trends Pharmacol Sci. 2011;32:591–600.

    CAS  Article  Google Scholar 

  23. 23.

    Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache. 2017;57:47–55.

    Article  Google Scholar 

  24. 24.

    Walker CS, Conner AC, Poyner DR, Hay DL. Regulation of signal transduction by calcitonin gene-related peptide receptors. Trends Pharmacol Sci. 2010;31:476–83.

    CAS  Article  Google Scholar 

  25. 25.

    Walker C, Sajedeh E, Bower RL, Wilderman A, Insel PA, Edvinsson L, et al. A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. Ann Clin Transl Neurol. 2015;2:595–608.

    CAS  Article  Google Scholar 

  26. 26.

    Walker C, Hay D. CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin andamylin receptors? Br J Pharmocol. 2013;170:1293–307.

    CAS  Article  Google Scholar 

  27. 27.

    McCulloch J, Uddman R, Kingman T, Edvinsson L. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci U S A. 1986;83:5731–5.

    CAS  Article  Google Scholar 

  28. 28.

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

    CAS  Article  Google Scholar 

  29. 29.

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

    CAS  Article  Google Scholar 

  30. 30.

    Lassen L, Haderslev P, Jacobsen V, Iversen H, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalagia. 2002;22:54–61.

    CAS  Article  Google Scholar 

  31. 31.

    Lennerz J, Rühle V, Ceppa E, Neuhuber W, Bunnett N, Grady E, 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;507:1277–99.

    CAS  Article  Google Scholar 

  32. 32.

    Russo A, Kuburas A, Kaiser E, Raddant A, Recober A. A potential preclinical migraine model: CGRP-sensitized mice. Mol Cell Pharmocol. 2009;1:264–70.

    CAS  Google Scholar 

  33. 33.

    Coull J, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005;438:1017–21.

    CAS  Article  Google Scholar 

  34. 34.

    Souslova V, Cesare P, Ding Y, Akopian A, Stanfa L, Suzuki R, et al. Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature. 2000;407:1015–7.

    CAS  Article  Google Scholar 

  35. 35.

    MacKenzie ET, Edvinsson LSB. Functional bases for a central serotonergic involvement in classic migraine: a speculative view. Cephalalgia. 1985;5:69–781.

    CAS  Article  Google Scholar 

  36. 36.

    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;49:1258–66.

    Article  Google Scholar 

  37. 37.

    •• Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123–32 Important STRIVE phase 3 trial demonstrating efficacy of erenumab for the prevention of episodic migraines.

    CAS  Article  Google Scholar 

  38. 38.

    Edvinsson L. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br J Clin Pharmacol. 2015;80:193–9.

    CAS  Article  Google Scholar 

  39. 39.

    Hostetler ED, Joshi AD, Sanabria-Bohorquez S, Fan H, Zeng Z, Purcell M, 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;347:478–86.

    CAS  Article  Google Scholar 

  40. 40.

    Pellesi L, Guerzoni S, Pini LA. Spotlight on anti-CGRP monoclonal antibodies in migraine: the clinical evidence to date. Clin Pharmacol Drug Dev. 2017;6:534–47.

    CAS  Article  Google Scholar 

  41. 41.

    Lipton RB, Brennan A, Palmer S, Hatswell AJ, Porter JK, Sapra S, et al. Estimating the clinical effectiveness and value-based price range of erenumab for the prevention of migraine in patients with prior treatment failures: a US societal perspective. J Med Econ. Informa UK Ltd. 2018;21:666–75.

    Article  Google Scholar 

  42. 42.

    Vu T, Ma P, Chen JS, de Hoon J, Van Hecken A, Yan L, et al. Pharmacokinetic-pharmacodynamic relationship of erenumab (AMG 334) and capsaicin-induced dermal blood flow in healthy and migraine subjects. Pharm Res Pharm Res. 2017;34:1784–95.

    CAS  PubMed  Google Scholar 

  43. 43.

    de Hoon J, Van Hecken A, Vandermeulen C, Yan L, Smith B, Chen JS, et al. Phase I, randomized, double-blind, placebo-controlled, single-dose, and multiple-dose studies of erenumab in healthy subjects and patients with migraine. Clin Pharmacol Ther. 2018;103:815–25.

    Article  Google Scholar 

  44. 44.

    Giamberardino MA, Affaitati G, Costantini R, Cipollone F, Martelletti P. Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: current evidence and safety profile of erenumab. J Pain Res. 2017;10:2751–60.

    CAS  Article  Google Scholar 

  45. 45.

    •• Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, et al. ARISE: the phase 2 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018;38:1026–37 The ARISE Phase 3 trial of erenumab for the prevention of episodic migraines.

    Article  Google Scholar 

  46. 46.

    Depre C, Antalik L, Starling A, Koren M, Eisele O, Lenz RA, et al. A randomized, double-blind, placebo-controlled study to evaluate the effect of erenumab on exercise time during a treadmill test in patients with stable angina. Headache. 2018;58:715–23.

    Article  Google Scholar 

  47. 47.

    de Hoon J, Van Hecken A, Vandermeulen C, Herbots M, Kubo Y, Lee E, et al. Phase I, randomized, parallel-group, double-blind, placebo-controlled trial to evaluate the effects of erenumab (AMG 334) and concomitant sumatriptan on blood pressure in healthy volunteers. Cephalalgia. 2018;0:1–11.

    Google Scholar 

  48. 48.

    Markham A. Pegvaliase: first global approval. Drugs. 2018;78:1157–61.

    CAS  Article  Google Scholar 

  49. 49.

    Reinke T. Aimovig for migraine prevention: the new kid may have trouble fitting in. Manag Care. 2018;27:10–1.

    PubMed  Google Scholar 

  50. 50.

    Traynor K. FDA approves licensing of erenumab-aooe to prevent migraine. Am J Heal Pharm. 2018;75:929–30.

    Google Scholar 

  51. 51.

    Choy M. Pharmaceutical approval update. Pharm Ther. 2018;43:461–2.

    Google Scholar 

  52. 52.

    •• Tepper S, Ashina M, Reuter U, Brandes JL, Doležil D, Silberstein S, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16:425–34 Excellent phase 2 randomized controlled trial demonstrating the safety and efficacy of erenumab for the treatment of chronic migraines.

    CAS  Article  Google Scholar 

  53. 53.

    Traynor J. μ-Opioid receptors and regulators of G protein signaling (RGS) proteins: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend. 2011;121:173–80.

    Article  Google Scholar 

  54. 54.

    • Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, 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. Elsevier Ltd; 2014;13:1100–1107. Excellent phase 2 trial of Eptinezumab for the prevention of frequent episodic migraine.

    CAS  Article  Google Scholar 

  55. 55.

    • Halker Singh RB, Aycardi E, Bigal ME, Loupe PS, McDonald M, Dodick DW. Sustained reductions in migraine days, moderate-to-severe headache days and days with acute medication use for HFEM and CM patients taking fremanezumab: post-hoc analyses from phase 2 trials. Cephalalgia. 2018;0:1–9 A phase 2 trial of Fremanezumab for the treatment of episodic and chronic migraines.

    Google Scholar 

  56. 56.

    • Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine. JAMA Neurol. 2018;85054. Excellent review of Galcanezumab for the treatment of episodic migraines.

  57. 57.

    Raffaelli B, Reuter U. The biology of monoclonal antibodies: focus on calcitonin gene-related peptide for prophylactic migraine therapy. Neurotherapeutics. 2018;15:324–35.

    CAS  Article  Google Scholar 

  58. 58.

    Kaplon H, Reichert JM. Antibodies to watch in 2018. MAbs. 2018;10:183–203.

    CAS  Article  Google Scholar 

  59. 59.

    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;6:871–8.

    Article  Google Scholar 

  60. 60.

    Bigal ME, Walter S, Bronson M, Alibhoy A, Escandon R. Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP. Cephalalgia. 2014;34:968–76.

    Article  Google Scholar 

  61. 61.

    Bigal ME, Escandon R, Bronson M, Walter S, Sudworth M, Huggins JP, 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. 2014;34:483–92.

    Article  Google Scholar 

  62. 62.

    Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377:2113–22.

    CAS  Article  Google Scholar 

  63. 63.

    Monteith D, Collins EC, Vandermeulen C, Van Hecken A, Raddad E, Scherer JC, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the CGRP binding monoclonal antibody LY2951742 (galcanezumab) in healthy volunteers. Front Pharmacol. 2017;8:1–11.

    Article  Google Scholar 

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Correspondence to Ivan Urits.

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Ivan Urits, Mark R. Jones, Kyle Gress, Karina Charipova, Jacob Fiocchi, and Omar Viswanath declare no conflict of interest. Dr. Kaye is a speaker for Depomed, Inc. and Merck, Inc.

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Urits, I., Jones, M.R., Gress, K. et al. CGRP Antagonists for the Treatment of Chronic Migraines: a Comprehensive Review. Curr Pain Headache Rep 23, 29 (2019). https://doi.org/10.1007/s11916-019-0768-y

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Keywords

  • Chronic migraines
  • Episodic migraines
  • Calcitonin gene receptor peptide (CGRP) antagonist
  • Erenumab