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pp 1-24 | Cite as

Calcitonin Gene-Related Peptide Antagonists and Therapeutic Antibodies

  • Roxana-Maria Rujan
  • Christopher A. ReynoldsEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series

Abstract

The calcitonin gene-related peptide (CGRP) receptor is composed of the calcitonin receptor-like receptor (CLR, a class B GPCR) and a single-pass membrane protein known as receptor activity modifying protein type 1 (RAMP1). The levels of the CGRP peptide increase during a migraine attack and infusion of CGRP can provoke a migraine attack. Consequently, there is much interest in inhibiting the actions of CGRP as a way to control migraine. Here we describe the development of small molecule antagonists designed to bind to the CGRP receptor to block its action by preventing binding of the CGRP peptide. We also describe the development of antibody drugs, designed to bind either to the CGRP receptor to block its action, or to bind directly to the CGRP peptide. The field has been very active, with one antibody drug approved and three antibody drugs in phase III clinical trial. Initial programs on the development CGRP antagonists were frustrated by liver toxicity but the current outlook is very promising with five small molecule antagonists in various stages of clinical trial.

Keywords

Antibody drugs Calcitonin-receptor-like receptor CGRP antagonist CGRP peptide Migraine 

References

  1. Ashina M, Dodick D, Goadsby PJ, Reuter U, Silberstein S, Zhang F, Gage JR, Cheng S, Mikol DD et al (2017) Erenumab (AMG 334) in episodic migraine: interim analysis of an ongoing open-label study. Neurology 89(12):1237–1243Google Scholar
  2. Barwell J, Wheatley M, Conner AC, Taddese B, Vohra S, Reynolds CA, Poyner DR (2013) The activation of the CGRP receptor. Biochem Soc Trans 41:180–184Google Scholar
  3. Bell IM (2014) Calcitonin gene-related peptide receptor antagonists: new therapeutic agents for migraine. J Med Chem 57:7838–7858Google Scholar
  4. Benemei S, Cortese F, Labastida-Ramirez A, Marchese F, Pellesi L, Romoli M, Vollesen AL, Lampl C, Ashina M (2017) Triptans and CGRP blockade – impact on the cranial vasculature. J Headache Pain 18:103Google Scholar
  5. Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, Loupe PS, Burstein R, Newman LC et al (2015a) 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 14:1081–1090Google Scholar
  6. Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings ELH, Diener HC, Burstein R, Loupe PS, Ma Y et al (2015b) 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 14:1091–1100Google Scholar
  7. Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltrán E, Vigneri S, Edvinsson L, MaassenVanDenBrink A (2017) Blocking CGRP in migraine patients – a review of pros and cons. J Headache Pain 18:96Google Scholar
  8. Dickerson IM (2013) Role of CGRP-receptor component protein (RCP) in CLR/RAMP function. Curr Protein Pept Sci 14:407–415Google Scholar
  9. Diener HC, Barbanti P, Dahlof C, Reuter U, Habeck J, Podhorna J (2010) BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia 31:573–584Google Scholar
  10. Diener HC, Charles A, Goadsby PJ, Holle D (2015) New therapeutic approaches for the prevention and treatment of migraine. Lancet Neurol 14:1010–1022Google Scholar
  11. Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R et al (2014a) 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 13:1100–1107Google Scholar
  12. Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS (2014b) 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 13:885–892Google Scholar
  13. Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, Palmer K, Picard H, Mikol DD et al (2018) ARISE: a phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia 38:1026–1037.  https://doi.org/10.1177/0333102418759786CrossRefGoogle Scholar
  14. Durham PL (2004) CGRP receptor antagonists: a new choice for acute treatment of migraine? Curr Opin Investig Drugs 5:731–735Google Scholar
  15. Durham PL, Vause CV (2010) CGRP receptor antagonists in the treatment of migraine. CNS Drugs 24:539–548Google Scholar
  16. Edvinsson L, Linde M (2010) New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet 376:645–655Google Scholar
  17. Eftekhari S, Edvinsson L (2011) Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level. BMC Neurosci 12:112Google Scholar
  18. Goadsby PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD et al (2017) A controlled trial of erenumab for episodic migraine. N Engl J Med 377:2123–2132Google Scholar
  19. Hay DL, Walker CS (2017) CGRP and its receptors. Headache 57:625–636Google Scholar
  20. Hay DL, Garelja ML, Poyner DR, Walker CS (2018) Update on the pharmacology of the calcitonin/CGRP family of peptides: IUPHAR review. Br J Pharmacol 175:3–17Google Scholar
  21. Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ, Bachman R, Taraborelli D, Fan X, Assaid C et al (2011) Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia 31:712–722Google Scholar
  22. Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C et al (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 372:2115–2123Google Scholar
  23. Holland PR, Goadsby PJ (2018) Targeted CGRP small molecule antagonists for acute migraine therapy. Neurotherapeutics 15:302–312Google Scholar
  24. Kandepedu N, Abrunhosa-Thomas I, Troin Y (2015) Targeting a hotspot in calcitonin gene related peptide receptor; how to proceed. Indo Am J Pharm Res 5:205–208Google Scholar
  25. Kuzawinska O, Lis K, Cessak G, Mirowska-Guzel D, Balkowiec-Iskra E (2016) Targeting of calcitonin gene-related peptide action as a new strategy for migraine treatment. Neurol Neurochir Pol 50:463–467Google Scholar
  26. Liang YL, Khoshouei M, Deganutti G, Glukhova A, Koole C, Peat TS, Radjainia M, Plitzko JM, Baumeister W, Miller LJ, Hay DL, Christopoulos A, Reynolds CA, Wootten D, Sexton PM (2018) Cryo-EM structure of the active Gs-protein complexed human CGRP receptor. Nature 561:492–497Google Scholar
  27. Luo G, Chen L, Conway CM, Denton R, Keavy D, Signor L, Kostich W, Lentz KA, Santone KS et al (2012) Discovery of (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9- tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1Himidazo[4,5-b]pyridin-1-yl) piperidine-1-carboxylate (BMS-927711): an oral calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraine. J Med Chem 55:10644–10651Google Scholar
  28. MaassenVanDenBrink A, Meijer J, Villalón CM, Ferrari MD (2016) Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci 37:779–788Google Scholar
  29. Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ (2014) BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 34:114–125Google Scholar
  30. Miller PS, Barwell J, Poyner DR, Wigglesworth MJ, Garland SL, Donnelly D (2010) Non-peptidic antagonists of the CGRP receptor, BIBN4096BS and MK-0974, interact with the calcitonin receptor-like receptor via methionine-42 and RAMP1 via tryptophan-74. Biochem Biophys Res Commun 391:437–442Google Scholar
  31. Monteith D, Collins EC, Vandermeulen C, van Hecken A, Raddad E, Scherer JC, Grayzer D, Schuetz TJ, de Hoon J (2017) Safety, tolerability, pharmacokinetics, and pharmacodynamics of the CGRP binding monoclonal antibody LY2951742 (galcanezumab) in healthy volunteers. Front Pharmacol 8:740Google Scholar
  32. O’Connell JP, Kelly SM, Raleigh DP, Hubbard JA, Price NC, Dobson CM, Smith BJ (1993) On the role of the C-terminus of alpha-calcitonin-gene-related peptide (alpha CGRP). The structure of des-phenylalaninamide37-alpha CGRP and its interaction with the CGRP receptor. Biochem J 291:205–210Google Scholar
  33. Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350:1104–1110Google Scholar
  34. Pal K, Melcher K, Xu HE (2012) Structure and mechanism for recognition of peptide hormones by class B G-protein-coupled receptors. Acta Pharmacol Sin 33(3):300–311Google Scholar
  35. Paone DV, Nguyen DN, Shaw AW, Burgey CS, Potteiger CM, Deng JZ, Mosser SD, Salvatore CA, Yu S et al (2011) Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: discovery of MK-2918. Bioorg Med Chem Lett 21:2683–2686Google Scholar
  36. Peroutka SJ (2014) Calcitonin gene-related peptide targeted immunotherapy for migraine: progress and challenges in treating headache. BioDrugs 28:237–244Google Scholar
  37. Peroutka SJ (2015) Clinical trials update 2014: year in review. Headache 55:149–157Google Scholar
  38. Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, Foord SM (2002) International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev 54:233–246Google Scholar
  39. Recober A, Russo AF (2007) Olcegepant, a non-peptide CGRP1 antagonist for migraine treatment. IDrugs 10:566–574Google Scholar
  40. Reichert JM (2017) Antibodies to watch in 2017. MAbs 9:167–181Google Scholar
  41. Schuster NM, Rapoport AM (2016) New strategies for the treatment and prevention of primary headache disorders. Nat Rev Neurol 12:635–650Google Scholar
  42. Silberstein SD (2017) Current management: migraine headache. CNS Spectr 22:4–12Google Scholar
  43. Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y et al (2017) Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 377:2113–2122Google Scholar
  44. Skljarevski V, Oakes TM, Zhang Q, Ferguson MB, Martinez J, Camporeale A, Johnson KW, Shan Q, Carter J et al (2018) Effect of different doses of Galcanezumab vs Placebo for episodic migraine prevention: a randomized clinical trial. JAMA Neurol 75:187–193Google Scholar
  45. Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, Saper J, Cady R, Chon Y et al (2016) Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomized, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 15:382–390Google Scholar
  46. Tepper S, Ashina M, Reuter U, Brandes JL, Dolezil D, Silberstein S, Winner P, Leonardi D, Mikol D et al (2017) Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 16:425–434Google Scholar
  47. ter Haar E, Koth CM, Abdul-Manan N, Swenson L, Coll JT, Lippke JA, Lepre CA, Garcia-Guzman M, Moore JM (2010) Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism. Structure 18:1083–1093Google Scholar
  48. Tvedskov JF, Tfelt-Hansen P, Petersen KA, Jensen LT, Olesen J (2010) CGRP receptor antagonist olcegepant (BIBN4096BS) does not prevent glyceryl trinitrate-induced migraine. Cephalalgia 30:1346–1353Google Scholar
  49. Voss T, Lipton RB, Dodick DW, Dupre N, Ge JY, Bachman R, Assaid C, Aurora SK, Michelson D (2016) A phase IIb randomized double-blind placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 36:887–898Google Scholar
  50. Walker CS, Raddant AC, Woolley MJ, Russo AF, Hay DL (2017) CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured. Cephalalgia:1–15.  https://doi.org/10.1177/0333102417691762Google Scholar
  51. Yasuda N, Cleator E, Kosjek B, Yin J, Xiang B, Chen F, Kuo SC, Belyk K, Mullens PR et al (2017) Practical asymmetric synthesis of a calcitonin gene-related peptide (CGRP) receptor antagonist ubrogepant. Org Process Res Dev 21:1851–1858Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.School of Biological SciencesUniversity of EssexColchesterUK

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