The Biology of Monoclonal Antibodies: Focus on Calcitonin Gene-Related Peptide for Prophylactic Migraine Therapy

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Abstract

Calcitonin gene-related peptide (CGRP) is 37-amino-acid neuropeptide, crucially involved in migraine pathophysiology. Four monoclonal antibodies (mAbs) targeting the CGRP pathway are currently under evaluation for the prevention of episodic and chronic migraine: eptinezumab (ALD403), fremanezumab (TEV-48125), galcanezumab (LY2951742), and erenumab (AMG334). As reviewed in this article, all 4 antibodies have been proven effective, tolerable, and safe as migraine prophylactic treatments in phase II clinical trials. The mean decrease in migraine days per month was between 3.4 and 6.3 days/month after 8 to 12 weeks of treatment, and the placebo subtracted benefit ranged from 1 to 2.18 days. Notably, up to 32% of subjects experienced total migraine freedom after drug administration. Substance class-specific adverse events and treatment-related serious adverse event did not occur. Further long-term and large-scale trials are currently under way to verify the safety and efficacy profile of mAbs. In particular, the potential risk of vascular adverse events and the role of anti-drug antibodies deserve special attention. Anti-CGRP peptide and anti-CGRP receptor antibodies are the first effective treatments, which were specifically developed for the prevention of migraine. Their site of action in migraine prevention is most likely peripheral due to large molecule size, which prevents the penetration through the blood–brain barrier and thereby shows that peripheral components play a pivotal role in the pathophysiology of a CNS disease.

Key Words

Migraine Tolerability Safety Efficacy 
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Notes

Compliance with Ethical Standards

Conflict of Interest

BR declares no conflict of interest. UR has received honoraria for several purposes (e.g. consultation, presentations and clinical trials) from Allergan, Amgen, Autonomic Technologies, CoLucid, Eli Lilly, Electrocore, Novartis, and TEVA.

Supplementary material

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References

  1. 1.
    Lipton RB, Bigal ME, Diamond M, et al., Migraine prevalence, disease burden, and the need for preventive therapy. Neurology2007;68:343–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Hepp Z, Dodick DW, Varon SF, et al., Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35:478–88.CrossRefPubMedGoogle Scholar
  3. 3.
    Giamberardino MA, Affaitati G, Curto M, et al. Anti-CGRP monoclonal antibodies in migraine: current perspectives. Intern Emerg Med. 2016;11(8):1045–1057.CrossRefPubMedGoogle Scholar
  4. 4.
    Ramadan NM, Buchanan TM. New and future migraine therapy. Pharmacol Ther. 2006;112:199–212.CrossRefPubMedGoogle Scholar
  5. 5.
    Gracia-Naya M, Santos-Lasaosa S, Rios-Gomez C, et al. Predisposing factors affecting drop-out rates in preventive treatment in a series of patients with migraine. Rev Neurol. 2011;53(4):201–8.PubMedGoogle Scholar
  6. 6.
    Goadsby PJ, Holland PR, Martins-Oliveira M, et al, Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97:553–622.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Goadbsy PJ, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N Engl J Med. 2002;346(4):257–270.CrossRefGoogle Scholar
  8. 8.
    Rosenfeld MG, Mermod JJ, Amara SG, et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature. 1983;304(5922):129–35.CrossRefPubMedGoogle Scholar
  9. 9.
    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; 23:193–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol. 2010;6:573–82.CrossRefPubMedGoogle Scholar
  11. 11.
    MaassenVanDenBrink A, Meijer J, Villalón CM, Ferrari MD. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci. 2016;37:779–788.CrossRefPubMedGoogle Scholar
  12. 12.
    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; 350:1104–10.CrossRefPubMedGoogle Scholar
  13. 13.
    Edvinsson L, Goadsby PJ. Extracerebral manifestations in migraine. A peptidergic involvement? J Intern Med. 1990;228:299–304.CrossRefPubMedGoogle Scholar
  14. 14.
    Ramos ML, Pascual J. AMG 334 CGRP antibody for migraine: time to celebrate? Lancet Neurol. 2016;15(4):347–349.CrossRefPubMedGoogle Scholar
  15. 15.
    Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28(2):183–7.CrossRefPubMedGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    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;81:1191–1196.CrossRefPubMedGoogle Scholar
  18. 18.
    Lassen LH, Haderslev PA, Jacobsen VB, et al. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54–61.CrossRefPubMedGoogle Scholar
  19. 19.
    Noseda R, Burstein R. Advances in understanding the mechanisms of migraine-type photophobia. Curr Opin Neurol. 2011;24(3):197–202.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kopruszinski CM, Xie JY, Eyde NM, et al. Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents. Cephalalgia. 2016;37(6):560–570.CrossRefPubMedGoogle Scholar
  21. 21.
    Benemei S, Nicoletti P, Capone JG, Geppetti P. CGRP receptors in the control of pain and inflammation. Curr Opin Pharmacol. 2009;9:9–14.CrossRefPubMedGoogle Scholar
  22. 22.
    Petersen KA, Lassen LH, Birk S, Lesko L, Olesen J. BIBN4096BS antagonizes human α-calcitonin gene related peptide-induced headache and extracerebral artery dilatation. Clin Pharmacol Ther. 2005;77(3):202–213.CrossRefPubMedGoogle Scholar
  23. 23.
    Ho TW, Ho AP, Ge YJ, et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology. 2014;83(11):958–66.CrossRefPubMedGoogle Scholar
  24. 24.
    Labruijere S, Ibrahimi K, Chan KY, MaassenVanDenBrink A. Discovery techniques for calcitonin gene-related peptide receptor antagonists for potential antimigraine therapies. Expert Opin Drug Discov. 2013;8:1309–23.CrossRefPubMedGoogle Scholar
  25. 25.
    Reuter U. Anti-CGRP antibodies: a new approach to migraine prevention. Lancet Neurol. 2014:13:857–859.CrossRefPubMedGoogle Scholar
  26. 26.
    Miller RA, Maloney DG, Warnke R, Levy R. Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N Engl J Med. 1982;306(9):517–22.CrossRefPubMedGoogle Scholar
  27. 27.
    Wu H, Dall’Acqua WF. Humanized antibodies and their applications. Methods. 2005;36(1):1–2.CrossRefPubMedGoogle Scholar
  28. 28.
    Bigal ME, Walter S, Rapoport AM. Therapeutic antibodies against CGRP or its receptor. Br J Clin Pharmacol. 2015;79(6):886–895.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    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. 2014:34(7):483–492.CrossRefPubMedGoogle Scholar
  30. 30.
    Pellesi L, Guerzoni S, Pini LA. Spotlight on Anti-CGRP monoclonal antibodies in migraine: the clinical evidence to date. Clin Pharmacol Drug Dev. 2017;00:1–14.Google Scholar
  31. 31.
    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):1100–1107.CrossRefPubMedGoogle Scholar
  32. 32.
    Baker B, Hodsman P, Smith J. PK & PD supporting a single dose, placebo-controlled randomized ascending dose study of ALD403, a humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody administered IV or SC. Available at: http://www.alderbio.com/wp-content/uploads/2016/08/ALD403-EHMTIC-Poster-Baker-29-August-2016-Portrait-WO-QR-Code.pdf. Accessed 29 August 2017.
  33. 33.
    Dodick DW, Goadsby PJ, Silberstein SD, et al. Randomized, double-blind, placebo-controlled trial of ALD403, an anti-CGRP antibody in the prevention of chronic migraine. Neurology 2017;88(16 Supplement):S52.003.Google Scholar
  34. 34.
    Alder Biopharmaceuticals, Inc. A multicenter assessment of ALD403 in frequent episodic migraine. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02559895. Accessed 29 August 2017.
  35. 35.
    Alder Biopharmaceuticals, Inc. Evaluation of ALD403 (eptinezumab) in the prevention of chronic migraine. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02974153. Accessed 29 August 2017.
  36. 36.
    Eli Lilly and Company. A study of LY2951742 in healthy participants. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02576951. Accessed 29 August 2017.
  37. 37.
    Eli Lilly and Company. A study of LY2951742 in healthy Japanese and Caucasian participants. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02104765. Accessed 29 August 2017.
  38. 38.
    Eli Lilly and Company. A study of LY2951742 in healthy volunteers. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT01337596. Accessed 29 August 2017.
  39. 39.
    Dodick DW, Goadsby PJ, Spierings ELH, 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):885–892.CrossRefPubMedGoogle Scholar
  40. 40.
    Skljarevski V, Oakes TM, Zhang Q, et al., Effect of different doses of galcanezumab vs placebo for episodic migraine prevention: a randomized clinical trial. JAMA Neurol. 2017. doi:  https://doi.org/10.1001/jamaneurol.2017.385
  41. 41.
    Eli Lilly and Company. Evaluation of LY2951742 in the prevention of episodic migraine—the EVOLVE-1 study. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02614183. Accessed 29 August 2017.
  42. 42.
    Eli Lilly and Company. Evaluation of LY2951742 in the prevention of episodic migraine—the EVOLVE-2 Study. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02614196. Accessed 29 August 2017.
  43. 43.
    Eli Lilly and Company. Evaluation of LY2951742 in the prevention of chronic migraine (REGAIN). 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02614261. Accessed 29 August 2017.
  44. 44.
    Eli Lilly and Company. A safety study of LY2951742 in participants with migraine, with or without aura. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02614287. Accessed 29 August 2017.
  45. 45.
    Walter S, Bigal ME. TEV-48125: a review of a monoclonal CGRP antibody in development for the preventive treatment of migraine. Curr Pain Headache Rep. 2015;19:6.CrossRefPubMedGoogle Scholar
  46. 46.
    Bigal ME, Dodick DW, Rapoport AM, et al. 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. 2015;14(11):1081–1090.CrossRefPubMedGoogle Scholar
  47. 47.
    Bigal ME, Edvinsson L, Rapoport AM, et al. 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. 2015;14(11):1091–1100.CrossRefPubMedGoogle Scholar
  48. 48.
    Bigal ME, Dodick DW, Krymchantowski AV, et al. TEV-48125 for the preventive treatment of chronic migraine: efficacy at early time points. Neurology. 2016; 87:41–48.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Teva Branded Pharmaceutical Products, R&D Inc. Efficacy and safety of 2 dose regimens of TEV-48125 versus placebo for the preventive treatment of episodic migraine. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02629861. Accessed 29 August 2017.
  50. 50.
    Silberstein SD, Dodick DW, Bigal ME, et al., Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377:2113–2122.CrossRefPubMedGoogle Scholar
  51. 51.
    Teva Branded Pharmaceutical Products, R&D Inc. Efficacy and safety of subcutaneous administration of TEV-48125 for the preventive treatment of migraine. Available at: https://clinicaltrials.gov/ct2/show/NCT02638103. Accessed 29 August 2017.
  52. 52.
    Shi L, Lehto SG, Zhu DXD, et al. Pharmacologic characterization of AMG 334, a potent and selective human monoclonal antibody against the calcitonin gene-related peptide receptor. J Pharmacol Exp Ther. 2016;356:223–231.CrossRefPubMedGoogle Scholar
  53. 53.
    De Hoon J, Van Hecken A, Vandermeulen C, Yan L, Vu T, Vargas G. Phase 1, randomized, double-blind, placebo-controlled, single-dose and multiple-dose studies of erenumab in healthy subjects and patients with migraine. Clin Pharmacol Ther. 2017Google Scholar
  54. 54.
    Amgen. Study to evaluate the effect on blood pressure of AMG 334 given concomitantly with subcutaneous sumatriptan. 2017. Available at: https://clinicaltrials.gov/ct2/show/NTC02741310. Accessed 29 August 2017.
  55. 55.
    Sun H, Dodick DW, Silberstein SD, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):382–390.CrossRefPubMedGoogle Scholar
  56. 56.
    Ashina M, Dodick D, Goadsby PJ, et al. Erenumab (AMG334) in episodic migraine. Interim analysis of an ongoing open-label study. Neurology. 2017;89:1237–43.CrossRefPubMedGoogle Scholar
  57. 57.
    Tepper S, Ashina M, Reuter U, 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.CrossRefPubMedGoogle Scholar
  58. 58.
    Dodick DW, Ashina M, Kudrow D, et al. A phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab in migraine prevention: primary results of the ARISE trial. J Neurol Neurosurg Psychiatry. 2017;88:e1.Google Scholar
  59. 59.
    Goadsby PJ, Reuter U, Hallström Y, et al., A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123–2132.CrossRefPubMedGoogle Scholar
  60. 60.
    Amgen. A study to assess the long-term safety and efficacy of AMG 334 in chronic migraine prevention. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02174861. Accessed 29 August 2017.
  61. 61.
    Mitsikostas DD, Reuter U. Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies. Curr Opin Neurol. 2017;30:272–80.CrossRefPubMedGoogle Scholar
  62. 62.
    Charles A. Migraine. N Engl J Med. 2017 ;377:553–561.CrossRefPubMedGoogle Scholar
  63. 63.
    Diener HC. CGRP as a new target in prevention and treatment of migraine. Lancet Neurol. 2014;13(11):1065–7.CrossRefPubMedGoogle Scholar
  64. 64.
    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.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2018

Authors and Affiliations

  1. 1.Department of NeurologyCharité Universitätsmedizin BerlinBerlinGermany

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