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Internal and Emergency Medicine

, Volume 11, Issue 8, pp 1045–1057 | Cite as

Anti-CGRP monoclonal antibodies in migraine: current perspectives

  • Maria Adele Giamberardino
  • Giannapia Affaitati
  • Martina Curto
  • Andrea Negro
  • Raffaele Costantini
  • Paolo MartellettiEmail author
IM - REVIEW

Abstract

Migraine is a highly disabling neurological pain disorder in which management is frequently problematic. Most abortive and preventative treatments employed are classically non-specific, and their efficacy and safety and tolerability are often unsatisfactory. Mechanism-based therapies are, therefore, needed. Calcitonin gene-related peptide (CGRP) is recognized as crucial in the pathophysiology of migraine, and new compounds that target the peptide have been increasingly explored in recent years. First tested were CGRP receptor antagonists; they proved effective in acute migraine treatment in several trials, but were discontinued due to liver toxicity in long-term administration. Monoclonal antibodies against CGRP (LY2951742, ALD-403, and LBR-101/TEV-48125) or its receptor (AMG334) were subsequently developed. As reviewed in this study, numerous phase 1 and 2 trials and preliminary results of phase 3 trials have shown a good safety/tolerability profile and efficacy in migraine prevention, especially in high frequent episodic and chronic forms. Being macromolecules, these mAbs are not suitable for oral administration; however, their intravenous or subcutaneous delivery can be performed at relatively low frequency—every month or even quarterly—which enhances patients’ compliance. Although not all migraineurs respond to this treatment, and longer administration periods will be needed to assess long-term effects, the results so far obtained are extraordinarily promising. The future introduction of mAbs on the market will probably represent a turning point for prevention similar to that represented by triptans for abortive treatment in migraine.

Keywords

Migraine CGRP Monoclonal antibodies against CGRP Migraine prophylaxis 

Notes

Compliance with ethical standards

Conflict of interest

In the past 3 years: Maria Adele Giamberardino received research funding from Epitech Group, honoraria for participation in Advisory Board Meeting from Bayer, and participation in conferences from IBSA Institute Biochimique and Helsinn Healthcare, and Royalties from IASP Press. Giannapia Affaitati received honoraria for participation in conferences from Helsinn Healthcare and IBSA Institute Biochimique. Raffaele Costantini declares no conflict of interest. Martina Curto declares no conflict of interest. Andrea Negro received travel grants and participated to the Advisory Boards of Allergan, Electrocore and Medtronic. Paolo Martelletti received travel grants, honoraria consultancy and participated to in the Advisory Boards of Allergan, Bayer, Medtronic, Mylan and Teva.

Statement of human and animal rights

There is no need to cite/report any Ethical Statement.

Informed consent

This is an Invited review and no patients have been involved in this research study.

References

  1. 1.
    Global Burden of Disease Study 2013 Collaborators (2015) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet (published online June 8, 2015 at http://dx.doi.org/10.1016/S0140-6736(15)60692-4)
  2. 2.
    Pieroni A, Caso V, Cittadini E, Hamam M, Paciaroni M (2012) A case of typical headache with an atypical diagnosis. Intern Emerg Med 7(Suppl 2):S121–S123CrossRefPubMedGoogle Scholar
  3. 3.
    Steiner TJ, Birbeck GL, Jensen RH, Katsarava Z, Stovner LJ, Martelletti P (2015) Headache disorders are third cause of disability worldwide. J Headache Pain 16:58CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Giamberardino MA, Martelletti P (2015) Emerging drugs for migraine treatment. Expert Opin Emerg Drugs 20:137–147CrossRefPubMedGoogle Scholar
  5. 5.
    Martelletti P (2015) The therapeutic armamentarium in migraine is quite elderly. Expert Opin Drug Metab Toxicol 11:175–177CrossRefPubMedGoogle Scholar
  6. 6.
    Curto M, Lionetto L, Fazio F, Mitsikostas DD, Martelletti P (2015) Fathoming the kynurenine pathway in migraine: why understanding the enzymatic cascades is still critically important. Intern Emerg Med 10(4):413–421CrossRefPubMedGoogle Scholar
  7. 7.
    Bigal ME, Walter S, Rapoport AM (2013) Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development. Headache 53(8):1230–1244CrossRefPubMedGoogle Scholar
  8. 8.
    Diener HC, Charles A, Goadsby PJ, Holle D (2015) New therapeutic approaches for the prevention and treatment of migraine. Lancet Neurol 14:1010–1022CrossRefPubMedGoogle Scholar
  9. 9.
    Edvinsson L (2015) The journey to establish CGRP as a migraine Target: A Retrospective View. Headache 55:1249–1255CrossRefPubMedGoogle Scholar
  10. 10.
    Edvinsson L (2015) CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br J Clin Pharmacol 80:193–199CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Karsan N, Goadsby PJ (2015) Calcitonin gene-related peptide and migraine. Curr Opin Neurol 28:250–254CrossRefPubMedGoogle Scholar
  12. 12.
    Mitsikostas DD, Rapoport AM (2015) New players in the preventive treatment of migraine. MC Med 13:279Google Scholar
  13. 13.
    Russo AF (2015) Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol 55:533–552CrossRefPubMedGoogle Scholar
  14. 14.
    Sabato D, Lionetto L, Martelletti P (2015) The therapeutic potential of novel anti-migraine acute therapies. Expert Opin Investig Drugs 24:141–144CrossRefPubMedGoogle Scholar
  15. 15.
    Schuster NM, Vollbracht S, Rapoport AM (2015) Emerging treatments for the primary headache disorders. Neurol Sci 36:109–113CrossRefPubMedGoogle Scholar
  16. 16.
    Wrobel Goldberg S, Silberstein SD (2015) Targeting CGRP: a new era for migraine treatment. CNS Drugs 29:443–452CrossRefPubMedGoogle Scholar
  17. 17.
    Bigal ME, Walter S, Rapoport AM (2015) Therapeutic antibodies against CGRP or its receptor. Br J Clin Pharmacol 79:886–895CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Bigal ME, Walter S (2014) Monoclonal antibodies for migraine: preventing calcitonin gene-related peptide activity. CNS Drugs 28:389–399CrossRefPubMedGoogle Scholar
  19. 19.
    Edvinsson L, Warfvinge K (2013) CGRP receptor antagonism and migraine therapy. Curr Protein Pept Sci 14(5):386–392CrossRefPubMedGoogle Scholar
  20. 20.
    Negro A, Lionetto L, Simmaco M, Martelletti P (2012) CGRP receptor antagonists: an expanding drug class for acute migraine? Expert Opin Investig Drugs 21:807–818CrossRefPubMedGoogle Scholar
  21. 21.
    Silberstein SD (2013) Emerging target-based paradigms to prevent and treat migraine. Clin Pharmacol Ther 93:78–85CrossRefPubMedGoogle Scholar
  22. 22.
    Silberstein SD (2015) Therapeutic monoclonal antibodies for migraine. US Neurol US Neurology 11(1):64–65CrossRefGoogle Scholar
  23. 23.
    Silberstein S, Lenz R, Xu C (2015) Therapeutic monoclonal antibodies: what headache specialists need to know. Headache 55:1171–1182CrossRefPubMedGoogle Scholar
  24. 24.
    Headache Classification of the International Headache Society (2013) The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 33:627–808CrossRefGoogle Scholar
  25. 25.
    Manzoni GC, Torelli P (2010) Epidemiological classification and social impact of chronic headache. Intern Emerg Med 5(Suppl 1):S1–S5CrossRefPubMedGoogle Scholar
  26. 26.
    Negro A, D’Alonzo L, Martelletti P (2010) Chronic migraine: comorbidities, risk factors, and rehabilitation. Intern Emerg Med 5(Suppl 1):S13–S19CrossRefPubMedGoogle Scholar
  27. 27.
    Farinelli I, Dionisi I, Martelletti P (2011) Rehabilitating chronic migraine complicated by medication overuse headaches: how can we prevent migraine relapse? Intern Emerg Med 6(1):23–28CrossRefPubMedGoogle Scholar
  28. 28.
    Geppetti P, De Cesaris F, Nicoletti P, Benemei S (2010) Chronic headaches and medication overuse. Intern Emerg Med 5(Suppl 1):S7–S11CrossRefPubMedGoogle Scholar
  29. 29.
    Giamberardino MA, Mitsikostas DD, Martelletti P (2015) Update on medication-overuse headache and its treatment. Curr Treat Options Neurol 17:368CrossRefPubMedGoogle Scholar
  30. 30.
    Bartolini M, Giamberardino MA, Lisotto C, Martelletti P, Moscato D, Panascia B, Savi L, Pini LA, Sances G, Santoro P, Zanchin G, Omboni S, Ferrari MD, Brighina F, Fierro B (2011) A double-blind, randomized, multicenter, Italian study of frovatriptan versus almotriptan for the acute treatment of migraine. J Headache Pain 12:361–368CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Loder E (2010) Triptan therapy in migraine. N Engl J Med 363:63–70CrossRefPubMedGoogle Scholar
  32. 32.
    Ungprasert P (2016) NSAIDs and cardiovascular disease: time to say no to diclofenac. Intern Emerg Med 11(1):1–2CrossRefPubMedGoogle Scholar
  33. 33.
    Affaitati G, Costantini R, Fabrizio A, Lapenna D, Tafuri E, Giamberardino MA (2011) Effects of treatment of peripheral pain generators in fibromyalgia patients. Eur J Pain 15(1):61–69CrossRefPubMedGoogle Scholar
  34. 34.
    Affaitati G, Fabrizio A, Savini A, Lerza R, Tafuri E, Costantini R, Lapenna D, Giamberardino MA (2009) A randomized, controlled study comparing a lidocaine patch, a placebo patch, and anesthetic injection for treatment of trigger points in patients with myofascial pain syndrome: evaluation of pain and somatic pain thresholds. Clin Ther 31(4):705–720CrossRefPubMedGoogle Scholar
  35. 35.
    Giamberardino MA, Affaitati G, Costantini R (2006) Chapter 24 referred pain from internal organs. Handb Clin Neurol 81:343–361Google Scholar
  36. 36.
    Giamberardino MA, Affaitati G, Costantini R (2010) Visceral referred pain. J Musculoskelet Pain 18:403–410CrossRefGoogle Scholar
  37. 37.
    Giamberardino MA, Affaitati G, Fabrizio A, Costantini R (2011) Myofascial pain syndromes and their evaluation. Best Pract Res Clin Rheumatol 25:185–198CrossRefPubMedGoogle Scholar
  38. 38.
    Giamberardino MA, Affaitati G, Fabrizio A, Costantini R (2011) Effects of treatment of myofascial trigger points on the pain of fibromyalgia. Curr Pain Headache Rep 15:393–399CrossRefPubMedGoogle Scholar
  39. 39.
    Giamberardino MA, Affaitati G, Martelletti P, Tana C, Negro A, Lapenna D, Curto M, Schiavone C, Stellin L, Cipollone F, Costantini R (2016) Impact of migraine on fibromyalgia symptoms. J Headache Pain. doi: 10.1186/s10194-016-0619-8 (Epub 2016 Mar 22)
  40. 40.
    Giamberardino MA, Costantini R, Affaitati G, Fabrizio A, Lapenna D, Tafuri E, Mezzetti A (2010) Viscero-visceral hyperalgesia: characterization in different clinical models. Pain 151(2):307–322CrossRefPubMedGoogle Scholar
  41. 41.
    Giamberardino MA, Tafuri E, Savini A, Fabrizio A, Affaitati G, Lerza R, Di Ianni L, Lapenna D, Mezzetti A (2007) Contribution of myofascial trigger points to migraine symptoms. J Pain 8:869–878CrossRefPubMedGoogle Scholar
  42. 42.
    Giamberardino MA, Tana C, Costantini R (2014) Pain thresholds in women with chronic pelvic pain. Curr Opin Obstet Gynecol 26:253–259CrossRefPubMedGoogle Scholar
  43. 43.
    Tana C, Santilli F, Martelletti P, di Vincenzo A, Cipollone F, Davì G, Giamberardino MA (2015) Correlation between Migraine severity and cholesterol levels. Pain Pract 15:662–670CrossRefPubMedGoogle Scholar
  44. 44.
    Tana C, Tafuri E, Tana M, Martelletti P, Negro A, Affaitati G, Fabrizio A, Costantini R, Mezzetti A, Giamberardino MA (2013) New insights into the cardiovascular risk of migraine and the role of white matter hyperintensities: is gold all that glitters? J Headache Pain 1(14):9CrossRefGoogle Scholar
  45. 45.
    Bagnato F, Good J (2016) The use of antiepileptics in migraine prophylaxis. Headache 56(3):603–615CrossRefPubMedGoogle Scholar
  46. 46.
    Goadsby PJ (2009) The vascular theory of migraine—a great story wrecked by the facts. Brain 132:6–7CrossRefPubMedGoogle Scholar
  47. 47.
    Silberstein SD (2004) Migraine pathophysiology and its clinical implications. Cephalalgia 24(Suppl 2):2–7CrossRefPubMedGoogle Scholar
  48. 48.
    Durham PL (2006) Calcitonin gene-related peptide (CGRP) and migraine. Headache 46(Suppl 1):S3–S8Google Scholar
  49. 49.
    Messlinger K (2009) Migraine: where and how does the pain originate? Exp Brain Res 196:179–193CrossRefPubMedGoogle Scholar
  50. 50.
    Goadsby PJ (2007) Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med 13:39–44CrossRefPubMedGoogle Scholar
  51. 51.
    Cao T, Pinter E, Al Rashed S, Gerard N, Hoult JR, Brain SD (2000) Neurokinin-1 receptor agonists are involved in mediating neutrophil accumulation in the inflamed, but not normal, cutaneous microvasculature: an in vivo study using neurokinin-1 receptor knockout mice. J Immunol 164:5424–5429CrossRefPubMedGoogle Scholar
  52. 52.
    Markowitz S, Saito K, Moskowitz MA (1987) Neurogenically mediated leakage of plasma protein occurs from blood vessels in dura mater but not brain. J Neurosci 7:4129–4136PubMedGoogle Scholar
  53. 53.
    Raddant AC, Russo AF (2011) Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation. Expert Rev Mol Med 13:e36CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Akerman S, Holland PR, Goadsby PJ (2011) Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 12:570–584CrossRefPubMedGoogle Scholar
  55. 55.
    Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, Vale WW, Evans RM (1983) Production of a novel neuropeptide encoded by the calcitonin gene via tissue specific RNA processing. Nature 304:129–135CrossRefPubMedGoogle Scholar
  56. 56.
    Eftekhari S, Salvatore CA, Johansson S, Chen TB, Zeng Z, Edvinsson L (2015) Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the bloodbrain barrier. Brain Res 1600:93–109CrossRefPubMedGoogle Scholar
  57. 57.
    Eftekhari S, Warfvinge K, Blixt FW, Edvinsson L (2013) Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain 14:1289–1303CrossRefPubMedGoogle Scholar
  58. 58.
    Mulderry PK, Ghatei MA, Bishop AE, Allen YS, Polak JM, Bloom SR (1985) Distribution and chromatographic characterisation of CGRP-like immunoreactivity in the brain and gut of the rat. Regul Pept 12:133–143CrossRefPubMedGoogle Scholar
  59. 59.
    Wimalawansa SJ, Morris HR, Etienne A, Blench I, Panico M, MacIntyre I (1990) Isolation, purification and characterization of beta-hCGRP from human spinal cord. Biochem Biophys Res Commun 167:993–1000CrossRefPubMedGoogle Scholar
  60. 60.
    Russell FA, King R, Smillie S-J, Kodji X (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Brain Physiol Rev 94:1099–1142CrossRefPubMedGoogle Scholar
  61. 61.
    Barwell J, Wootten D, Simms J, Hay DL, Poyner DR (2012) RAMPs and CGRP receptors. Adv Exp Med Biol 744:13–24CrossRefPubMedGoogle Scholar
  62. 62.
    Marvizón JC, Pérez OA, Song B, Chen W, Bunnett NW, Grady EF, Todd AJ (2007) Calcitonin receptor-like receptor and receptor activity modifying protein 1 in the rat dorsal horn: localization in glutamatergic presynaptic terminals containing opioids and adrenergic alpha2C receptors. Neuroscience 148:250–265CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Oku R, Satoh M, Fujii N, Otaka A, Yajima H, Takagi H (1987) Calcitonin gene-related peptide promotes mechanical nociception by potentiating release of substance P from the spinal dorsal horn in rats. Brain Res 403:350–354CrossRefPubMedGoogle Scholar
  64. 64.
    Seybold VS (2009) The role of peptides in central sensitization. Handb Exp Pharmacol 194:451–491CrossRefGoogle Scholar
  65. 65.
    Walker CS, Hay DL (2013) CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors? Br J Pharmacol 170(7):1293–1307CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Gallai V, Sarchielli P, Floridi A, Franceschini M, Codini M, Glioti G, Trequattrini A, Palumbo R (1995) Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 15:384–390CrossRefPubMedGoogle Scholar
  67. 67.
    Goadsby PJ, Edvinsson L (1993) The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 33:48–56CrossRefPubMedGoogle Scholar
  68. 68.
    Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28:183–187CrossRefPubMedGoogle Scholar
  69. 69.
    Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G (2005) Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia 25:179–183CrossRefPubMedGoogle Scholar
  70. 70.
    Sarchielli P, Alberti A, Codini M, Floridi A, Gallai V (2000) Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia 20:907–918CrossRefPubMedGoogle Scholar
  71. 71.
    Asghar MS, Hansen AE, Amin FM, van der Geest RJ, Koning P, Larsson HB, Olesen J, Ashina M (2011) Evidence for a vascular factor in migraine. Ann Neurol 4:635–645CrossRefGoogle Scholar
  72. 72.
    Hansen JM, Hauge AW, Olesen J, Ashina M (2010) Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30:1179–1186CrossRefPubMedGoogle Scholar
  73. 73.
    Lassen L, Haderslev P, Jacobsen V, Iversen H, Sperling B, Olesen J (2002) CGRP may play a causative role in migraine. Cephalalgia 2:54–61CrossRefGoogle Scholar
  74. 74.
    Lassen LH, Jacobsen VB, Haderslev PA, Sperling B, Iversen HK, Olesen J, Tfelt-Hansen P (2008) Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients. J Headache Pain 9:151–157CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Petersen KA, Lassen LH, Birk S, Lesko L, Olesen J (2005) BIBN4096BS antagonizes human alpha-calcitonin gene related peptide-induced headache and extracerebral artery dilatation. Clin Pharmacol Ther 3:202–213CrossRefGoogle Scholar
  76. 76.
    Cernuda-Morollón E, Larrosa D, Ramón C, Vega J, Martínez-Camblor P, Pascual J (2013) Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 81:1191–1196CrossRefPubMedGoogle Scholar
  77. 77.
    Strassman AM, Raymond SA, Burstein R (1996) Sensitization of meningeal sensory neurons and the origin of headaches. Nature 384:560–564CrossRefPubMedGoogle Scholar
  78. 78.
    Recober A, Kuburas A, Zhang Z, Wemmie JA, Anderson MG, Russo AF (2009) Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine. J Neurosci 29:8798–8804CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Hougaard A, Tfelt-Hansen P (2015) Review of dose-response curves for acute antimigraine drugs: triptans, 5-HT1F agonists and CGRP antagonists. Expert Opin Drug Metab Toxicol 11:1409–1418CrossRefPubMedGoogle Scholar
  80. 80.
    Neal F, Arnold J, Rossant CJ, Podichetty S, Lowne D, Dobson C, Wilkinson T, Colley C, Howes R, Vaughan TJ (2016) Isolation of potent CGRP neutralizing antibodies using four simple assays. J Biomol Screen 21(1):24–34Google Scholar
  81. 81.
    Vermeersch S, Benschop RJ, Van Hecken A, Monteith D, Wroblewski VJ, Grayzel D, de Hoon J, Collins EC (2015) translational pharmacodynamics of calcitonin gene-related peptide monoclonal antibody LY2951742 in a capsaicin-induced dermal blood flow model. J Pharmacol Exp Ther 354:350–357CrossRefPubMedGoogle Scholar
  82. 82.
    Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS (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 13:885–892CrossRefPubMedGoogle Scholar
  83. 83.
    Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J (2014) ALD403 study investigators. 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 13:1100–1107CrossRefPubMedGoogle Scholar
  84. 84.
    Goadsby PJ, Dodick DW, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J (2015) Randomized, double-blind, placebo-controlled trial of ALD403, an anti-CGRP antibody in the prevention of frequent episodic migraine. In: 17th Congress of the International Headache Society, Valencia, 2015Google Scholar
  85. 85.
    Walter S, Alibhoy A, Escandon R, Bigal ME (2014) Evaluation of cardiovascular parameters in cynomolgus monkeys following IV administration of LBR-101, a monoclonal antibody against calcitonin gene-related peptide. MAbs 6:871–878CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Bigal ME, Escandon R, Bronson M, Walter S, Sudworth M, Huggins JP, Garzone P (2013) 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 34:483–492CrossRefPubMedGoogle Scholar
  87. 87.
    Bigal ME, Walter S, Bronson M, Alibhoy A, Escandon R (2014) Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP. Cephalalgia 34:968–976CrossRefPubMedGoogle Scholar
  88. 88.
    Walter S, Bigal ME (2015) TEV-48125: a review of a monoclonal CGRP antibody in development for the preventive treatment of migraine. Curr Pain Headache Rep 19:6CrossRefPubMedGoogle Scholar
  89. 89.
    Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, Loupe PS, Burstein R, Newman LC, Lipton RB (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 14:1081–1090CrossRefPubMedGoogle Scholar
  90. 90.
    Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings EL, Diener HC, Burstein R, Loupe PS, Ma Y, Yang R, Silberstein SD (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 14:1091–1100CrossRefPubMedGoogle Scholar
  91. 91.
    Lenz R, Silberstein S, Dodick D, Reuter U, Ashina M, Saper J, Cady R, Chon Y, Dietrich J, Sun H (2015) Results of a randomized, double-blind, placebo-controlled, phase 2 study to evaluate the efficacy and safety of AMG 334 for the prevention of episodic migraine. In: 17th Congress of the International Headache Society, Valencia, 2015Google Scholar
  92. 92.
    Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, Saper J, Cady R, Chon Y, Dietrich J, Lenz R (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
  93. 93.
    Zeller J, Poulsen KT, Sutton JE, Abdiche YN, Collier S, Chopra R, Garcia CA, Pons J, Rosenthal A, Shelton DL (2008) CGRP function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure in the rat. Br J Pharmacol 155:1093–1103CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Pascual J (2015) CGRP antibodies: the Holy Grail for migraine prevention? Lancet Neurol 14:1066–1067CrossRefPubMedGoogle Scholar
  95. 95.
    Gazerani P, Cairns BE (2013) New insight in migraine pathogenesis: Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the circulation after sumatriptan. Scand J Pain 4:208–210CrossRefGoogle Scholar
  96. 96.
    Tfelt-Hansen P (2015) Site of effect of LY2951742 for migraine prophylaxis. Lancet Neurol 14:31–32CrossRefPubMedGoogle Scholar
  97. 97.
    Edvinsson L, Ekman R, Uddman R, Kingman TA, McCulloch J (1984) Calcitonin gene related peptide (CGRP)-containing perivascular fibres in brain vessels: Localization and its effects in vitro and in situ. In: Presented at INSERM Symposium no. 25: Regulatory Peptides in Digestive, Nervous and Endocrine Systems. CNRS, ParisGoogle Scholar

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© SIMI 2016

Authors and Affiliations

  1. 1.Department of Medicine and Science of Aging, Headache Center and Geriatrics ClinicGabriele D’Annunzio UniversityChietiItaly
  2. 2.Department of Clinical and Molecular Medicine, Regional Referral Headache CenterSapienza UniversityRomeItaly
  3. 3.Regional Referral Headache CenterSant’Andrea HospitalRomeItaly
  4. 4.Department of PsychiatryHarvard Medical SchoolBostonUSA
  5. 5.Bipolar and Psychotic Disorders ProgramMcLean HospitalBelmontUSA
  6. 6.Institute of Surgical PathologyGabriele D’Annunzio UniversityChietiItaly

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