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.
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Introduction
Almost all migraine episodes require acute therapy. Patients with high-frequency episodic migraine (EM) and with chronic migraine (CM) should receive preventative treatment [1]. The indications for migraine prevention are manifold. It can be necessary to start prophylaxis in subjects with only 1 attack/month, e.g., if the pain cannot be controlled with acute medication [1]. With limited progress in the last decades, migraine frequency management remains often problematic. Approximately half of the patients with an indication for preventive treatment do not receive therapy for several reasons [2]. Moreover, all preventive therapies on the market have not been developed primarily for migraine and were originally licensed for other purposes. Their efficacy and tolerability are often unsatisfactory [3, 4]. In fact, ~50% of CM patients treated with current available preventive medications discontinue therapy because of poor tolerability or safety issues within half a year, and in a substantial percentage, treatment response is insufficient [2, 5].
Migraine’s pathophysiology is complex and multifactorial. However, migraine is a CNS disorder, in which activation and sensitization of the trigeminovascular system plays a pivotal role [6]. Stimulation of the trigeminal nerve system leads to the release of neuropeptides, notably calcitonin gene-related peptide (CGRP) [7]. CGRP binds to the CGRP receptor on vascular smooth muscle cells and thereby causes vasodilatation. Neurons also express the receptor, which mediates the neurotransmitter function of the peptide [6, 8].
CGRP and Its Role in Migraine Pathophysiology
CGRP was discovered 35 years ago in rats as a potent endogenous vasodilator [8, 9]. In the peripheral nervous system, it is located in unmyelinated C fibers and small myelinated Aδ fibers, both responsible for pain transmission [10]. Centrally, it is widely distributed throughout several structures, including the hypothalamus, thalamus, and cerebellum [10]. CGRP exists in 2 isoforms, α and β. αCGRP results from alternative splicing of mRNA and proteolytic processing of the calcitonin gene [9]. It consists of 37 amino acids and is particularly present in the trigeminal system, where half of the neurons synthesize it [9]. βCGRP is transcribed from a different gene and is expressed primarily in the enteric nervous system [9]. Based on several lines of evidence which suggest CGRP as an important molecule in the pathogenesis of migraine [10,11,12,13,14,15,16,17,18,19,11]. All studies conducted so far in vitro and in vivo did not show any harmful vasoconstriction [9, 64]. However, the effects of anti-CGRP antibodies in patients suffering ischemic events remain largely unknown [11].
One final issue to discuss relates to the site of action of anti-CGRP antibodies. Antibodies are large molecules, with a molecular weight of ~150,000 Da. Therefore, they have only a minimal possibility (0.1–0.5%) to cross the blood brain barrier under physiological condition [9]. Even if a sporadic dysfunction exists, the amount of antibodies trespassing it would be too low to block CGRP effectively [9]. Consequently, antibodies are supposed to have a primary peripheral site of action, binding to the CGRP released at trigeminal nerve endings or its receptor in ganglion or dura mater. The efficacy of anti-CGRP antibodies supports the hypothesis that a peripheral component plays a pivotal role in migraine pathophysiology and migraine can be aborted by blocking peripheral mechanisms.
Conclusion
Phases I and II trials show us that mAbs, which block the CGRP pathway, are safe, tolerable, and effective treatment options. Each phase II study has produced positive efficacy results, and no safety issues have emerged. The positive results of large phase III trials in EM and CM for erenumab and fremanezumab confirm phase II data, and further long-term studies are under way to confirm their safety and efficacy profile. However, registries for use in the real world, e.g., for pregnancy, are needed. Anti-CGRP and anti-CGRP-receptor antibodies are the first effective treatment specifically developed for the prevention of migraine based on molecular pattern involved in disease pathogenesis. The efficacy of monoclonal antibodies provides further evidence for the importance of CGRP in migraine pathophysiology and the therapeutic value to antagonize its effect within the trigeminovascular system.
References
Lipton RB, Bigal ME, Diamond M, et al., Migraine prevalence, disease burden, and the need for preventive therapy. Neurology2007;68:343–9.
Hepp Z, Dodick DW, Varon SF, et al., Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35:478–88.
Giamberardino MA, Affaitati G, Curto M, et al. Anti-CGRP monoclonal antibodies in migraine: current perspectives. Intern Emerg Med. 2016;11(8):1045–1057.
Ramadan NM, Buchanan TM. New and future migraine therapy. Pharmacol Ther. 2006;112:199–212.
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.
Goadsby PJ, Holland PR, Martins-Oliveira M, et al, Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97:553–622.
Goadbsy PJ, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N Engl J Med. 2002;346(4):257–270.
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.
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.
Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol. 2010;6:573–82.
MaassenVanDenBrink A, Meijer J, Villalón CM, Ferrari MD. Wi** out CGRP: potential cardiovascular risks. Trends Pharmacol Sci. 2016;37:779–788.
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.
Edvinsson L, Goadsby PJ. Extracerebral manifestations in migraine. A peptidergic involvement? J Intern Med. 1990;228:299–304.
Ramos ML, Pascual J. AMG 334 CGRP antibody for migraine: time to celebrate? Lancet Neurol. 2016;15(4):347–349.
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.
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.
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.
Lassen LH, Haderslev PA, Jacobsen VB, et al. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54–61.
Noseda R, Burstein R. Advances in understanding the mechanisms of migraine-type photophobia. Curr Opin Neurol. 2011;24(3):197–202.
Kopruszinski CM, **e 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.
Benemei S, Nicoletti P, Capone JG, Geppetti P. CGRP receptors in the control of pain and inflammation. Curr Opin Pharmacol. 2009;9:9–14.
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.
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.
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.
Reuter U. Anti-CGRP antibodies: a new approach to migraine prevention. Lancet Neurol. 2014:13:857–859.
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.
Wu H, Dall’Acqua WF. Humanized antibodies and their applications. Methods. 2005;36(1):1–2.
Bigal ME, Walter S, Rapoport AM. Therapeutic antibodies against CGRP or its receptor. Br J Clin Pharmacol. 2015;79(6):886–895.
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.
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.
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.
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.
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.
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.
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.
Eli Lilly and Company. A study of LY2951742 in healthy participants. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02576951. Accessed 29 August 2017.
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.
Eli Lilly and Company. A study of LY2951742 in healthy volunteers. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT01337596. Accessed 29 August 2017.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
Silberstein SD, Dodick DW, Bigal ME, et al., Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377:2113–2122.
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.
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.
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. 2017
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.
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.
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.
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.
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.
Goadsby PJ, Reuter U, Hallström Y, et al., A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123–2132.
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.
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.
Charles A. Migraine. N Engl J Med. 2017 ;377:553–561.
Diener HC. CGRP as a new target in prevention and treatment of migraine. Lancet Neurol. 2014;13(11):1065–7.
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.
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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.
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Raffaelli, B., Reuter, U. The Biology of Monoclonal Antibodies: Focus on Calcitonin Gene-Related Peptide for Prophylactic Migraine Therapy. Neurotherapeutics 15, 324–335 (2018). https://doi.org/10.1007/s13311-018-0622-7
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DOI: https://doi.org/10.1007/s13311-018-0622-7