DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20213373

Gepants, calcitonin gene-related peptide antagonists, for abortive treatment of migraine: current status

Soni Gaddam, Satyanarayana S. V. Padi

Abstract


Migraine is a neurovascular disorder characterized by unilateral, recurrent, pulsating, throbbing, and moderate to severe headache. Triptans use is often limited by their poor efficacy, reports of poor responders, and contraindicated in patients with cardiovascular disorders. Calcitonin gene-related peptide (CGRP), a neuropeptide, regulates vascular tonicity as well as potent pain mediator, and both the mechanisms involved in development of migraine headache. Gepants are non-peptide, small molecules, highly selective, and potent CGRP antagonists. These novel drugs have been approved for abortive treatment of acute migraine with or without aura. These are being evaluated for their effectiveness and showing promising results in the prevention of migraine. Gepants do not have vasoconstrictive properties, are safe to use in patients with cardiovascular risk, and best alternative to triptan therapy. These are available in tablet, orally disintegrating tablet, and nasal forms to improve patient compliance. Ubrogepant and rimegepant are the two oral CGRP antagonists approved whereas atogepant and zavegepant are at late stage of development for approval.


Keywords


Atogepant, Calcitonin gene-related peptide, Gepants, Migraine, Rimegepant, Ubrogepant, Zavegepant

Full Text:

PDF

References


Charles A. The pathophysiology of migraine: implications for clinical management. Lancet Neurol. 2018;17(2):174-82.

Peters GL. Migraine overview and summary of current and emerging treatment options. Am J Manag Care. 2019;25(2):23-34.

Steiner TJ, Stovner LJ, Jensen R, Uluduz D, Katsarava Z. Lifting the burden: the global campaign against headache. Migraine remains second among the world's causes of disability, and first among young women: findings from GBD2019. J Headache Pain. 2020;21(1):137.

Buse DC, Fanning KM, Reed ML, Murray S, Dumas PK, Adams AM, et al. Life with migraine: effects on relationships, career, and finances from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. Headache. 2019;59(8):1286-99.

Chen D, Parker M, Lundberg GP. Migraine headache: Is it only a neurological disorder? Links between migraine and cardiovascular disorders. Trends Cardiovasc Med. 2020;30(7):424-30.

Quintanilla V, Toriello M, Palacio E, Gay MA, Castillo J, Montes S, et al. Systemic and cerebral endothelial dysfunction in chronic migraine. A case-control study with an active comparator. Cephalalgia. 2016;36(6):552-60.

Sumelahti ML, Sumanen MS, Mattila KJ, Sillanmäki L, Sumanen M. Stroke and cardiovascular risk factors among working-aged Finnish migraineurs. BMC Public Health. 2021;21(1):1088.

Takahashi TT, Ornello R, Quatrosi G, Torrente A, Albanese M, Vigneri S, et al. European Headache Federation School of Advanced Studies (EHF-SAS). Medication overuse and drug addiction: a narrative review from addiction perspective. J Headache Pain. 2021;22(1):32.

Ong JJY, De Felice M. Migraine treatment: current acute medications and their potential mechanisms of action. Neurotherapeutics. 2018;15(2):274-90.

Mayans L, Walling A. Acute migraine headache: treatment strategies. Am Fam Physician. 2018;97(4):243-51.

Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97(2):553-622.

Negro A, Martelletti P. Gepants for the treatment of migraine. Expert Opin Investig Drugs. 2019;28(6):555-67.

Macone AE, Perloff MD. Triptans and migraine: advances in use, administration, formulation, and development. Expert Opin Pharmacother. 2017;18(4):387-97.

Roberto G, Raschi E, Piccinni C, Conti V, Vignatelli L, Alessandro R, et al. Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine: systematic review of observational studies. Cephalalgia. 2015;35(2):118-31.

Li H, Vincent M, Zhang X, Dennehy EB, Goodloe R, Aurora SK, Smith TR. Acute migraine prescription patterns vary by baseline cardiovascular risk and clinical characteristics: a real-world evidence study. Pain Ther. 2020;9(2):499-509.

Leroux E, Buchanan A, Lombard L, Loo LS, Bridge D, Rousseau B, et al. Evaluation of patients with insufficient efficacy and/or tolerability to triptans for the acute treatment of migraine: a systematic literature review. Adv Ther. 2020;37(12):4765-96.

Hirata K, Ueda K, Komori M, Ye W, Kim Y, Cotton S, et al. Unmet needs in japanese patients who report insufficient efficacy with triptans for acute treatment of migraine: retrospective analysis of real-world data. Pain Ther. 2021;10(1):415-32.

Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099-142.

Edvinsson L. The Trigeminovascular Pathway: Role of CGRP and CGRP Receptors in Migraine. Headache. 2017;57(2):47-55.

Tepper SJ. History and review of anti-calcitonin gene-related peptide (CGRP) therapies: from translational research to treatment. Headache. 2018;58(3):238-75.

Edvinsson L, Warfvinge K. Recognizing the role of CGRP and CGRP receptors in migraine and its treatment. Cephalalgia. 2019;39(3):366-73.

Lassen LH, Jacobsen VB, Haderslev PA, Sperling B, Iversen HK, Olesen J, Hansen P. Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients. J Headache Pain. 2008;9(3):151-7.

Ashina H, Schytz HW, Ashina M. CGRP in human models of migraine. Handb Exp Pharmacol. 2019;255:109-20.

Asghar MS, Hansen AE, Kapijimpanga T, Geest RJ, Koning P, Larsson HB, et al. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology. 2010;75(17):1520-6.

Christensen CE, Amin FM, Younis S, Lindberg U, Koning P, Petersen ET, et al. Sildenafil and calcitonin gene-related peptide dilate intradural arteries: A 3T MR angiography study in healthy volunteers. Cephalalgia. 2019;39(2):264-73.

Haanes KA, Edvinsson L. Pathophysiological mechanisms in migraine and the identification of new therapeutic targets. CNS Drugs. 2019;33(6):525-37.

Hong P, Tan T, Liu Y, Xiao J. Gepants for abortive treatment of migraine: A network meta-analysis. Brain Behav. 2020;10(8):1701.

Chiang CC, Schwedt TJ. Calcitonin gene-related peptide (CGRP)-targeted therapies as preventive and acute treatments for migraine-The monoclonal antibodies and gepants. Prog Brain Res. 2020;255:143-70.

Holland PR, Goadsby PJ. Targeted CGRP small molecule antagonists for acute migraine therapy. Neurotherapeutics. 2018;15(2):304-12.

Diener HC, Barbanti P, Dahlöf C, Reuter U, Habeck J, Podhorna J. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia. 2011;31(5):573-84.

Moore E, Fraley ME, Bell IM, Burgey CS, White RB, Li CC, et al. Characterization of Ubrogepant: a potent and selective antagonist of the human calcitonin gene‒related peptide receptor. J Pharmacol Exp Ther. 2020;373(1):160-66.

Scott LJ. Ubrogepant: first approval. Drugs. 2020;80(3):323-28.

Yang Y, Chen M, Sun Y, Gao B, Chen Z, Wang Z. Safety and efficacy of ubrogepant for the acute treatment of episodic migraine: a meta-analysis of randomized clinical trials. CNS Drugs. 2020;34(5):463-71.

Dodick DW, Lipton RB, Ailani J, Lu K, Finnegan M, Trugman JM, et al. Ubrogepant for the treatment of migraine. N Engl J Med. 2019;381(23):2230-41.

Edinoff AN, Casey CA, Colon MA, Zaheri AR, Gregoire CM, Bourg MM, et al. Ubrogepant to treat acute migraine in adults. Neurol Int. 2021;13(1):32-45.

Allerga. Highlights of prescribing information, 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211765s000lbl.pdf. Accessed on 01 July 2021.

Ankrom W, Bondiskey P, Li CC, Palcza J, Liu W, Dockendorf MF, et al. Ubrogepant is not associated with clinically meaningful elevations of alanine aminotransferase in healthy adult males. Clin Transl Sci. 2020;13(3):462-72.

Smith B, Rowe J, Watkins PB, Ashina M, Woodhead JL, Sistare FD, et al. Mechanistic investigations support liver safety of ubrogepant. Toxicol Sci. 2020;177(1):84-93.

Luo G, Chen L, Conway CM, Denton R, Keavy D, Signor L, et al. Discovery of (5S,6S,9R)-5-amino-6-(2,3difluorophenyl)6,7,8,9tetrahydro5Hcyclohepta[b]pyri din-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[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. 2012;55(23):10644-51.

Ajona D, Rodríguez A, Goadsby PJ. A new approach to the acute and preventive treatment of migraine. Med Drug Discov. 2020;(7):100053.

Falco AP, Lazim R, Cope NE. Rimegepant Orally Disintegrating tablet for acute migraine treatment: a review. Ann Pharmacother. 2021;55(5):650-7.

Berman G, Croop R, Kudrow D, Halverson P, Lovegren M, Thiry AC, et al. Safety of rimegepant, an oral CGRP receptor antagonist, plus CGRP monoclonal antibodies for migraine. Headache. 2020;60(8):1734-42.

Mullin K, Kudrow D, Croop R, Lovegren M, Conway CM, Coric V, et al. Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy. Neurology. 2020;94(20):2121-5.

Pan KS, Siow A, Hay DL, Walker CS. Antagonism of CGRP signaling by rimegepant at two receptors. Front Pharmacol. 2020;11:1240.

Min KC, Kraft WK, Bondiskey P, González F, Liu W, Xu J, et al. Atogepant Is not associated with clinically meaningful alanine aminotransferase elevations in healthy adults. Clin Transl Sci. 2021;14(2):599-605.

Goadsby PJ, Dodick DW, Ailani J, Trugman JM, Finnegan M, Lu K, et al. Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. Lancet Neurol. 2020;19(9):727-37.

Mercer SE, Chaturvedula PV, Conway CM, Cook DA, Davis CD, Pin SS, et al. Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists. Bioorg Med Chem Lett. 2021;31:127624.

Chaturvedula PV, Mercer SE, Pin SS, Thalody G, Xu C, Conway CM, et al. Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): a potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery. Bioorg Med Chem Lett. 2013;23(11):3157-61.