Current status of calcitonin gene-related peptide-based therapies in migraine: a scoping review

Marya Ahsan, Ayaz Khurram Mallick


A significant proportion of patients exhibit sub-optimal response to the standard treatment of acute migraine such as triptans and NSAIDs. Even the conventional preventive therapies (e.g. beta-blockers) indicated for patients with frequent migraine attacks have varying responses. Moreover, evidence from animal studies elucidated the role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine. Currently two classes are drug, the small molecule CGRP receptor antagonist or the ‘gepants’ (Ubrogepant, Rimegepant, Atogepant, Zavegepant) and CGRP monoclonal antibodies (Erenumab, Galcanezumab, Fremanezumab, Eptinezumab) have been found efficacious and safe in various clinical trials for the treatment and prevention of migraine. While the small molecule CGRP receptor antagonists are given orally, the monoclonal antibodies are injectable drugs. Ubrogepant and Rimegepant are the second-generation gepants approved for treatment of migraine. Zavegepant is a third generation gepant which has proven efficacy for acute treatment of migraine in a phase III trial. Atogepant has been approved for prevention of migraine. Rimegepant has also proven to be efficacious for preventing migraine attacks but has not yet been approved for this indication. Erenumab is the only monoclonal antibody which neutralizes the CGRP receptor. The latter three monoclonal antibodies target the CGRP peptide. The monoclonal antibodies have been approved for the prevention of migraine as a subcutaneously or intravenous infusion (Eptinezumab) given once a month or quarterly. Both the classes of drugs were well-tolerated in the clinical trials. Nausea was the most common adverse effect with gepants while injection-site pain was commonly reported with the antibodies.


Episodic migraine, Calcitonin gene-related peptide, CGRP receptor antagonists, CGRP monoclonal antibodies

Full Text:



Burstein R, Noseda R, Borsook D. Migraine: multiple processes, complex pathophysiology. J Neurosci. 2015;35(17):6619-29.

Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders. Cephalalgia. 2018;38(1):1-211.

Goadsby PJ, Holland PR, Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017;97(2):553-622.

Harbi FG, Ateeq MA. Quality of life of migraine patients followed in neurology clinics in Riyadh, Saudi Arabia. J Family Community Med. 2020;27(1):37-45.

Steiner TJ, Stovner LJ, Jensen R, Uluduz D, Katsarava Z, et al. 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.

Hansen JM, Charles A. Differences in treatment response between migraine with aura and migraine without aura: lessons from clinical practice and RCTs. J Headache Pain. 2019;20(1):96.

Charles A. Migraine. N Engl J Med. 2017;377(6):553-61.

Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. Neurology. 2015;84(7):688-95.

Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48(8):1157-68.

Chiang CC, Schwedt TJ, Wang SJ, Dodick DW. Treatment of medication-overuse headache: A systematic review. Cephalalgia. 2016;36(4):371-86.

Bigal ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology. 2008;71(8):559-66.

Alstadhaug KB, Ofte HK, Kristoffersen ES. Preventing and treating medication overuse headache. Pain Rep. 2017;2(4):612.

American Headache Society. The American Headache Society Position Statement On Integrating New Migraine Treatments Into Clinical Practice. Headache. 2019;59(1):1-18.

Blumenfeld AM, Bloudek LM, Becker WJ, Buse DC, Varon SF, Maglinte GA, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 2013;53(4):644-55.

Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338-50.

Hargreaves R, Olesen J. Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class. Headache. 2019;59(6):951-70.

Eftekhari S, Warfvinge K, Blixt FW, Edvinsson L. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain. 2013;14(11):1289-303.

Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010;169(2):683-96.

Miller S, Liu H, Warfvinge K, Shi L, Dovlatyan M, Xu C, Edvinsson L. Immunohistochemical localization of the calcitonin gene-related peptide binding site in the primate trigeminovascular system using functional antagonist antibodies. Neuroscience. 2016;328:165-83.

Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL. Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat--intravital microscope studies. Cephalalgia. 1997;17(4):525-31.

Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(1):54-61.

Scott LJ. Ubrogepant: First Approval. Drugs. 2020;80(3):323-8.

Scott LJ. Rimegepant: First Approval. Drugs. 2020;80(7):741-6.

Deeks ED. Atogepant: First Approval. Drugs. 2021.

Markham A. Erenumab: First Global Approval. Drugs. 2018;78(11):1157-61.

Lamb YN. Galcanezumab: First Global Approval. Drugs. 2018 Nov;78(16):1769-75.

Hoy SM. Fremanezumab: First Global Approval. Drugs. 2018;78(17):1829-34.

Dhillon S. Eptinezumab: First Approval. Drugs. 2020;80(7):733-9.

Vries T, Villalón CM, MaassenVanDenBrink A. Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans. Pharmacol Ther. 2020;211:107528.

Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350(11):1104-10.

Edvinsson L, Linde M. New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet. 2010;376(9741):645-55.

Voss T, Lipton RB, Dodick DW, Dupre N, Ge JY, Bachman R, et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia. 2016;36(9):887-98.

Dodick DW, Lipton RB, Ailani J, Lu K, Finnegan M, Trugman JM, Szegedi A. Ubrogepant for the Treatment of Migraine. N Engl J Med. 2019;381(23):2230-41.

Lipton RB, Dodick DW, Ailani J, Lu K, Finnegan M, Szegedi A, Trugman JM. Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial. JAMA. 2019;322(19):188798.

Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34(2):114-25.

Lipton RB, Croop R, Stock EG, Stock DA, Morris BA, Frost M, et al. Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. N Engl J Med. 2019;381(2):142-9.

Croop R, Goadsby PJ, Stock DA, Conway CM, Forshaw M, Stock EG, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet. 2019;394(10200):737-45.

U.S National Library of Medical Clinical Trials Registry. Safety and Efficacy Study in Adult Subjects With Acute Migraines, 2021. Available at: Accessed on 16 December 2021.

Croop R, Madonia J, Conway C, Thiry A, Forshaw M, Murphy A, et al. Intranasal Zavegepant is Effective and Well Tolerated for the Acute Treatment of Migraine: A Phase 2/3 Dose-Ranging Clinical trial (4976). Neurology. 2021;9(15):4976.

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.

Ailani J, Lipton RB, Goadsby PJ, Guo H, Miceli R, Severt L, et al. Atogepant for the Preventive Treatment of Migraine. N Engl J Med. 2021;385(8):695-706.

Croop R, Lipton RB, Kudrow D, Stock DA, Kamen L, Conway CM, et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. 2021;397(10268):51-60.

Sakai F, Takeshima T, Tatsuoka Y, Hirata K, Lenz R, Wang Y, et al. A Randomized Phase 2 Study of Erenumab for the Prevention of Episodic Migraine in Japanese Adults. Headache. 2019;59(10):1731-42.

Ashina M, Kudrow D, Reuter U, Dolezil D, Silberstein S, Tepper SJ, et al. Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: A pooled analysis of four placebo-controlled trials with long-term extensions. Cephalalgia. 2019;39(14):1798-808.

Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, et al. One-year sustained efficacy of erenumab in episodic migraine: Results of the STRIVE study. Neurology. 2020;95(5):469-79.

Skljarevski V, Oakes TM, Zhang Q, Ferguson MB, Martinez J, Camporeale A, et al. Effect of Different Doses of Galcanezumab vs Placebo for Episodic Migraine Prevention: A Randomized Clinical Trial. JAMA Neurol. 2018;75(2):187-93.

Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial. JAMA Neurol. 2018;75(9):1080-8.

Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442-54.

Mulleners WM, Kim BK, Láinez MJA, Lanteri-Minet M, Pozo-Rosich P, Wang S, et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2020;19(10):814-25.

Shibata M, Nakamura T, Ozeki A, Ueda K, Nichols RM. Migraine-Specific Quality-of-Life Questionnaire (MSQ) Version 2.1 Score Improvement in Japanese Patients with Episodic Migraine by Galcanezumab Treatment: Japan Phase 2 Study. J Pain Res. 2020;13:3531-8.

Ferrari MD, Diener HC, Ning X, Galic M, Cohen JM, Yang R, et al. Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial. Lancet. 2019;394(10203):1030-40.

Goadsby PJ, Silberstein SD, Yeung PP, Cohen JM, Ning X, Yang R, et al. Long-term safety, tolerability, and efficacy of fremanezumab in migraine: A randomized study. Neurology. 2020;95(18):2487-99.

Buse DC, Gandhi SK, Cohen JM, Campos V, Cloud B, Yang R, et al. Improvements across a range of patient-reported domains with fremanezumab treatment: results from a patient survey study. J Headache Pain. 2020;21(1):109.

Ashina M, Saper J, Cady R, Schaeffler BA, Biondi DM, Hirman J, et al. Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia. 2020;40(3):241-54.

Winner PK, McAllister P, Chakhava G, Ailani J, Ettrup A, Krog JM, et al. Effects of Intravenous Eptinezumab vs Placebo on Headache Pain and Most Bothersome Symptom When Initiated During a Migraine Attack: A Randomized Clinical Trial. JAMA. 2021;325(23):2348-56.