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Galcanezumab: Mechanism of Action in Migraine Prevention
Galcanezumab is a humanized IgG4 mAb that binds CGRP and prevents its biological activity without blocking the CGRP receptor.
The information contained in this letter may not completely match the current local labeling for GALCANEZUMAB. Please see local labeling approved in your country.
The Role of CGRP in Migraine
- a 37-amino acid peptide commonly found in the peripheral and central nervous systems, and
- considered a potent microvascular vasodilator.1-3
It has a potency approximately
- 10 times higher than the most potent prostaglandins and
- 10 to 100 times greater than acetylcholine and neuropeptide substance P.2
The CGRP neuropeptide has a wide range of physiological actions including cardiovascular regulatory processes and other conditions including but not limited to neurogenic inflammation, pain, and migraine. Migraine pathogenesis is thought to be associated with the activation of the trigeminovascular system. CGRP is distributed throughout the trigeminovascular system and is released from trigeminal ganglia nerves upon activation.2
The role of CGRP in migraine has been underscored by several experimental and clinical findings including,
- an increase of jugular CGRP venous blood concentration during spontaneous migraine attacks
- IV infusion of recombinant human CGRP triggered a migraine attack in migraine sufferers
- elevated CGRP serum concentrations were inhibited by triptan treatment, and
- small-molecule CGRP receptor antagonists were effective in relieving acute migraine headache in double-blind, randomized, placebo-controlled trials.4
Mechanism of Action of Galcanezumab
Galcanezumab is a humanized IgG4 mAb that
- binds CGRP, and
- prevents its biological activity without blocking the CGRP receptor.7
Galcanezumab targets CGRP and binds with high
When galcanezumab is administered, the premise is that
- CGRP will bind to galcanezumab, and
- the amount of free CGRP that is available to interact with the CGRP receptors will be reduced.7
Galcanezumab-bound CGRP is expected to take on the disposition characteristics of galcanezumab resulting in
- a lower clearance than free CGRP, and
- an increase in total CGRP concentration upon galcanezumab administration.7
In the phase 3 placebo-controlled, double-blind migraine prevention studies,9-11 total CGRP concentrations increased after galcanezumab administration in patients with episodic or chronic migraine compared to placebo. This indicated that the antibody was
The binding of galcanezumab to CGRP is slowly reversible based on the off-rate for the CGRP/galcanezumab interaction determined experimentally. However, any released CGRP is likely to be quickly bound to the same or a different antibody based on the rapid on-rate for binding.1
Being a macromolecule, galcanezumab does not appreciably cross the blood-brain barrier. Therefore, it is thought that galcanezumab acts peripherally in structures involved in migraine pathogenesis, including the trigeminal ganglia.5,13,14
1Benschop RJ, Collins EC, Darling RJ, et al. Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain. Osteoarthritis Cartilage. 2014;22(4):578-585. http://dx.doi.org/10.1016/j.joca.2014.01.009
2Russell FA, King R, Smillie SJ, et al. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099-1142. http://dx.doi.org/10.1152/physrev.00034.2013
3Conner DL, Hay SG, Howitt K, et al. Interaction of calcitonin-gene-related peptide with its receptors. Biochem Soc Trans. 2002;30(4):451-455. http://dx.doi.org/10.1042/bst0300451
4Dodick 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. http://dx.doi.org/10.1016/S1474-4422(14)70128-0
5Giamberardino MA, Affaitati G, Curto M, et al. Anti-CGRP monoclonal antibodies in migraine: current perspectives. Intern Emerg Med. 2016;11(8):1045-1057. http://dx.doi.org/10.1007/s11739-016-1489-4
6CGRP and Migraine. Available at https://www.kaltura.com/tiny/u8dls. Accessed July 10, 2019.
7Data on file, Eli Lilly and Company and/or one of its subsidiaries.
8Monteith D, Collins EC, Vandermeulen C, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the CGRP binding monoclonal antibody LY2951742 (galcanezumab) in healthy volunteers. Front Pharmacol. 2017;8:740. http://dx.doi.org/10.3389/fphar.2017.00740
9Stauffer VL, Dodick DW, Zhang Q, et al. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080-1088. http://dx.doi.org/10.1001/jamaneurol.2018.1212
10Skljarevski V, Matharu M, Millen BA, et al. 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):1442-1454. http://dx.doi.org/10.1177/0333102418779543
11Detke HC, Goadsby PJ, Wang S, et al. Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018;91(24):e2211-e2221. http://dx.doi.org/10.1212/WNL.0000000000006640
12Kielbasa W. Assessment of pharmacokinetics, target engagement and immunogenicity in patients with migraine administered galcanezumab, and anti-CGRP antibody. Poster presented at: 60th Annual Meeting of the American Headache Society (AHS): June 28 - July 1, 2018; San Francisco, CA.
13Nakano M, Uenaka K, Kielbasa W, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of LY2951742 (galcanezumab), a monoclonal antibody to calcitonin gene-related peptide, in healthy Japanese and Caucasian subjects. Poster presented at: the International Association of the Study of Pain (IASP)-World Congress on Pain Annual Meeting; September 26-30, 2016; Yokohama, Japan.
14Johnson K, Johnson MP, Ellis B, et al. Peripheral and central distribution of the CGRP neutralizing antibody [125I]-LY2951742 in male rats [abstract]. Headache. 2016;56(suppl 1):67:PS41. http://dx.doi.org/10.1111/head.12832
15Galcanezumab Binds to CGRP: Migraine. Available at https://www.kaltura.com/tiny/u8dls. Accessed July 10, 2019.
CGRP = calcitonin gene-related peptide
IgG = immunoglobulin G
IgG4 = immunoglobulin G (subclass) 4
IV = intravenous
Kd = dissociation constant
mAb = monoclonal antibody
Fecha de la última revisión: 2019 M02 18