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Emgality ® (galcanezumab-gnlm) injection
100 mg/mL, 120 mg/mL
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.
What is the mechanism of action of Emgality® (galcanezumab-gnlm) in migraine prevention?
Emgality (galcanezumab) is a humanized IgG4 mAb that binds CGRP and prevents its biological activity without blocking the CGRP receptor.
Mechanism of Action of Galcanezumab
Galcanezumab is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) that
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.5
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.5
In the phase 3, double-blind, placebo-controlled migraine prevention studies,6-8 total CGRP concentrations increased after galcanezumab administration 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.4
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.9-11
The Role of CGRP in Migraine
CGRP is
- a 37-amino acid peptide commonly found in the peripheral and central nervous systems, and
- considered a potent vasodilator in both the peripheral and cerebral vasculatures.12,13
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.12
The CGRP neuropeptide has a wide range of physiological actions including, but not limited to
- cardiovascular regulatory processes
- neurogenic inflammation
- pain, and
- migraine.12
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.12
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
- intravenous (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.3,13,14
Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Emgality [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021.
2Kielbasa W, Helton DL. A new era for migraine: pharmacokinetic and pharmacodynamic insights into monoclonal antibodies with a focus on galcanezumab, an anti-CGRP antibody. Cephalalgia. 2019;39(10):1284-1297. http://dx.doi.org/10.1177/0333102419840780
3Monteith 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
4Benschop 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
5Data on file, Eli Lilly and Company and/or one of its subsidiaries.
6Stauffer 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
7Skljarevski 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
8Detke 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
9Giamberardino 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
10Nakano M, Uenaka K, Kielbasa W, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of galcanezumab, a monoclonal antibody to calcitonin gene-related peptide, in healthy Japanese and Caucasian subjects. Jpn J Clin Pharmacol Ther. 2017;48(4):131-139. https://www.jstage.jst.go.jp/article/jscpt/48/4/48_131/_pdf
11Johnson KW, Morin SM, Wroblewski VJ, Johnson MP. Peripheral and central nervous system distribution of the CGRP neutralizing antibody [125I] galcanezumab in male rats. Cephalalgia. 2019;39(10):1241-1248. http://dx.doi.org/10.1177/0333102419844711
12Russell 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
13Charles A, Pozo-Rosich P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 2019;394(10210):1765-1774. https://doi.org/10.1016/S0140-6736(19)32504-8
14Dodick 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
15Conner AC, Hay DL, Howitt SG, 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
Date of Last Review: March 25, 2024