Emgality ® (galkanezumab)

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Emgality® ▼ (galcanezumab): Verkningsmekanism vid förebyggande av migrän

Galcanezumab är en humaniserad IgG4 mAb som binder CGRP och förhindrar dess biologiska aktivitet utan att blockera CGRP-receptorn.

Short Answer Summary

CGRP is a potent microvascular vasodilator found throughout the body that plays an important role in numerous pain and inflammation processes.1

CGRP is found throughout the trigeminovascular system and in central brain regions regarded as important in migraine pathogenesis.1

Elevated blood concentrations of CGRP have been associated with migraine attacks.2

Galcanezumab is a humanised IgG4 monoclonal antibody that binds CGRP thus preventing its biological activity.2

Galcanezumab binds to CGRP with high affinity (KD = 31 pM) and high specificity (> 10,000-fold vs related peptides adrenomedullin, amylin, calcitonin and intermedin).2

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 microvascular vasodilator.1,3,4

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.1

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.1

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.5

The CGRP neuropeptide exists as α-CGRP and β-CGRP. The α-CGRP form is primarily associated with sensory neurons and is thought to have a major role in the pathogenesis of the migraine headache.1,4,6

Mechanism of Action of Galcanezumab

Galcanezumab is a humanized IgG4 mAb that

  • binds CGRP, thus

  • preventing its biological activity.2

Galcanezumab binds to CGRP with high

  • affinity (KD=31 pM), and

  • specificity (>10,000-fold versus related peptides adrenomedullin, amylin, calcitonin, and intermedin).2

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,8-10 total CGRP concentrations increased after galcanezumab administration in patients with episodic or chronic migraine compared to placebo. This indicated that the antibody was

  • binding to CGRP, and

  • slowing the clearance of the CGRP that was bound to the antibody.7,11

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.3

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.6,12,13

References

1. Russell 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

2. Emgality [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

3. Benschop 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

4. Conner 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

5. Dodick DW, Goadsby PJ, Spierings EL, 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

6. Giamberardino 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

7. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

8. Stauffer 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

9. Skljarevski 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

10. Detke 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

11. Kielbasa 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.

12. Nakano 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.

13. Johnson 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

Glossary

CGRP = calcitonin gene-related peptide

IgG = immunoglobulin G

IgG4 = immunoglobulin G (subclass) 4

IV = intravenous

Kd = dissociation constant

mAb = monoclonal antibody

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Datum fӧr senaste ӧversyn February 18, 2019


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