Galcanezumab is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) that

• binds calcitonin gene-related peptide (CGRP), and
• prevents its biological activity without blocking the CGRP receptor.1,2

Galcanezumab targets CGRP and binds with high

• affinity (dissociation constant [K_D] 31 pM), and3,4
• specificity (>10,000-fold vs related peptides adrenomedullin, amylin, calcitonin, and intermedin).4,5

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

• binding to CGRP, and
• slowing the clearance of the CGRP that was bound to the antibody.2,5

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

See Galcanezumab Mechanism of Action Video: http://www.kaltura.com/tiny/0f8le  for a video illustrating the mechanism of action of galcanezumab.