Fremanezumab for the preventive treatment of migraine in adults

An Evidence-Based Review of Fremanezumab for the Treatment of Migraine

“…Advances in therapies have made it possible to effectively prevent or reduce symptoms of migraine. Humanized monoclonal antibodies targeting CGRP and its receptor have recently been approved for migraine prophylaxis in adults [75,79,91,101,127,128]. Fremanezumab, a monoclonal antibody specific to CGRP, was approved by the FDA in September 2018 and by the EMA in March 2019 for migraine prevention in adults [76,90].…”

“…The pathophysiology of migraine is linked to activation of the trigeminovascular system, which releases several neuropeptides including CGRP, a 37-amino acid peptide neurotransmitter found in sensory nerves throughout the central and peripheral nervous systems [36,[77][78][79][86][87][88]. CGRP exists in two isoforms, a and b, but since the b form is found in the enteric nervous system, hereafter the paper will focus on a-CGRP, which is a peptide derived from the calcitonin gene on chromosome 11 via alternative mRNA splicing and proteolytic cleavage [75,79,89,90]. Since its discovery in 1982, CGRP has been found to play a critical role in the mechanism of migraine pathology [79,91,92].…”

“…Some clinical studies also provided evidence for a causal role of CGRP in migraine [97][98][99]. In response to cerebrovascular vasoconstriction, CGRP is released from vesicles in the trigeminal ganglion via calcium-dependent exocytosis and binds to the CGRP receptor, a heterodimer of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), to exert its potent vasodilatory effects [36,79,90,100]. The CGRP receptor complex is coupled to Ga so that, when stimulated, it activates intracellular cAMP, amplifying protein kinase A, which then phosphorylates multiple downstream targets [79,90].…”

“…In response to cerebrovascular vasoconstriction, CGRP is released from vesicles in the trigeminal ganglion via calcium-dependent exocytosis and binds to the CGRP receptor, a heterodimer of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), to exert its potent vasodilatory effects [36,79,90,100]. The CGRP receptor complex is coupled to Ga so that, when stimulated, it activates intracellular cAMP, amplifying protein kinase A, which then phosphorylates multiple downstream targets [79,90]. CGRP signaling ultimately results in vasodilation of intracranial blood vessels, contributing to the neurogenic inflammation that triggers migraine nociception [79,87].…”

“…The pharmacological properties of fremanezumab make it a safe and tolerable drug for migraine prophylaxis. A single subcutaneous (SC) injection (225 mg, 675 mg, or 900 mg) took a median of 5-7 days to reach maximum concentration (t max ) [76,80,90]. Dosing regimens of 225 mg SC monthly and 675 mg SC quarterly took about 168 days (* 6 months) to reach steady state [76,80].…”