Fremanezumab blocks CGRP induced dilatation in human cerebral, middle meningeal and abdominal arteries

Background: Fremanezumab (TEV-48125) is a fully humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) that has shown positive results in the prevention of episodic migraine and chronic migraine. Previous preclinical studies have revealed CGRP antagonistic effects on intracranial arteries (ICA). The aim of the study was to evaluate the in vitro antagonistic effects of fremanezumab on human arteries. Methods: Arteries were removed in conjunction with neurosurgery (cerebral, CA, and middle meningeal artery, MMA, n = 7) or reconstructive abdominal surgery (abdominal artery, AA, n = 6). Ring segments of the vessels were mounted in a sensitive myograph, the functional responses of vasoactive intestinal peptide (VIP), substance P and CGRP in increasing concentrations (10(-10)-10(-7) M) were studied using pre-contraction with 30 mM potassium chloride (KCI). The concentrations of fremanezumab or isotype control antibody (66.7 nM, 0.33 mu M, 0.67 mu M) were given 30 min prior to CGRP administration. Results: All included arteries responded with a strong stable contraction to the application of 30 mM KCI. During this pre-contraction, CGRP caused a concentration-dependent relaxation which differed slightly in maximum effect (I-max) between the types of arteries (ICA = 100%; AA 80%). Fremanezumab (66.7 nM) showed a shift in the IC50 value of CGRP, but no significant change in I-max. At higher doses there was also a reduction of I-max . For AA, the I-max decreased from 71% at 66.7 nM, to 4.5% with 0.33 mu M of fremanezumab. Isotype control antibody did not modify the responses. There was no effect on concentration-dependent relaxation with VIP with 66.7 nM of fremanezumab or isotype control. Conclusion: CGRP relaxes pre-contracted human arteries by 80-100%, but with different IC50; the potency range was ICA < AA. The antagonistic effect and potency of fremanezumab was similar, suggesting that there are vasodilatory CGRP receptors present in all studied arteries and that the antibody may have effect in all studied vessels.