Tessa de Vries (Rotterdam/ NL), Antoon van den Bogaerdt (Beverwijk/ NL), A.H. Jan Danser (Rotterdam/ NL), Josefin Snellman (Basel/ CH), Jeanine Bussiere (Thousand Oaks, CA/ US), Antoinette Maassen van den Brink (Rotterdam/ NL)
Abstract text (incl. figure legends and references)
Objective
Multiple drugs targeting the calcitonin gene-related peptide (CGRP) pathway have been developed for the acute and preventive treatment of migraine. In this study, the effect of the monoclonal antibody erenumab in combination with the acute anti-migraine medication rimegepant, olcegepant or sumatriptan (5-HT-R agonist), on CGRP-induced vasorelaxation was investigated in human isolated coronary arteries (HCA).
Methods
HCA segments from 17 donors (11 female and 6 male, 53±3 years) were incubated overnight with 3 µM erenumab, which is the concentration of erenumab causing a maximum rightward shift of relaxations to CGRP. Next, the segments were mounted on a Mulvany myograph system, in the presence of 3 µM erenumab, and precontracted with 30 mM KCl and subsequently exposed to CGRP. Rimegepant, olcegepant or sumatriptan was added in increasing concentrations to assess whether these compounds did exert additional CGRP-blocking effects on top of erenumab. In addition, full concentration-response curves to CGRP, adrenomedullin or pramlintide were constructed in HCA segments incubated with or without erenumab (3 µM) and/or olcegepant (1 µM).
Results
The relaxation caused by CGRP in segments incubated with 3 µM erenumab was reversed by rimegepant (91%), olcegepant (92%) and sumatriptan (134%, physiological antagonism). Olcegepant seemed to further shift the concentration-response curve to CGRP when administered on top of erenumab, while no further shift of the responses to adrenomedullin and pramlintide was observed.
Conclusion
Both rimegepant and olcegepant exert additional effects on top of a maximal effect of erenumab, suggesting that the mechanism of action of erenumab and gepants may not be identical. In contrast, olcegepant does not induce additional effects on top of erenumab for the agonists adrenomedullin and pramlintide. This suggests that different receptor populations may mediate responses to CGRP, adrenomedullin and pramlintide in HCA.