CGRP antagonists show different potencies for CGRP isoforms in different vascular compartments

The α-CGRP and β-CGRP isoforms might induce a different functional response across vascular beds, including small human coronary arteries. Furthermore, as the 2 isoforms are impacted differently by CGRP antagonists, there is a potential for clinical consequences, such as the development of adverse events driven by each individual isoform.

In the presentation that won the Best Poster Prize, PhD candidate Ms Deirdre Boucherie (Erasmus University Medical Centre Rotterdam, the Netherlands) and colleagues assessed the effect of α-CGRP and β-CGRP in human coronary arteries and middle meningeal arteries [1]. Distal coronary arteries (<1 mm in internal diameter – small; >2 mm in internal diameter – large) were collected post-mortem from heart valve donors, while middle meningeal arteries were obtained from patients receiving neurosurgery. The overall aims of the study were to compare the functional responses of α-CGRP and β-CGRP, and to assess the potency of different CGRP-targeting agents on these isoforms. Functional responses were assessed as half maximal effective concentration converted to a negative logarithm (pEC₅₀).

The functional response of α-CGRP and β-CGRP was similar in middle meningeal arteries (pEC₅₀ 8.3 vs 8.7) and in large coronary arteries (pEC₅₀ 8.2 vs 8.3) but was significantly lower in small coronary arteries (pEC₅₀ 8.7 vs 9.1; P<0.05). Assessment of CGRP antagonists on the 2 CGRP isoforms showed that olcegepant has similar inhibitory potencies, while fremanezumab has a significantly higher potency towards β-CGRP. Furthermore, the CGRP inhibitor CGRP_8-37 showed higher potency against β-CGRP in middle meningeal arteries and large distal coronary arteries but similar potency in small coronary arteries.

The authors concluded that “α-CGRP and β-CGRP exhibit subtle differences across the vascular beds.” CGRP pathway antagonists have different inhibitory ratios, suggesting “possible clinical implications for CGRP-pathway-targeting drugs, such as side effects.” Multiple potential underlying mechanisms exist, including “different binding sites, receptor internalisation, and potency at receptor-activity-modifying proteins.”

1. Boucherie DM, et al. αCGRP versus βCGRP: don’t overlook the differences. 18^th European Headache Congress, 4–7 December 2024, Rotterdam, the Netherlands.

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Posted on 6 January 20256 January 2025