Characterization of transit rates in the large intestine of mice following treatment with a CGRP antibody, CGRP receptor antibody, and small molecule CGRP receptor antagonists

Abstract

Objective: To characterize the effects of blocking calcitonin gene-related peptide (CGRP) activity in a mouse model of gastrointestinal transport.Background: Migraine management using CGRP modulating therapies can cause constipation of varying frequency and severity. This variation might be due to the different mechanisms through which therapies block CGRP activity (e.g., blocking CGRP, or the CGRP receptor) with antibodies or receptor antagonists. The charcoal meal gastrointestinal transit assay was used to characterize constipation produced by these modes of therapy in transgenic mice expressing the human receptor activitymodifying protein 1 (hRAMP1) subunit of the CGRP receptor complex.Methods: Male and female hRAMP1 mice were dosed with compound or vehicle and challenged with a charcoal meal suspension via oral gavage. The mice were then humanely euthanized and the proportion of the length of the large intestine that the charcoal meal had traveled indicated gastrointestinal transit.Results: Antibody to the CGRP receptor produced % distance traveled (mean ± standard deviation) of 31.8 ± 8.2 (4 mg/kg; p = 0.001) and 33.2 ± 6.0 (30 mg/kg; p < 0.001) compared to 49.7 ± 8.3 (control) in female mice (n = 6-8), and 35.6 ± 13.5 (30 mg/kg, p = 0.019) compared to 50.2 ± 14.0 (control) in male mice (n = 10). Telcagepant (5 mg/kg, n = 8) resulted in % travel of 30.6 ± 14.7 versus 41.2 ± 8.3 (vehicle; p = 0.013) in male mice. Atogepant (3 mg/kg, n = 9) resulted in % travel of 30.6 ± 12.0, versus 41.2 ± 3.7 (control; p = 0.030) in female mice. The CGRP antibody galcanezumab (n = 7-10; p = 0.958 and p = 0.929) did not have a statistically significant effect.Conclusions: These results are consistent with reported clinical data. Selectively blocking the CGRP receptor may have a greater impact on gastrointestinal transit than attenuating the activity of the ligand CGRP. This differential effect may be related to physiologically opposing mechanisms between the CGRP and AMY1 receptors, as the CGRP ligand antibody could inhibit the effects of CGRP at both the CGRP and AMY1 receptors.

Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonism Reduces Motion Sickness Indicators in Mouse Migraine Models

“…Others have shown in human subjects and in mouse models that CGRP causes diarrhea by disrupting peristaltic intestinal activity and promoting ion and water secretion in the intestinal lumen, and that CGRP signaling antagonism can reverse these effects [35][36][37] . Thus, it is expected that CGRPinduced diarrhea would cause noticeable increases in the motion sickness index (MSI) calculation.…”

Role of Calcitonin Gene-Related Peptide on the Gastrointestinal Symptoms of Migraine—Clinical Considerations

“…44,e26,e31,e32 It has been postulated that differences in effects on motility observed among CGRP-based therapies may involve the ability of the anti-CGRP ligand antibody to inhibit the effects of CGRP at both receptor types. 47 CGRP-induced diarrhea in mice was blocked by prophylactic administration of an anti-CGRP antibody and was attenuated by administration of olcegepant. 48 An anti-CGRP receptor mAb and acute dosing with telcagepant also significantly inhibited GI transit in the large intestine of transgenic mice (expressing human receptor activity modifying protein 1 [RAMP1], the receptor subunit common to the CGRP receptor, and the related AMY 1 ); however, no significant effect was seen with a mAb targeting CGRP.…”

“…[RAMP1], the receptor subunit common to the CGRP receptor and the related AMY 1 ); however, no significant effect was seen with a mAb targeting CGRP. 47 Given the commonality of innervation and the role of CGRP in GI function, it is reasonable to postulate that therapeutic modulation of CGRP in migraine might prove useful in the management of Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.…”

“…48 An anti-CGRP receptor mAb and acute dosing with telcagepant also significantly inhibited GI transit in the large intestine of transgenic mice (expressing human receptor activity modifying protein 1 [RAMP1], the receptor subunit common to the CGRP receptor, and the related AMY 1 ); however, no significant effect was seen with a mAb targeting CGRP. 47 Given the commonality of innervation and the role of CGRP in GI function, it is reasonable to postulate that therapeutic modulation of CGRP in migraine might prove useful in the management of functional and GI motility disorders; this warrants further study given the limited existing treatment options.…”

“…48 An anti-CGRP receptor mAb and acute dosing with telcagepant also significantly inhibited GI transit in the large intestine of transgenic mice (expressing human receptor activity modifying protein 1 [RAMP1], the receptor subunit common to the CGRP receptor, and the related AMY 1 ); however, no significant effect was seen with a mAb targeting CGRP. 47…”