Abstract
The development of small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and of monoclonal antibodies targeting the CGRP system has been a major advance in the management of migraine. In the randomized controlled trials before regulatory approval, the safety of these anti-CGRP migraine therapeutics was considered favorable and to stay within the expected profile. Post-approval real-world surveys reveal, however, constipation to be a major adverse event which may affect more than 50% of patients treated with erenumab (an antibody targeting the CGRP receptor), fremanezumab or galcanezumab (antibodies targeting CGRP). In this review article we address the question whether constipation caused by inhibition of CGRP signaling can be mechanistically deduced from the known pharmacological actions and pathophysiological implications of CGRP in the digestive tract. CGRP in the gut is expressed by two distinct neuronal populations: extrinsic primary afferent nerve fibers and distinct neurons of the intrinsic enteric nervous system. In particular, CGRP is a major messenger of enteric sensory neurons which in response to mucosal stimulation activate both ascending excitatory and descending inhibitory neuronal pathways that enable propulsive (peristaltic) motor activity to take place. In addition, CGRP is able to stimulate ion and water secretion into the intestinal lumen. The motor-stimulating and prosecretory actions of CGRP combine in accelerating intestinal transit, an activity profile that has been confirmed by the ability of CGRP to induce diarrhea in mice, dogs and humans. We therefore conclude that the constipation elicited by antibodies targeting CGRP or its receptor results from interference with the physiological function of CGRP in the small and large intestine in which it contributes to the maintenance of peristaltic motor activity, ion and water secretion and intestinal transit.
Highlights
Calcitonin gene-related peptide was overtaking many a neuropeptide in its path to clinical exploitation, given that only some 20 years after its discovery (Rosenfeld et al, 1983) a landmark paper (Olesen et al, 2004) provided clinical proof of the concept that a small molecule antagonist of calcitonin gene-related peptide (CGRP) is able to prevent and treat migraine
Constipation caused by CGRP antagonism/neutralization is the prime focus of this review article which seeks to provide a mechanistic explanation of this adverse effect which in hindsight was not totally unforeseen
We first survey the gastrointestinal adverse effect profile of gepants and monoclonal antibodies targeting either CGRP or the CGRP receptor, collectively termed anti-CGRP migraine therapeutics, that came to light in the phase 3 trials prior to marketing authorization
Summary
Calcitonin gene-related peptide was overtaking many a neuropeptide in its path to clinical exploitation, given that only some 20 years after its discovery (Rosenfeld et al, 1983) a landmark paper (Olesen et al, 2004) provided clinical proof of the concept that a small molecule antagonist of CGRP (code name BIBN4096BS, later given the international nonproprietary name olcegepant) is able to prevent and treat migraine. We take into account that certain neuroendocrine tumors expressing and releasing CGRP are known to cause watery diarrhea, which indirectly ascribes CGRP a role in promoting propulsive motility in the human intestine With these considerations in mind we provide a rational explanation why long-term blockade of CGRP signaling results in constipation as a major adverse effect of monoclonal antibodies targeting CGRP or its receptor. The ongoing phase 3 trials did not disclose any substantial gastrointestinal adverse effect potential of the anti-CGRP migraine therapeutics under clinical development It came as an unforeseen surprise that in postapproval real-world surveys constipation emerged as a major unwanted side effect of monoclonal antibodies targeting the CGRP system. Antibodies targeting CGRP itself appear to be liable to cause constipation as erenumab
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
