Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) with monoclonal antibodies in migraine prevention: a brief review

Abstract

Introduction: Interest is growing in the role of pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific PAC1 receptor in migraine and in their antagonism as a strategy for migraine prevention. Areas covered: We discuss and critically evaluate (i) the evidence of the role of PACAP in migraine pathophysiology and (ii) the first clinical trials in migraine prophylaxis with monoclonal antibodies AMG 301 and ALD1910 which act against PAC1 and PACAP38 respectively. We examined PubMed, Scopus, and ClinicalTrials.gov electronic databases to examine the relevant material. Expert opinion: There is much proof of the ability of PACAP to cause migraine, but there is limited evidence that blocking PACAP or PAC1 receptor can prevent migraine. However, the potential of anti-PACAP antibodies in migraine prophylaxis is high. Theoretically, if these antibodies block the activation of the trigeminovascular system, they will prevent the onset of migraine attacks. There are still knowledge gaps in the role of PACAP in migraine and the risk/benefit ratio of anti-PACAP antibodies must be carefully studied.

Characterisation of agonist signalling profiles and agonist‐dependent antagonism at PACAP‐responsive receptors: Implications for drug discovery

“…Clinical efforts to develop new anti-migraine drugs targeting the PACAP system have focused on anti-PACAP and anti-PAC 1 receptor monoclonal antibodies (mAb) (Hoffmann et al, 2020;Moldovan Loomis et al, 2019;Rustichelli et al, 2020). Despite promising preclinical evidence, an anti-PAC 1 receptor mAb failed to display efficacy for the treatment of migraine (Ashina et al, 2021).…”

First‐in‐human development of a pharmacodynamic biomarker for PAC1 receptor antagonists using intradermal injections of maxadilan

“… 11 , 12 In the context of migraine, PACAP‐binding sites were found in the trigeminal system and on nerve fibers innervating the dura mater and cerebral arteries. 14 , 19 In contrast, this biomarker model evaluates maxadilan‐induced DBF changes on the forearm. Nevertheless, as both regions are located in the peripheral nervous system without any particular barrier, there is no reason to expect major deviations from general plasma levels in the trigeminal system.…”

Using Monozygotic Twins to Dissect Common Genes in Posttraumatic Stress Disorder and Migraine

“…Methylation in peripheral blood samples of ADCYAP1 (PACAP protein) and its receptor ADCYAP1R1 (PAC1 protein), genes involved in regulating the cellular stress response, were associated with PTSD diagnosis and symptom severity, specifically in females ( Ressler et al, 2011 ). There is emerging evidence of a link between PACAP and migraine, with clinical trials targeting PACAP as a likely prevention for migraine ( Sundrum and Walker, 2018 ; Rustichelli et al, 2020 ).…”