From CGRP to PACAP: Unraveling the Next Chapter in Migraine Treatment

Abstract

Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. However, the efficacy of calcitonin gene-related peptide (CGRP) receptor antagonists and monoclonal antibodies (mAbs) in treating migraines can vary among patients, and tolerance may develop over time, reducing their effectiveness. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Animal models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology. Intriguingly, the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. In addition, another secretin family peptide vasoactive intestinal peptide is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment. Recent findings highlight the importance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to anti-CGRP therapies. By updating our knowledge on PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides as a novel treatment approach for migraines.