Targeting the PACAP-38 pathway is an emerging therapeutic strategy for migraine prevention

ABSTRACT

Introduction

The pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) has emerged as a key mediator of migraine pathogenesis. PACAP-38 and its receptors are predominantly distributed in arteries, sensory and parasympathetic neurons of the trigeminovascular system. Phase 2 trials have tested human monoclonal antibodies designed to bind and inhibit PACAP-38 and the pituitary adenylate cyclase-activating polypeptide type I (PAC₁) receptor for migraine prevention.

Areas covered

This review focuses on the significance of the PACAP-38 pathway as a target in migraine prevention. English peer-reviewed articles were searched in PubMed, Scopus and ClinicalTrials.gov electronic databases.

Expert opinion

A PAC₁ receptor monoclonal antibody was not effective for preventing migraine in a proof-of-concept trial, paving the way for alternative strategies to be considered. Lu AG09222 is a humanized monoclonal antibody targeting PACAP-38 that was effective in preventing physiological responses of PACAP38 and reducing monthly migraine days in individuals with migraine. Further studies are necessary to elucidate the clinical utility, long-term safety and cost-effectiveness of therapies targeting the PACAP pathway.

KEYWORDS:

• CGRP
• headache
• medication overuse headache
• monoclonal antibodies
• pain
• VIP

Article highlights

• Targeting the PACAP-38 peptide is a promising new therapeutic strategy for migraine prevention.

• Antagonising the PAC1 receptor has proven ineffective in migraine prevention.

• New therapeutic targets of the PACAP-38 pathway include VIP and PACAP-27 peptides.

Declaration of interest

L Pellesi has been employed by Lundbeck in the past two years. M Ashina is Associate Editor for The Journal of Headache and Pain, and Brain. M Ashina also received personal fees from AbbVie, Amgen, Astra Zeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Novartis, Pfizer and Teva Pharmaceuticals outside of this work. P Martelletti is Editor-in-Chief for The Journal of Headache and Pain, and SN Comprehensive Clinical Medicine. He is also EU Expert for the European Medicines Agency.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.