Journal Article

PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial

Ashina, Håkan, Ashina, Messoud, Al-Karagholi, Mohammad Al-Mahdi, Zhuang, Zixuan Alice, Beich, Signe

2025

Overview

Background Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) are key pathogenic drivers of migraine. While CGRP has become the target of several mechanism-based therapies, less is known about PACAP38 signaling in migraine pathogenesis. Previous studies suggest that PACAP38 can modulate CGRP release, but it might also induce migraine attacks via CGRP-independent mechanisms. Whether PACAP38 signaling is independent of and parallel to CGRP signaling has implications for future therapeutic strategies. Here, we aimed to ascertain whether PACAP-38 can mediate migraine attacks independently of CGRP signaling by assessing the ability of eptinezumab to prevent PACAP38-induced migraine attacks. Methods In a double-blind, placebo-controlled, parallel-group study, we randomly allocated adults with migraine without aura to receive either an intravenous infusion of 300-mg eptinezumab or matching placebo (isotonic saline) over 30 min. Two hours post-infusion, all participants were administered PACAP38 intravenously at 10 pmol/kg/min for 20 min. The primary endpoint was the incidence of migraine attacks during the 24-hour observational period post-infusion of eptinezumab or placebo. Key secondary endpoints included between-group differences in incidence of headache, and area under the curve (AUC) for headache intensity scores, diameter of the superficial temporal artery (STA) and facial skin blood flow. Results A total of 38 participants were enrolled and completed the study. No difference was observed in the incidence of PACAP38-induced migraine attacks between the eptinezumab (10 [53%] of 19) and placebo (12 [63%] of 19) groups (Fisher’s exact test: P  = 0.74). Headache of any intensity was reported by 15 (79%) participants in the eptinezumab group, compared with 16 (84%) participants in the placebo group (Fisher’s exact test: P  > 0.99). The AUC for headache intensity scores did not differ between the two groups during the first 12 h post-infusion of PACAP38 (Mann-Whitney U-test: P  = 0.96). No differences were observed in AUC between the eptinezumab and placebo groups with respect to changes in STA diameter and facial skin blood flow ( P  > 0.05). No serious adverse events occurred. Conclusions Our results suggest that PACAP38 may mediate its signaling independently of CGRP in migraine pathogenesis. Therapies targeting PACAP signaling are thus a promising new avenue for treating migraine. Trial registration ClinicalTrials.gov, NCT05635604. Registered on November 15 2022. Graphical abstract

• Publisher: Springer Milan,Springer Nature B.V,BMC
• Subject: Adult / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - pharmacology / Antibodies, Monoclonal, Humanized - therapeutic use / Blood flow / Calcitonin / Calcitonin gene-related peptide / Calcitonin Gene-Related Peptide - metabolism / CGRP / Double-Blind Method / Female / Headache / Headaches / Humans / Internal Medicine / Male / Medicine / Medicine & Public Health / Middle Aged / Migraine / Migraine Disorders - chemically induced / Migraine Disorders - drug therapy / Neurology / PACAP-38 / Pain / Pain Medicine / Pathogenesis / Pathophysiology / Pituitary Adenylate Cyclase-Activating Polypeptide / Placebos / Signal Transduction - drug effects / Signal Transduction - physiology / Young Adult