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

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.