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

backgroundCalcitonin 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.

methodsIn 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.

resultsA 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.

conclusionsOur 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 registrationClinicalTrials.gov, NCT05635604. Registered on November 15 2022.