PACAP-targeting therapies: a future option for migraine?

In a study testing eptinezumab versus placebo for the prevention of migraine induced by pituitary adenylate cyclase-activating polypeptide 38 (PACAP-38), no significant differences were found in migraine development or headache intensity between groups. According to the authors, this means that agents targeting PACAP signalling could be an option for future management of migraine.

The double-blind, placebo-controlled, parallel-group study randomised 38 participants with migraine and aura 1:1 to 300 mg eptinezumab (a CGRP-targeted antibody) or placebo; 2 hours post-infusion, both groups received 10 pmol/kg/min of PACAP-38 for 20 minutes, to induce migraine attacks [1]. Participants were then discharged and asked to fill in a headache diary every hour for 24 hours. Enrolled participants had to be headache-free for 48 hours prior to the baseline of the study and were required to reschedule their treatment if headache symptoms were present.

Overall, 63% of participants receiving placebo plus PACAP-38 and 53% receiving eptinezumab plus PACAP-38 developed migraine attacks over the 24 hours after discharge, with the between-group comparison not reaching significance (P=0.74). Furthermore, the median headache intensity of PACAP-38-induced attacks, assessed by a Numerical Rating Scale, did not show a difference between the placebo and eptinezumab groups. Other measured parameters, such as facial skin blood flow, superficial temporal artery diameter, mean arterial blood pressure, and heart rate measured during the in-hospital phase of the trial, did not significantly vary between the treatment groups.

“Based on these results, we can conclude that PACAP acts as an independent and parallel pathway to CGRP,” said Dr Zixuan Alice Zhuang (University of Copenhagen, Denmark). “So we are not talking about a sequential relationship. This implies that targeting PACAP signalling might offer a novel, mechanism-based approach to treat migraine. For patients who cannot tolerate or who show no efficacy of anti-CGRP treatment, anti-PACAP treatment could be of benefit.”

1. Al-Karagholi MA, et al. PACAP38-induced migraine attacks are independent of CGRP signaling. 18^th European Headache Congress, 4–7 December 2024, Rotterdam, the Netherlands.

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Posted on 6 January 20256 January 2025