Novel PACAP-Targeted Antibody Reduces Monthly Migraine Days in Phase 2 HOPE Trial

A single 750 mg intravenous infusion of Lu AG09222 showed a 2-day difference in reducing monthly migraine day compared with placebo.

An investigational monoclonal antibody targeting a novel migraine prevention pathway showed success in the phase 2 HOPE clinical trial.1

A single 750 mg intravenous infusion of Lu AG09222 (Lundbeck) showed superiority over placebo in reducing migraine frequency over the subsequent 4 weeks, reported Messoud Ashina, MD, of Copenhagen University Hospital–Rigshospitalet in Denmark, and coauthors in The New England Journal of Medicine.1

In the study of 237 patients with episodic or chronic migraine who had failed 2 to 4 previous preventive treatments, the mean number of monthly migraine days was 16.7 at baseline. Through week 4, participants who received Lu AG09222 had 6.2 fewer monthly migraine days, while the placebo group had 4.2 fewer days (difference -2.0 days, 95% CI -3.8 to -0.3; P = 0.02).1

Lu AG09222 targets pituitary adenylate cyclase-activating polypeptide (PACAP), a vasodilating polypeptide thought be involved in migraine pathophysiology, which is a new avenue for treating migraine, according to Ashina and colleagues.1

"These findings affirm the proof of concept, showing that inhibition of PACAP signaling by Lu AG09222 represents a new and potentially effective mechanism for migraine prevention," investigators wrote.1

Previous studies have shown that intravenous infusion of PACAP induced attacks in patients with migraine.2 A phase 1 clinical trial of healthy participants reported that Lu AG09222 inhibited PACAP-induced cranial artery dilation and reduced concomitant headache.3

In the HOPE trial, participants were randomly assigned to receive a single-dose baseline infusion of 750 mg (n=97) or 100 mg (n=46) of LuAG09222 or placebo (n=94). Baseline characteristics were generally similar across the 3 trial groups. Mean age was 42.5 years, 100% of participants were White, and 88% were women.1

The study included a 4-week treatment period and 8 weeks of follow-up. The primary end point was the mean change from baseline in the number of monthly migraine days during weeks 1 through 4 in the 750-mg group compared with the placebo group. Participants completed a daily electronic diary to capture headache events, symptoms, and other data.1

In the 4-week treatment period, the percentage of participants who had a reduction from baseline of at least 50% in the number of monthly migraine days was 32% in the 750-mg group and 27% in the placebo group.1

Most adverse events were mild, according to the study results. Adverse events with a higher incidence in Lu AG09222 750-mg group compared to the placebo group over 12 weeks included COVID-19 (7% vs 3%), nasopharyngitis (7% vs 4%), and fatigue (5% vs 1%).1

The study had several limitations, Ashina and colleagues acknowledged. "As a proof-of-concept trial, the sample size was small, the trial was short in duration and follow-up, and participants received only one dose of Lu AG09222," they wrote.1

If Lu AG09222 ultimately is approved by the FDA, it will be the second class of monoclonal antibody treatments for migraine prevention—the first being antibodies to calcitonin gene-related peptide (CGRP) or its receptor, noted Elizabeth Loder, MD, MPH, of Brigham and Women's Hospital in Boston, in an accompanying editorial.4

"Although caution is advisable when results across trials are compared, the modest between-group difference of 2 migraine days per month observed in the current trial is similar to the results of trials of the CGRP monoclonal antibodies and lower than the difference observed with some established non-antibody preventive treatments for migraine, such as Onabotulinum toxin A or topiramate," Loder stated.4

Loder continued: "Even if a new PACAP antibody is not more effective than existing treatments, its arrival is still valuable. It is always good news when another potential target for migraine is identified and proves amenable to treatment."4

References:

  1. Ashina M, Phul R, Khodaie M, Florea I. A monoclonal antibody to PACAP for migraine prevention. N Engl J Med. 2024;391:800-809. doi:10.1056/NEJMoa2314577
  2. Ghanizada H, Al-Karagholi MA, Arngrim N, Olesen J, Ashina M. PACAP27 induces migraine-like attacks in migraine patients. Cephalalgia. 2020;40:57-67. doi:10.1177/0333102419864507
  3. Rasmussen NB, Deligianni C, Christensen CE, et al. The effect of Lu AG09222 on PACAP38- and VIP-induced vasodilation, heart rate increase, and headache in healthy subjects: an interventional, randomized, double-blind, parallel-group, placebo-controlled study. J Headache Pain. 2023;24:60. doi:10.1186/s10194-023-01599-w
  4. Loder E. A new antibody treatment for migraine. N Engl J Med. 2024;391:855-857. doi:10.1056/NEJMe2406401