Phase 2 HOPE Study of PACAP-Targeting Treatment Lu AG09222 Published in New England Journal of Medicine

Messoud Ashina, MD, PhD, DMSc

Recently, investigators published pivotal data from the phase 2 HOPE trial (NCT05133323) assessing Lundbeck’s pituitary adenylate cyclase-activating polypeptide (PACAP)-targeting therapy, Lu AG09222, in the New England Journal of Medicine. All told, results revealed that treatment with a single intravenous infusion of 750 mg of Lu AG09222 was superior over placebo in reducing migraine frequency over a 4-week period, further supporting its development as an alternative treatment for migraine.¹

In this double-blind, randomized trial, 237 patients with migraine for whom 2-4 previous preventive treatments had failed to provide a benefit were enrolled, 97 of which received 750 mg of Lu AG09222, 46 on 100 mg of Lu AG09222, and 94 on placebo. After a 4-week treatment period, patients in the 750 mg active treatment group had a mean change of –6.2 days in migraine days per month compared with –4.2 days in the placebo group (difference, –2.0 days; 95% CI, –3.8 to –0.3; P = .02).

"An important aspect to consider is the previous failure of a monoclonal antibody directed against a specific PACAP-responsive receptor for migraine prevention,” lead study author Messoud Ashina, MD, PhD, DMSc, director of the Human Migraine Research Unity at the Danish Headache Center, University of Copenhagen, et al wrote.¹ "PACAP binds to four receptor subtypes; the specific receptor or receptors crucial for migraine remain uncertain. In this context, Lu AG09222 offers a different mechanism, targeting the PACAP ligand itself."

The aim of HOPE was to establish whether the inhibition of PACAP signaling by Lu AG09222 represents an effective mechanism for migraine prevention. Lu AG09222 is a humanized monoclonal antibody delivered through intravenous infusion that binds to the PACAP ligand with high affinity, prevents PACAP from activating its receptors, and prevents PACAP-induced arterial dilation in humans. Prior to HOPE, the agent showed promising target engagement in a phase 1 study of healthy volunteers, as well as experiments in animal models.

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In the study, participants received Lu AG09222 or placebo at baseline visit by means of a one-time intravenous infusion. At baseline, the mean number of headache days per month was 17.4, the mean number of migraine days per month was 16.7, and the mean number of days per month in which medications for the treatment of headache or migraine were used was 13.1. All the participants took concomitant medications during the trial, with no clinically relevant differences among the trial groups in their use.

A reduction in at least 50% in the number of migraine days per month was found in 32% of patients in the 750 mg Lu AG09222 group vs 27% of those on placebo. The mean change from baseline in the number of headache days per month over the 4-week treatment period were –5.8 days in the higher dose Lu AG09222 group vs –4.1 days in the placebo group (difference, –1.7 days; 95% CI, –3.5 to 0.0). In addition, for the 750 mg Lu AG09222 group, investigators recorded a mean change of –5.1 days in the number of days per month in which medications for the treatment of headache or migraine were used. In comparison, those on placebo saw changes of –3.4 days (difference, –1.7 days; 95% CI, –3.0 to –0.3).

In terms of safety, the most common adverse events (AEs) that started or increased in intensity on or after the date of the infusion were coronavirus disease 2019, nasopharyngitis, and fatigue. Notably, There was one serious adverse event in the Lu AG09222 750-mg group, which was identified as sympathetic posterior cervical syndrome and reported 1 month after the infusion. This event was deemed by the investigator to be unrelated to Lu AG09222; the participant had a preexisting medical history of vertebrogenic pain syndrome.

The study was limited, as it was a proof-of-concept trial with small sample size, short treatment duration and follow-up, and patients only received 1 dose of the study drug. Investigators concluded that the findings may not be fully generalizable to the broader population of persons with migraine given that the trial population was predominantly White and from European countries. Lastly, the study did not include those with clinically significant cardiovascular disease or other confounding health issues, and thus, the findings may not be indicative of efficacy or safety in all patients with migraine.

Earlier this year, Lundbeck announced the initiation of a phase 2 study further testing Lu AG09222 as a potential migraine preventive. Dubbed PROCEED, the double-blind, placebo-controlled, dose-finding study is expected to include 498 patients and is intended to establish the optimal dose for future global pivotal trials. The trial, which tests 4 different doses of Lu AG09222 vs placebo, is expected to complete in the second half of 2025.²

REFERENCES
1. Ashina M, Phul R, Khodaie M, Lof E, Florea I. A monoclonal antibody to PACAP for migraine prevention. NEJM. 2024;391:800-9. doi:10.1056/NEJMoa2314577
2. Lundbeck’s potential first-in-class therapy for migraine prevention enters advanced clinical stage. News release. Lundbeck. March 15, 2024. Accessed September 10, 2024. https://mb.cision.com/Main/18215/3945776/2669590.pdf