Investigational PACAP Inhibitor Reduces Monthly Migraine Days, Lundbeck Reports

A single intravenous infusion of Lu AG0922, a novel investigational pituitary adenylate cyclase-activating polypeptide (PACAP)-targeting therapy, reduced migraine frequency over 4 weeks compared with placebo in adults with migraine who had not achieved benefit from between 2 and 4 previous treatments.¹

Targeting PACAP is “a new avenue for treating migraine,” wrote investigators in the New England Journal of Medicine, and the current study is part of a clinical trial program to determine whether inhibition of PACAP signaling is a safe and effective mechanism for migraine prevention.¹

"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, and colleagues 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."¹

HOPE proof-of-concept trial

In the HOPE trial, Ashina and team enrolled 237 adults (mean age, 42.5 years, 88% women) with migraine for whom 2 to 4 preventive migraine therapies had not provided relief. Participants were randomly assigned 2:1:2 to receive a single dose baseline infusion of Lu AG09222 750 mg (n = 97), Lu AG09222 100 mg (n = 46; to evaluate dose range only), or placebo (n = 94).¹ The primary endpoint of interest was mean change from baseline to week 4 in the number of migraine days per month withLu AG09222 750 mg vs with placebo. At 4 weeks post-infusion, according to investigators, the active treatment group had a mean change in migraine days per month of –6.2 compared with a mean –4.2 days for participants in the placebo group (difference –2.0 days; 95% CI, –3.8 to –0.3; P = .02). At the end of the 4 weeks, participants entered an 8-week follow-up period.¹

At study baseline, participants reported a mean 17.4 headache days per month, 16.7 migraine days per month, and use of medications to treat headache or migraine on an average of 13.1 days per month. Participants were permitted to use concomitant medications during the trial and the researchers reported no clinically relevant differences among the groups in their use.¹

Ashina and colleagues reported that 32% of participants who received 750 mg of Lu AG0922 had a reduction of at least 50% in the number of migraine days per month compared with just 27% of those who were given a placebo infusion.

Participants in the higher dose Lu AG09222 group reported an average of 5.8 fewer headache (vs migraine) days over the 4-week period compared with 4.1 fewer days among participants in the placebo group (difference, –1.7 days; 95% CI, –3.5 to 0.0),¹ according to the study. In addition, for those in the 750 mg Lu AG09222-dose group, investigators recorded a mean change of –5.1 in the number of days per month on which participants used medications to treat headache or migraine. Participants in the placebo group, in comparison, used medications on 3.4 fewer days (difference, –1.7 days; 95% CI, –3.0 to –0.3).¹

In their evaluation of Lu AG09222 safety, the research team found the most common adverse events (AEs) that started or increased in intensity on or after the date of infusion were COVID-19, nasopharyngitis, and fatigue; AEs overall were described as “mild.”¹

As a proof-of-concept study, the authors note, the HOPE trial had several limitations including small size, limited follow-up, and a single dose of the study drug administered. In addition, the trial did not include individuals with potentially confounding health issues, including cardiovascular disease, and enrolled a homogenous population, both of these facts limiting the generalizability of the findings outside of the study.¹

PROCEED phase 2 dose-finding trial

Earlier this year, Lundbeck announced the initiation of a phase 2 study to further evaluate Lu AG09222 as a potential migraine preventive. The PROCEED trial, a double-blind, placebo-controlled, dose-finding study, will evaluate the efficacy and safety of a subcutaneous injection of LuAG09222.² The company expects to enroll 498 participants in PROCEED to establish the optimal dose for future global pivotal trials. The trial, which evaluates 4 different doses of Lu AG09222 vs placebo and will be conducted across Europe, the US, and Japan, is expected to complete in the second half of 2025.²

"The diverse nature of the disease highlights the need for exploring novel therapeutic approaches that can address unmet needs. Lu AG09222 has a good chance of being first-in- class with this interesting mechanism"2 Johan Luthman, executive vice president, and head of research and development at Lundbeck, said in a previous Lundbeck statement.²

References

1. Ashina M, Phul R, Khodaie M, Lof E, Florea I. A monoclonal antibody to PACAP for migraine prevention. New Engl J Med. 2024;391:800-9. doi:10.1056/NEJMoa2314577

2. Meglio M. Lundbeck moves PACAP-targeting antibody into multinational phase 2b clinical trial. Patient Care. March 18, 2024. https://www.patientcareonline.com/view/lundbeck-moves-pacap-targeting-antibody-into-multinational-phase-2b-clinical-trial