PACAP-Targeted Antibody Lu AG09222 Demonstrates Positive Results in Phase 2 Migraine Trial

Johan Luthman

At the recently concluded 2023 International Headache Congress, held September 14-17, in Seoul, Korea, new data from the phase 2 HOPE trial (NCT05133323) highlighted the effects of Lu AG09222 (Lundbeck), a pituitary adenylate cyclase-activating polypeptide (PACAP)-targeting agent, as a potential preventive for migraine. All told, the trial met its primary end point, with significant between-group differences observed in the high dose group of treated patients over a 12-week double-blind period.

The multinational, multisite trial featured 237 individuals with episode or chronic migraine who failed 2-4 previous preventives and were randomized to either high (n = 97) or low dose Lu AG09222 (n = 46) or placebo (n = 94) for 4-week treatment period with 12 weeks of safety follow-up. At the end of the 4-week period, investigators observed a 2.0-day difference (95% CI, –3.5 to –0.6; P = .0106) in the reduction of monthly migraine days (MMDs) between those in the high dose treated group and placebo.

"I am proud to present these data for the first time at a key medical conference. We are committed to advancing novel and effective treatment options for the many patients still suffering from migraine and who are not sufficiently treated by current medications," Johan Luthman, executive vice president and head of Research and Development at Lundbeck, said in a statement.¹ "Lu AG09222 holds a promising position and has a good chance of being a first-in-class with this interesting mechanism."

READ MORE: Visual Hypersensitivity Positively Associated With Patient Outcomes in CGRP-Treated Individuals With Migraine

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. While calcitonin gene-related peptide (CGRP)-targeting therapies have become a standard in the migraine treatment paradigm, PACAP has emerged as neuropeptide implicated in the pathophysiology of migraine and represents a novel target to treat.

The study featured mainly females (87.8%), with 16.7 total MMDs at baseline and a mean age of 42.5 years. Over the 4-week treatment span, the change from baseline in mean MMDs was –6.2 (SE, 0.66) in the high-dose Lu AG09222 group, –6.0 (SE, 0.94) in the low dose group, and –4.2 (SE, 0.67) for those on placebo. The investigators noted that the agent was well tolerated with no safety concerns documented. In the study, the overall anti-drug antibody incidence was 11% (16 of 142) with Lu AG09222, and the presence of anti-drug antibodies did not change safety or efficacy outcomes.

At the meeting, Lundbeck also presented data from a double-blind, parallel-group, placebo-controlled, phase 1 trial (NCT049766309) highlighting the ability of Lu AG09222 to inhibit PACAP38-induced cephalic vasodilation. The trial featured 25 healthy volunteers aged 18 to 45 years who were assessed on change in superficial temporal artery (STA) diameter from 0 to 120 minutes after the start of PACAP38 infusion.

All told, the therapy was successful in demonstrating proof-of-concept in inhibiting PACAP38-induced changes in STA, the primary end point, as well as changes in facial blood flow and heart rate, 2 secondary end points. Headache intensity, an exploratory end point, showed a least square mean difference of –606 (95% CI, –1140 to –74.1; P = .0279) between placebo + PACAP38 and Lu AG09222 and PACAP38. Above all, the findings confirmed the role of PACAP in migraine pathophysiology, in addition to the established role of CGRP that is targeted by the current advanced migraine therapies.³

REFERENCES
1. Lundbeck presents clinical advances in migraine prevention with positive trial results at international headache congress. News release. Lundbeck. September 14, 2023. Accessed September 26, 2023. https://news.cision.com/h--lundbeck-a-s/r/lundbeck-presents-clinical-advances-in-migraine-prevention-with-positive-trial-results-at-internatio,c3835332
2. Ashina M, Phul R, Khodaie M, Florea I. Efficacy and safety of Lu AG09222 for migraine prevention in patients with 2-4 previous preventive treatment failures: HOPE, an interventional, randomized, double-blind, parallel-group, placebo-controlled phase 2 trial. Presented at IHC 2023; September 14-17; Seoul, South Korea.
3. Rasmussen NB, Deligiannia C, Christensen CE, et al. PACAP-targeted antibody Lu AG09222 inhibits vasodilation in healthy volunteers. Presented at IHC 2023; September 14-17; Seoul, South Korea.