Lundbeck Moves PACAP-Targeting Antibody into Multinational Phase 2b Clinical Trial

Lundbeck has announced the initiation of a phase 2 trial, dubbed PROCEED, that will assess its investigational agent Lu AG09222, a pituitary adenylate cyclase-activating polypeptide (PACAP)-targeting therapy, as a potential preventive treatment for individuals with migraine. The double-blind, placebo-controlled, dose-finding study is expected to include 498 participants and is intended to establish the optimal dose for future global pivotal trials.¹

_{^{©mopic/shutterstock.com}}

PROCEED, which will span Europe, Japan, and the US, is expected to conclude in the second half of 2025. The trial will assess 4 different doses of Lu AG09222 vs placebo, administered subcutaneously once monthly for 3 months, in participants with migraine who have failed to respond to 2-4 different preventive migraine medications in the past 10 years.¹ It acts as a follow-up to the HOPE trial (NCT05133323), a successful phase 2, proof-of-concept study that first demonstrated the effects of Lu AG09222 in this patient population.¹

"Initiation of this phase IIb trial of Lu AG09222 further progresses our neurology pipeline and emphasizes Lundbeck’s commitment to people living with migraine and headache-related disorders,” Johan Luthman, executive vice president, and head of Research & Development at Lundbeck, said in a statement.¹ "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."¹

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. In recent years, the emergence of calcitonin gene-related peptide (CGRP)-targeting therapies have become a standard of care; however, some participants still struggle with migraines despite their efficacy. As a neuropeptide implicated in the pathophysiology of migraine, PACAP represents a novel target to treat.¹

The HOPE trial, presented at the 2023 International Headache Congress,² was a multinational, multisite study featuring 237 individuals, mainly women (87.8%) with episodic or chronic migraine who were randomly assigned to receive either high (n = 97) or low dose Lu AG09222 (n = 46) or placebo (n = 94) for a 4-week treatment period, followed by a 12-week safety follow-up.² Participants had a mean age of 42.5 years and 16.7 monthly migraine days (MMDs) at baseline. At the conclusion of the 4-week time point, participants in the high-dose active group demonstrated a 2.0-day difference (95% CI, –3.5 to –0.6; P = .0106) in the reduction of MMDs.²

The final data showed no safety concerns documented. In the study, the overall antidrug antibody incidence was 11% (16 of 142) with Lu AG09222, and the presence of antidrug antibodies did not change safety or efficacy outcomes.² Overall, 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.²

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.³ 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.³

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 PACAP38.³

REFERENCES
1. Lundbeck’s potential first-in-class therapy for migraine prevention enters advanced clinical stage. News release. Lundbeck. March 15, 2024. Accessed March 15, 2024. https://news.cision.com/h--lundbeck-a-s/r/lundbeck-s-potential-first-in-class-therapy-for-migraine-prevention-enters-advanced-clinical-stage,c3945776

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.