Phase 2 PROCEED Trial of PACAP-Targeting Antibody Lu AG09222 in Migraine Announced

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The phase 2 multisite trial is expected. to include 498 patients to assess the efficacy, safety, and tolerability of Lu AG09222 as a potential migraine preventive.

Johan Luthman, executive vice president, and head of Research & Development at Lundbeck

Johan Luthman

Credit: Lundbeck

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 for patients with migraine. 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.1

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

"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."

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 patients still struggle with migraines despite their efficacy. As a neuropeptide implicated in the pathophysiology of migraine, PACAP represents a novel target to treat.

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HOPE, a multinational, multisite trial, featured 237 individuals, mainly females (87.8%) with episodic or chronic migraine who were randomized to 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. Patients 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, patients 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.

The data, presented at the 2023 International Headache Congress, showed that the therapy was safe, 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. 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. 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 PACAP38.3

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.
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.
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