New Monoclonal Antibody Class Shows Promise for Migraine

A potential first-in-class therapy for migraine prevention has shown promise in a phase 2a proof-of-concept study, with a single infusion reducing migraine frequency over 4 weeks.

The drug Lu AG09222 from Lundbeck is an investigational monoclonal antibody that targets a pathway in migraine that is distinct from pathways targeted by the calcitonin gene-related peptide (CGRP) migraine treatment drug class. It binds and inhibits pituitary adenylate cyclase–activating polypeptide (PACAP), a neuropeptide implicated in migraine pathophysiology.

Results of the HOPE trial “support the concept that targeting PACAP signaling with Lu AG09222 could be an effective new approach for migraine prevention,” lead author Messoud Ashina, MD, professor of neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, told Medscape Medical News.

“Lu AG09222 is novel because it targets the PACAP ligand itself, rather than specific PACAP receptors,” Ashina explained. “This approach avoids the complexities of identifying which PACAP receptor(s) are involved in migraine, offering a potentially more direct and effective mechanism for treatment.” 

Results of the HOPE trial were published online on September 4, 2024, in The New England Journal of Medicine.

Proof-of-Concept

Results from an earlier phase 1 trial in healthy individuals showed that the investigational drug inhibited physiological responses mediated by PACAP and reduced concomitant headache. Based on those results, investigators designed a proof-of-concept study to analyze the drug’s efficacy and safety in individuals with migraine.

This international, double-blind, randomized, placebo-controlled trial enrolled 237 adults (mean age, 42.5 years, 88% women) who had failed two to four previous preventive migraine treatments. Participants had a substantial headache burden at baseline, with a mean of 16.7 migraine days per month, documented via an electronic headache diary during a 4-week run-in period.

Participants received a single IV infusion of Lu AG0922 (750 mg or 100 mg) or placebo. The primary endpoint was the mean change from baseline in the number of monthly migraine days during weeks 1 through 4 in the Lu AG09222 750 mg group vs the placebo group. The 100 mg group was included for exploratory purposes only, to evaluate dose range for future studies.

The 750 mg infusion of the antibody, given over a period of 30 min, reduced the number of migraine days per month by 6.2 days, as compared with a reduction of 4.2 days with the placebo infusion (difference, −2.0 days; 95% CI, −3.8 to −0.3; P = .02).

Additionally, a greater percentage of patients in the Lu AG09222 750 mg group had at least a 50% reduction from baseline in the number of migraine days per month compared with the placebo group (32% vs 27%, respectively).

Adverse events with a higher incidence in the Lu AG09222 750 mg group vs the placebo group during the 12-week observation period included nasopharyngitis (7% vs 4%), fatigue (5% vs 1%), and COVID-19 (7% vs 3%).

Overall, most adverse events were mild. Antidrug antibodies developed in 12% and 9% of patients in the 750 mg and 100 mg Lu AG09222 groups, respectively.

As this was a proof-of-concept trial, the number of participants was small, the trial was short in duration and follow-up, participants received only one dose of Lu AG09222, and people with clinically significant cardiovascular disease or other confounding health issues were excluded, the study team cautioned.

Based on the positive HOPE trial results, Lundbeck has initiated the PROCEED phase 2b study testing the efficacy and safety of a subcutaneous injection of Lu AG09222 for the prevention of migraine.

Important Validation 

In an accompanying editorial, Elizabeth Loder, MD, MPH, with Brigham and Women’s Hospital, Boston, noted that the HOPE trial helps validate the PACAP strategy for migraine prevention.

“Although caution is advisable when results across trials are compared, the modest between-group difference of 2 migraine days per month observed in the current trial is similar to the results of trials of the CGRP monoclonal antibodies and lower than the difference observed with some established nonantibody preventive treatments for migraine, such as onabotulinum toxin A or topiramate,” Loder wrote.

At the same time, Loder said it’s important not to dismiss this result, even if it is less than hoped. “An average of 2 fewer migraine days a month might not seem like much, but over a year that adds up to almost a month of better quality life,” she noted.

“Even if a new PACAP antibody is not more effective than existing treatments, its arrival is still valuable. It is always good news when another potential target for migraine is identified and proves amenable to treatment. Partial efficacy is the rule for preventive migraine treatments, and this new monoclonal antibody is no exception,” Loder added.

The HOPE trial was supported by H. Lundbeck A/S. Ashina reported receiving consulting, speaker, and/or advisory board fees from AbbVie, Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, H. Lundbeck A/S, Novartis, Pfizer, and Teva Pharmaceutical Industries. Loder reported serving as a medical editor for the British Medical Association and is a member of the Headache Cooperative of the Northeast. Full disclosures are available in the original articles on NEJM.org.