Novel Agent Shows Superiority Over Placebo in Reducing Monthly Migraine Days
Lu AG09222 shows promise as first-in-class medication that prevents neurogenic inflammation, vasodilation, and parasympathetic lacrimation, which are considered to be surrogate markers of migraine attacks.
Image credit: Damir Khabirov | stock.adobe.com
A single intravenous (IV) infusion of Lundbeck’s investigational agent Lu AG09222 achieved superiority over placebo in lowering the frequency of migraine headaches over the following four weeks, according to the results of the Phase IIa HOPEtrial (NCT05133323) published by The New England Journal of Medicine.1,2 Lu AG09222, pituitary adenylate cyclase-activating polypeptide (PACAP)-targeting therapy, demonstrated efficacy for this patient population in prior clinical research.3
“Experimental studies have shown that intravenous infusion of PACAP induces migraine attacks in persons with migraine. Blocking PACAP signaling may therefore constitute a promising drug target for migraine prevention,” the study authors wrote. “Lu AG09222 is a humanized monoclonal antibody that binds to both isoforms of PACAP and inhibits their receptor-mediated signaling. Experiments in animals have shown that Lu AG09222 prevents neurogenic inflammation, vasodilation, and parasympathetic lacrimation, which are considered to be surrogate markers of migraine in rodent models. Furthermore, a recent phase I trial involving healthy volunteers showed that pretreatment with Lu AG09222 can inhibit PACAP-induced dilation of cranial arteries and reduce concomitant headache.”1
Lu AG09222 is delivered via IV infusion and binds to the PACAP ligand with high affinity, thereby inhibiting PACAP from activating its receptors and stopping PACAP-induced arterial dilation.3
"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,” said Johan Luthman, executive vice president, and head of Research and Development at Lundbeck, in a prior press release. "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."3
The multicenter, double-blind, randomized, placebo-controlled HOPE trial screened 337 adults, aged 18 to 65 years, of whom 237 underwent randomization and 233 were included in the full analysis population. Investigators sought to determine whether inhibiting PACAP signaling with Lu AG09222 is effective in migraine prevention.
Patients were randomly assigned in a 2:1:2 ratio to receive either 750 mg of Lu AG09222, 100 mg of Lu AG09222, or placebo. The trial’s primary endpoint was mean change from baseline in number of monthly migraine days during weeks one through four in the Lu AG09222 750 mg cohort compared to placebo.
Among the participants, 97 were administered 750 mg of Lu AG09222, 46 were administered 100 mg of Lu AG09222, and 94 were administered placebo. In the overall trial population, the mean number of baseline migraine days per month was 16.7. Mean change from baseline from weeks one through four was −6.2 days in the Lu AG09222 750 mg cohort compared to −4.2 days in the placebo cohort (difference, −2.0 days; 95% confidence interval, −3.8 to −0.3; P=0.02).
In terms of safety, there were a higher incidence of adverse events (AEs) in the Lu AG09222 750 mg cohort compared to placebo across the 12-week observation period. The most frequently reported AEs included COVID-19 (7% in the treatment cohort vs. 3% with placebo), nasopharyngitis (7% vs. 4%), and fatigue (5% vs. 1%).
“In this trial involving persons with migraine, a one-time 750-mg infusion of Lu AG09222 showed superiority over placebo in reducing the number of migraine days per month over the subsequent 4 weeks,” the study authors concluded. “This finding establishes proof of concept, supporting the notion that inhibition of PACAP signaling by Lu AG09222 represents a potentially effective mechanism for migraine prevention. Longer trials are warranted to ascertain the efficacy and safety of Lu AG09222 in persons with migraine.”1
References
1. Ashina, M., et al. A Monoclonal Antibody to PACAP for Migraine Prevention. Published September 4, 2024. N Engl J Med 2024;391:800-809. DOI: 10.1056/NEJMoa2314577. Vol. 391 No. 9.
2. A Study With Lu AG09222 in Adults With Migraine Who Have Not Been Helped by Prior Preventive Treatments. ClinicalTrials.gov. March 13, 2024. Accessed September 5, 2024. https://clinicaltrials.gov/study/NCT05133323
3. Lundbeck’s potential first-in-class therapy for migraine prevention enters advanced clinical stage. News release. Lundbeck. March 15, 2024. Accessed September 5, 2024. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://mb.cision.com/Main/18215/3945776/2669590.pdf
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