RCT: PACAP Monoclonal Antibody Lu AG09222 Reduced Migraine Days in Patients with Refractory Migraine
20 Sep, 2024 | 17:56h | UTCBackground: Migraine affects approximately 1 billion people worldwide and is a leading cause of disability. While calcitonin gene–related peptide (CGRP)-targeted therapies have advanced migraine prevention, many patients do not achieve sufficient benefit. Pituitary adenylate cyclase–activating polypeptide (PACAP) is implicated in migraine pathogenesis, and blocking its signaling may offer a new therapeutic target.
Objective: To assess the efficacy and safety of Lu AG09222, a monoclonal antibody against PACAP, for migraine prevention in adults who failed two to four prior preventive treatments.
Methods: In a phase 2, double-blind, randomized, placebo-controlled trial (HOPE), 237 adults aged 18–65 years with migraine (mean baseline of 16.7 migraine days per month) were randomized 2:1:2 to receive a single intravenous infusion of 750 mg Lu AG09222, 100 mg Lu AG09222, or placebo. The primary endpoint was the mean change from baseline in migraine days per month over weeks 1–4 in the 750 mg Lu AG09222 group compared to placebo. Secondary endpoints included the proportion achieving ≥50% reduction in migraine days per month and change in headache days per month.
Results: Of 237 participants, 97 received 750 mg Lu AG09222, 46 received 100 mg, and 94 received placebo. Over weeks 1–4, the 750 mg Lu AG09222 group had a mean reduction of 6.2 migraine days per month versus 4.2 days in the placebo group (difference –2.0 days; 95% CI, –3.8 to –0.3; P=0.02). A ≥50% reduction in migraine days per month was achieved by 32% in the 750 mg group versus 27% with placebo. The most common adverse events in the 750 mg group compared to placebo were COVID-19 (7% vs 3%), nasopharyngitis (7% vs 4%), and fatigue (5% vs 1%).
Conclusions: A single intravenous infusion of 750 mg Lu AG09222 significantly reduced migraine frequency over 4 weeks compared to placebo in patients with migraine refractory to prior preventive treatments.
Implications for Practice: Lu AG09222, by targeting PACAP signaling, may provide a novel preventive therapy for patients who have not responded to existing treatments, including CGRP antagonists.
Study Strengths and Limitations: Strengths include the randomized, double-blind, placebo-controlled design. Limitations encompass the short trial duration, small sample size, single-dose administration, predominantly White and European study population, and exclusion of patients with significant cardiovascular disease.
Future Research: Long-term studies are needed to evaluate the sustained efficacy and safety of Lu AG09222, optimal dosing strategies, and its effectiveness in diverse patient populations.