HOPE
(2024)Objective
To evaluate the efficacy and safety of intravenous Lu AG09222, a humanized monoclonal antibody targeting the PACAP ligand, for migraine prevention in adults with prior preventive treatment failures.
Study Summary
• ≥50% reduction in migraine days achieved in 32% (Lu AG09222 750 mg) vs 27% (placebo)
• Headache days fell by −5.8 vs −4.1 days/month (difference −1.7; 95% CI −3.5 to 0.0)
• Migraine attacks decreased by −4.7 vs −3.1/month (difference −1.7; 95% CI −2.9 to −0.4)
• More frequent adverse events with 750 mg vs placebo: COVID-19 (7% vs 3%), nasopharyngitis (7% vs 4%), fatigue (5% vs 1%); one unrelated serious adverse event
Intervention
Single intravenous infusion of Lu AG09222 (750 mg or 100 mg) vs placebo, administered over 30 minutes at baseline, with 4-week treatment and 8-week follow-up periods.
Inclusion Criteria
Adults 18–65 years with migraine without aura, with aura, or chronic migraine (ICHD-3); migraine onset by age 50; ≥8 migraine days during 4-week screening; documented failure of 2–4 preventive migraine medications within the past 10 years.
Study Design
Arms: Lu AG09222 750 mg IV (n=97) vs Lu AG09222 100 mg IV (n=46) vs Placebo IV (n=94)
Patients per Arm: 750 mg: 97; 100 mg: 46; Placebo: 94
Outcome
• ≥50% migraine-day responder rate: 32% vs 27% (750 mg vs placebo)
• Headache day reduction: −5.8 vs −4.1 days/month
• Adverse events more common with 750 mg: COVID-19 (7%), nasopharyngitis (7%), fatigue (5%)
• One serious adverse event (sympathetic posterior cervical syndrome) deemed unrelated to drug
Bottom Line
In this phase 2 proof-of-concept trial, a single 750-mg IV infusion of the anti-PACAP monoclonal antibody Lu AG09222 reduced monthly migraine days by 2.0 days more than placebo over the subsequent 4 weeks, supporting PACAP inhibition as a viable mechanism for migraine prevention and warranting larger phase 3 trials.
Major Points
- First randomized trial showing efficacy of PACAP-targeted monoclonal antibody therapy in migraine prevention
- Single 750-mg IV infusion of Lu AG09222 reduced migraine days by −6.2 vs −4.2 with placebo (difference −2.0 days; 95% CI −3.8 to −0.3; P=0.02)
- ≥50% responder rate was 32% with 750 mg vs 27% with placebo
- Headache days reduced by −5.8 vs −4.1 days/month (difference −1.7; 95% CI −3.5 to 0.0)
- Drug was generally well tolerated; most common adverse events were COVID-19 (7%), nasopharyngitis (7%), and fatigue (5%) in 750-mg group
- Provides clinical proof-of-concept that PACAP signaling is a viable migraine drug target distinct from CGRP
Study Design
- Study Type
- Phase 2a, multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial
- Randomization
- Yes
- Blinding
- Double-blind (participants and assessing personnel; preparation personnel were unblinded)
- Sample Size
- 237
- Follow-up
- 12 weeks total (4-week treatment + 8-week safety follow-up)
- Centers
- 25
- Countries
- Europe, North America
Primary Outcome
Definition: Mean change from baseline in number of migraine days per month, Lu AG09222 750 mg vs placebo
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| −4.2 days | −6.2 days | - (−3.8 to −0.3) | 0.02 |
Limitations & Criticisms
- Phase 2a proof-of-concept with modest sample size (n=237)
- Short follow-up — only 4-week primary endpoint window after a single infusion
- Population was 100% White and predominantly female, limiting generalizability
- Only 25 sites, limited geographic representation
- Modest absolute treatment effect (−2.0 days/month) and small responder-rate difference (32% vs 27%)
- No formal power calculation or multiplicity correction for the 100-mg arm or secondary endpoints
- Industry-sponsored with sponsor controlling data and protocol
Citation
N Engl J Med 2024;391:800-9