HOPE
A Monoclonal Antibody to PACAP for Migraine Prevention
Clinical Question
Does a single intravenous infusion of Lu AG09222, an anti-PACAP monoclonal antibody, reduce migraine days in patients with prior preventive treatment failures?
Study Overview
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
- Single 750-mg infusion of Lu AG09222 reduced migraine days by −6.2/month vs −4.2 with placebo (difference −2.0 days; 95% CI −3.8 to −0.3; P=0.02) over weeks 1–4
- ≥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.
Patients per Arm
750 mg: 97; 100 mg: 46; Placebo: 94
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
Design
Study Type: Phase 2a, multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial
Randomization: 1
Blinding: Double-blind (participants and assessing personnel; preparation personnel were unblinded)
Allocation: 2:1:2 (750 mg : 100 mg : placebo) via interactive-response technology, stratified by region and CAPS score
Follow-up Duration: 12 weeks total (4-week treatment + 8-week safety follow-up)
Centers: 25
Countries: Europe, North America
Sample Size: 237
Analyzed: 233
Analysis: All-participants-treated population for primary endpoint; ANCOVA with baseline migraine days as covariate; multiple imputation for missing data
Power Calculation: 86 participants per group (750 mg and placebo) provided ≥80% power at one-sided 5% significance to detect treatment effect of ≥2.1 days; 5% dropout assumed; total planned N=230
Registration: NCT05133323
Inclusion Criteria
- Age 18 to 65 years
- Diagnosis of migraine without aura, with aura, or chronic migraine per ICHD-3
- Migraine onset at age 50 or younger
- At least 8 migraine days during 4-week screening period
- Documented failure of 2 to 4 preventive migraine medications within past 10 years (due to inadequate efficacy, safety, or contraindications)
Exclusion Criteria
- Personal history of any headache disorder other than migraine
- Previous receipt of monoclonal antibody targeting PACAP ligand
- History of confounding or clinically significant pain disorder (e.g., fibromyalgia, chronic low back pain, complex regional pain syndrome)
Arms
| Field | Lu AG09222 750 mg | Lu AG09222 100 mg | Control |
|---|---|---|---|
| N | 97 | 46 | 94 |
| Intervention | Single intravenous infusion of Lu AG09222 750 mg in 100 mL of 0.9% saline over ~30 minutes at baseline | Single intravenous infusion of Lu AG09222 100 mg in 100 mL of 0.9% saline over ~30 minutes at baseline (exploratory) | Single intravenous infusion of 100 mL of 0.9% normal saline over ~30 minutes at baseline |
| Duration | Single dose; 12-week observation | Single dose; 12-week observation | Single dose; 12-week observation |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Mean change from baseline in number of migraine days per month, Lu AG09222 750 mg vs placebo | Primary | −4.2 days | −6.2 days | −2.0 days | 0.02 |
| ≥50% reduction from baseline in monthly migraine days | Secondary | 27% | 32% | ||
| Mean change from baseline in monthly headache days | Secondary | −4.1 days | −5.8 days | −1.7 days | |
| Mean change from baseline in monthly migraine attacks (exploratory) | Secondary | −3.1 attacks | −4.7 attacks | −1.7 attacks | |
| Mean change from baseline in monthly headache episodes (exploratory) | Secondary | −3.0 episodes | −4.4 episodes | −1.4 episodes | |
| Mean change from baseline in monthly days using acute headache/migraine medication (exploratory) | Secondary | −3.4 days | −5.1 days | ||
| One serious adverse event (sympathetic posterior cervical syndrome) in 750-mg group, deemed unrelated to Lu AG09222 | Safety | ||||
| No adverse events led to withdrawal or interruption of infusion | Safety | ||||
| Safety also assessed by vital signs, lab values, antidrug/neutralizing antibodies, and Columbia–Suicide Severity Rating Scale | Safety | ||||
| COVID-19 (Lu AG09222 750 mg vs placebo) | Adverse | 7% vs 3% | |||
| Nasopharyngitis (Lu AG09222 750 mg vs placebo) | Adverse | 7% vs 4% | |||
| Fatigue (Lu AG09222 750 mg vs placebo) | Adverse | 5% vs 1% | |||
| Serious adverse events | Adverse | 1 (sympathetic posterior cervical syndrome, unrelated) | |||
Subgroup Analysis
Stratified by type of migraine (episodic vs chronic) and CAPS score (>0 vs 0); detailed subgroup results not provided in abstract
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
Funding
H. Lundbeck (sole sponsor and data owner)
Based on: HOPE (New England Journal of Medicine, 2024)
Authors: Ashina M, Phul R, Khodaie M, ..., Florea I
Citation: N Engl J Med 2024;391:800-9
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