PDF: Erenumab CM-MO
(2019)Objective
To determine the effect of erenumab, a human anti-CGRP receptor monoclonal antibody, in patients with chronic migraine and medication overuse, as a planned subgroup analysis of a pivotal CM prevention trial.
Study Summary
• ≥50% MMD reduction achieved by 36% (70 mg, OR 2.67 [1.36–5.22]) and 35% (140 mg, OR 2.51 [1.28–4.94]) vs 18% with placebo
• Acute migraine-specific medication treatment days fell by −5.4 (70 mg) and −4.9 (140 mg) vs −2.1 days with placebo
• Erenumab improved HIT-6, MIDAS, and MSQ scores beyond minimally important differences and shifted many patients from medication-overuse to nonoveruse status
Intervention
Subcutaneous erenumab 70 mg or 140 mg monthly vs placebo for 3 months in patients with chronic migraine, with prespecified subgroup analysis by baseline medication overuse status.
Inclusion Criteria
Adults with chronic migraine (≥15 headache days/month, ≥8 migraine days/month); medication overuse subgroup defined per IHS-style criteria as ≥15 days/month simple analgesics (>3 d/wk in each week with ≥5 diary days), ≥10 days/month triptans (>2 d/wk in each week with ≥5 diary days), or ≥10 days/month combination therapy (>3 d/wk in each week with ≥5 diary days).
Study Design
Arms: Placebo (n=286) vs Erenumab 70 mg monthly SC (n=191) vs Erenumab 140 mg monthly SC (n=190); medication overuse subgroup: Placebo n=117, Erenumab 70 mg n=79, Erenumab 140 mg n=78
Patients per Arm: Medication overuse subgroup: Placebo 117, Erenumab 70 mg 79, Erenumab 140 mg 78 (Total subgroup n=274 of 667 randomized; ITT analyzed n=656)
Outcome
• ≥50% responders (medication overuse): 36% and 35% (erenumab) vs 18% (placebo)
• Acute migraine-specific medication days: −5.4 and −4.9 vs −2.1 days; treatment differences −3.3 (70 mg) and −2.8 (140 mg)
• Transition to nonoveruse at month 3: simple analgesics 60%/71% vs 52% placebo; triptans 65%/54% vs 33% placebo; combination 45%/59% vs 40% placebo
• AE frequency similar across groups; most common erenumab AEs (≥2%) were injection-site erythema, muscle spasms, migraine, injection-site pain, constipation, cough, oropharyngeal pain, upper respiratory tract infection, nausea, and nasopharyngitis
Bottom Line
In patients with chronic migraine and medication overuse, erenumab 70 mg or 140 mg monthly approximately doubled the chance of ≥50% migraine-day reduction at 3 months (≈35% vs 18% placebo), cut monthly migraine days by ~6.6 days vs 3.5 with placebo, and meaningfully reduced acute migraine-specific medication days while improving disability and quality-of-life measures, supporting CGRP-receptor blockade as an effective preventive option in this hard-to-treat population.
Major Points
- 274 of 667 randomized CM patients (41%) met medication overuse criteria; this subgroup had higher baseline MMD (19.0 vs 17.3) and more prior preventive failures (75% vs 63%).
- At month 3, erenumab 70 mg and 140 mg both reduced MMD by −6.6 days vs −3.5 days with placebo in the medication-overuse subgroup (treatment difference −3.1 days, 95% CI −4.8 to −1.4).
- ≥50% MMD responder rates in the medication-overuse subgroup: 36% (70 mg, OR 2.67 [1.36–5.22]) and 35% (140 mg, OR 2.51 [1.28–4.94]) vs 18% (placebo).
- Acute migraine-specific medication days fell by −5.4 (70 mg) and −4.9 (140 mg) vs −2.1 days (placebo) in the medication-overuse subgroup.
- Substantial transition from overuse to nonoveruse status at month 3 with erenumab, particularly for simple analgesics (60%/71% vs 52% placebo) and triptans (65%/54% vs 33% placebo).
- HIT-6, MIDAS, and MSQ Role Function–Restrictive and Emotional Functioning scores improved beyond minimally important differences in both subgroups.
- Effects in the medication-overuse subgroup were similar in magnitude to those in the non–medication-overuse subgroup; safety profile mirrored the parent trial.
- Class II evidence that erenumab reduces MMD at 3 months in CM with medication overuse.
Study Design
- Study Type
- Preplanned subgroup analysis of a phase 2 randomized, double-blind, placebo-controlled trial in chronic migraine
- Randomization
- Yes
- Blinding
- Double-blind (patient and investigator)
- Sample Size
- 667
- Follow-up
- 3-month double-blind treatment phase
- Centers
- 69
Primary Outcome
Definition: Change from baseline in monthly migraine days (MMD) at month 3 in patients with chronic migraine and medication overuse
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo: −3.5 days (95% CI −4.6 to −2.4) | Erenumab 70 mg: −6.6 days (−8.0 to −5.3); Erenumab 140 mg: −6.6 days (−8.0 to −5.3) | - (−4.8 to −1.4 (treatment difference, medication overuse subgroup)) |
Limitations & Criticisms
- Subgroup analysis with no adjustment of p values for multiple comparisons; some analyses (PROs by overuse subgroup, overuse-by-visit) were post hoc
- Short 3-month double-blind phase limits assessment of durability and long-term safety
- Patients on opioid overuse and those on concurrent preventives were excluded, limiting generalizability to a subset of real-world refractory CM patients
- Industry-sponsored (Amgen) with multiple Amgen-employed authors
Citation
Neurology 2019;92:e2309-e2320. doi:10.1212/WNL.0000000000007497