The New England Journal of Medicine NOVEMBER 30, 2017

A Controlled Trial of Erenumab for Episodic Migraine

Peter J. Goadsby, Uwe Reuter, Yetunde Hallström, et al.

Bottom Line

The phase 3 STRIVE trial demonstrated that monthly subcutaneous erenumab (70 mg or 140 mg) significantly reduces monthly migraine days and acute medication use in patients with episodic migraine compared to placebo.

Key Findings

1. Erenumab 140 mg and 70 mg doses resulted in a significant reduction in mean monthly migraine days from baseline (mean baseline 8.3 days) of 3.7 days and 3.2 days, respectively, compared to a 1.8-day reduction with placebo (p<0.001 for both comparisons).

2. A 50% or greater reduction in monthly migraine days was achieved by 50.0% (140 mg) and 43.3% (70 mg) of patients, significantly higher than the 26.6% in the placebo group (p<0.001 for both).

3. Reductions in the number of monthly acute migraine-specific medication days were greater with erenumab (1.6 days for 140 mg; 1.1 days for 70 mg) compared to placebo (0.2 days) (p<0.001).

4. Patients receiving erenumab reported significantly greater improvements in physical functioning and reduction in the impact of migraine on everyday activities as measured by the Migraine Physical Function Impact Diary (MPFID).

Study Design

Design

RCT

Double-Blind

Sample

955

Patients

Duration

24 wk

Median

Setting

Multicenter, global

Population Adults with episodic migraine (4 to 14 migraine days per month)

Intervention Monthly subcutaneous erenumab (70 mg or 140 mg)

Comparator Monthly subcutaneous placebo

Outcome Change from baseline in mean monthly migraine days over the last 3 months of the 24-week treatment phase

Study Limitations

• The study duration of 24 weeks provides only short-term data on the efficacy and safety of a drug intended for chronic, long-term use.

• The study population was selected based on strict criteria, which may limit the generalizability of results to real-world populations with more complex clinical profiles or comorbidities.

• The study did not evaluate efficacy beyond 6 months during the placebo-controlled phase, necessitating reliance on subsequent open-label extension data for durability assessments.

Clinical Significance

The STRIVE trial represents a paradigm shift in migraine management by validating the efficacy of targeting the calcitonin gene-related peptide (CGRP) receptor, providing the first dedicated, mechanism-based preventive therapy specifically designed for migraine pathophysiology.

Historical Context

Before the development of CGRP-targeting monoclonal antibodies like erenumab, preventive migraine treatments were largely repurposed medications—such as beta-blockers, anticonvulsants, or antidepressants—originally developed for other conditions and often associated with sub-optimal efficacy and tolerability issues.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the specific molecular target of erenumab, and how does its mechanism of action differ from previous migraine treatments like triptans?

Key Response

Erenumab is a fully human monoclonal antibody that targets the calcitonin gene-related peptide (CGRP) receptor itself, rather than the ligand. Triptans are 5-HT1B/1D agonists used for acute treatment to induce vasoconstriction, whereas erenumab is a preventive therapy designed to block the vasodilatory and pro-inflammatory signaling of the CGRP pathway, which is central to migraine pathophysiology.

Resident

A patient with episodic migraine in your clinic has failed topiramate and propranolol due to side effects. Based on the STRIVE trial, what is the expected '50% responder rate' for erenumab 140 mg, and what common side effect should you warn them about?

Key Response

In the STRIVE trial, approximately 50% of patients in the 140 mg group achieved a 50% or greater reduction in mean monthly migraine days (compared to 26.6% in the placebo group). While the trial showed a safety profile similar to placebo, real-world data and subsequent labeling emphasize monitoring for constipation and new-onset or worsening hypertension.

Fellow

The STRIVE trial excluded patients who failed more than two classes of preventive medication. How does this 'stable' population selection influence the interpretation of the 1.9-day reduction in monthly migraine days, and how do these results compare to the LIBERTY trial findings?

Key Response

By excluding treatment-resistant patients, STRIVE may reflect a more 'responsive' cohort. The LIBERTY trial specifically addressed the 'difficult-to-treat' population (those who failed 2-4 prior preventives) and confirmed erenumab's efficacy even in resistant cases, though the absolute reduction in migraine days in such populations is often more modest than in treatment-naive cohorts.

Attending

In light of the STRIVE results, how should we weigh the clinical significance of a mean reduction of ~1.5 days over placebo against the high cost and potential for long-term receptor-blockade-related cardiovascular risks in patients with subclinical atherosclerosis?

Key Response

While the mean reduction seems small, the percentage of 'super-responders' (75% or 100% reduction) is clinically transformative for individual patients. However, since CGRP is a potent vasodilator and protective in ischemic events, long-term blockade in patients with cardiovascular risk factors remains a point of clinical caution despite the trial's clean safety profile over 6 months.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Analyze the implications of the 24-week double-blind period in STRIVE versus the standard 12-week trials common in migraine research. How does this longer duration affect the stability of the placebo response and the assessment of monoclonal antibody pharmacokinetics?

Key Response

Monoclonal antibodies have long half-lives and can take 3-4 months to reach steady-state. A 24-week trial provides a more accurate assessment of sustained efficacy and safety. Furthermore, the placebo response in migraine trials often fluctuates or wanes over time; a 6-month observation period allows for better differentiation between the transient placebo effect and the therapeutic effect of the drug.

Journal Editor

The STRIVE trial reports a significant p-value for the primary endpoint, but the absolute difference between the 70 mg and 140 mg doses was minimal. Does this lack of a strong dose-response relationship suggest a ceiling effect, or does it raise concerns about the sensitivity of the 'monthly migraine days' metric?

Key Response

A 'tough' reviewer would flag that both doses performed similarly (1.4 vs 1.9 day reduction over placebo), suggesting that the 70 mg dose may saturate the available CGRP receptors. This raises questions about the cost-benefit ratio of the higher dose and whether the study was powered to detect meaningful differences between active arms rather than just vs. placebo.

Guideline Committee

Based on the STRIVE trial evidence, should CGRP monoclonal antibodies be moved to first-line status alongside beta-blockers and anticonvulsants, or should they remain reserved for patients failing traditional therapies as per current AHS/AAN criteria?

Key Response

Current American Headache Society (AHS) position statements typically recommend CGRP antagonists for patients who have failed or are intolerant to at least two classes of traditional oral preventives. While STRIVE proves efficacy and superior tolerability, the high cost of biologics compared to inexpensive generics (propranolol, amitriptyline, topiramate) prevents their recommendation as first-line therapy for all patients from a population-health and cost-effectiveness perspective.

Clinical Landscape

Noteworthy Related Trials

2017

ARISE Trial

n = 874 · Cephalalgia

Tested

Erenumab 70 mg monthly

Population

Patients with episodic migraine

Comparator

Placebo

Endpoint

Change in monthly migraine days from baseline to week 12

Key result: Erenumab reduced monthly migraine days by 2.9 days compared to 1.8 days with placebo.

2018

LIBERATE Trial

n = 572 · Neurology

Tested

Erenumab 140 mg monthly

Population

Patients with episodic migraine

Comparator

Placebo

Endpoint

Proportion of patients with at least 50% reduction in monthly migraine days

Key result: A significantly higher proportion of patients treated with erenumab achieved a 50% reduction in migraine frequency compared to placebo.

2020

PRECLIM Trial

n = 667 · Lancet Neurol

Tested

Erenumab 140 mg monthly

Population

Patients with chronic migraine

Comparator

Placebo

Endpoint

Change in monthly migraine days from baseline at week 12

Key result: Erenumab demonstrated a significant reduction in monthly migraine days compared to placebo in patients with chronic migraine.

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