New England Journal of Medicine November 30, 2017

A Controlled Trial of Erenumab for Episodic Migraine

Peter J Goadsby et al.

Bottom Line

Erenumab, a monoclonal antibody targeting the CGRP receptor, significantly reduced monthly migraine days and acute medication use over 6 months in patients with episodic migraine.

Key Findings

1. From a baseline of 8.3 mean migraine days per month, erenumab reduced migraine days by 3.2 days (70 mg) and 3.7 days (140 mg), compared to 1.8 days for placebo (P<0.001 for both comparisons).

2. A 50% or greater reduction in monthly migraine days was achieved by 43.3% of the 70-mg group and 50.0% of the 140-mg group, compared to 26.6% of the placebo group (P<0.001).

3. Erenumab significantly improved physical impairment and everyday activities scores on the Migraine Physical Function Impact Diary compared to placebo.

4. The safety and tolerability profile of both erenumab doses was comparable to placebo, with overall adverse events and treatment discontinuation rates (2.2% for erenumab vs 2.5% for placebo) being similar.

Study Design

Design

RCT

Double-Blind

Sample

955

Patients

Duration

6 mo

Median

Setting

Multinational

Population Adults aged 18 to 65 years with a history of episodic migraine, experiencing 4 to 14 migraine days per month.

Intervention Erenumab administered as a monthly subcutaneous injection at a dose of either 70 mg or 140 mg for 6 months.

Comparator Matching placebo administered as a monthly subcutaneous injection for 6 months.

Outcome Change from baseline to months 4 through 6 in the mean number of migraine days per month.

Study Limitations

• The 6-month trial duration was relatively short, requiring longer extension phases to thoroughly assess long-term safety, durability of efficacy, and rare adverse events.

• Patients who had failed more than two previous classes of preventive migraine treatments were excluded, limiting generalizability to highly treatment-refractory populations.

• The study cohort was predominantly White and female, potentially limiting the extrapolation of findings across diverse demographic groups.

• The trial compared erenumab only to placebo, lacking a head-to-head comparison with established oral preventive therapies.

Clinical Significance

The STRIVE trial provided pivotal phase III evidence that targeting the CGRP receptor with erenumab is a safe and highly effective strategy for episodic migraine prevention. This ushered in a paradigm shift in headache medicine, moving the standard of care away from repurposed daily oral medications (such as beta-blockers and anticonvulsants), which often suffered from poor adherence due to systemic side effects, toward disease-specific, once-monthly biological therapies.

Historical Context

For decades, migraine prophylaxis relied heavily on serendipitously discovered, non-specific oral drugs (like amitriptyline, propranolol, and topiramate). The physiological understanding that calcitonin gene-related peptide (CGRP) levels spike during migraine attacks and that infused CGRP can trigger migraines paved the way for targeted therapeutic development. Erenumab was the first fully human monoclonal antibody designed to block the CGRP receptor to complete phase III trials. Its success in the STRIVE trial directly led to its FDA approval in 2018 (as Aimovig), making it the first-in-class CGRP-targeted preventive treatment for migraine.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the pathophysiological role of CGRP in migraine, and how does erenumab's mechanism of action differ from triptans and other newer monoclonal antibodies (like galcanezumab)?

Key Response

Tests foundational knowledge of migraine pathophysiology. CGRP is a potent vasodilator and pain-signaling neuropeptide released from the trigeminal nerve. Triptans are 5-HT1B/1D agonists that indirectly inhibit CGRP release, whereas erenumab specifically blocks the CGRP receptor (unlike galcanezumab, which binds the CGRP ligand).

Resident

When considering prophylactic therapy for a patient with episodic migraine, what specific patient characteristics or past treatment failures would prompt you to prescribe erenumab over traditional oral preventatives like topiramate or propranolol?

Key Response

Focuses on clinical decision-making. Standard oral prophylactics are often first-line due to cost and guidelines, but erenumab is ideal for patients who have failed or have contraindications/intolerance to multiple traditional classes, given its high efficacy, monthly subcutaneous dosing, and favorable adverse effect profile.

Fellow

In patients responding to erenumab, the STRIVE trial showed a reduction in acute migraine-specific medication use. How does the presence of medication overuse headache (MOH) at baseline impact the efficacy of CGRP receptor antagonism, and how should this influence our approach to withdrawal versus concurrent preventative initiation?

Key Response

Digs into a complex subspecialty issue. Traditional teaching required withdrawal of overused acute medications first. However, evidence from CGRP trials suggests these biologics can be effective even in the presence of MOH, allowing for concurrent initiation and organic reduction in acute medication use without a strict pre-withdrawal phase.

Attending

Considering the 6-month duration of the STRIVE trial, what are the long-term cardiovascular and gastrointestinal safety concerns of chronically blocking the CGRP receptor, a known potent vasodilator and motility regulator, particularly in our older migraine patient population?

Key Response

Evaluates long-term, real-world risks beyond the trial period. CGRP's protective vasodilatory role during ischemic events is theoretically blocked by erenumab, raising concerns for patients with vascular risk factors. Additionally, severe constipation and hypertension have emerged as post-marketing concerns, requiring clinical vigilance not fully captured in the 6-month trial window.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The STRIVE trial utilized a hierarchical testing procedure to handle multiple secondary endpoints. What are the statistical advantages and limitations of this approach in a phase 3 trial, and how might it mask or inflate the clinical relevance of patient-reported outcomes like the MPFID (Migraine Physical Function Impact Diary)?

Key Response

Explores advanced statistical methodology. Hierarchical testing controls the family-wise error rate by requiring each outcome to be significant before testing the next. However, if a higher-order endpoint fails, subsequent clinically meaningful endpoints cannot be formally claimed as statistically significant, potentially limiting the interpretation of valuable patient-reported data.

Journal Editor

The trial excluded patients with a history of poor response to more than two categories of migraine-preventive treatments. How does this exclusion criterion threaten the external validity of the study, and would a rigorous peer reviewer consider this a fatal flaw for a drug marketed primarily for refractory patients?

Key Response

Focuses on trial design and generalizability. By excluding highly refractory patients, the trial studied a less treatment-resistant population than the one likely to receive the expensive biologic in the real world (due to step-therapy insurance requirements), potentially overestimating real-world efficacy.

Guideline Committee

Based on the efficacy and safety data from the STRIVE trial, how should AHS/AAN guidelines position erenumab and other CGRP monoclonal antibodies relative to established Level A oral therapies (e.g., divalproex, topiramate, beta-blockers) in the treatment algorithm for episodic migraine?

Key Response

Connects trial data to guideline updates. Current consensus often places CGRP mAbs as second-line or for those who have failed/cannot tolerate 2 or more standard oral preventive medications, balancing the high Level A evidence of efficacy from trials like STRIVE against the high cost and lack of long-term safety data compared to traditional therapies.

Clinical Landscape

Noteworthy Related Trials

2018

HALO EM Trial

n = 875 · JAMA

Tested

Fremanezumab quarterly or monthly

Population

Patients with episodic migraine

Comparator

Placebo

Endpoint

Change in mean monthly migraine days

Key result: Fremanezumab significantly reduced the monthly average number of migraine days compared with placebo.

2018

EVOLVE-1 Trial

n = 858 · JAMA Neurol

Tested

Galcanezumab 120 mg or 240 mg monthly

Population

Patients with episodic migraine

Comparator

Placebo

Endpoint

Change in mean monthly migraine headache days

Key result: Galcanezumab demonstrated statistically significant reductions in monthly migraine headache days versus placebo.

2018

LIBERTY Trial

n = 246 · Lancet

Tested

Erenumab 140 mg monthly

Population

Episodic migraine patients with 2 to 4 prior preventive treatment failures

Comparator

Placebo

Endpoint

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

Key result: Erenumab significantly increased the odds of achieving a 50 percent or greater reduction in migraine days in a treatment-resistant population.

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