Elsevier

The Lancet

Volume 392, Issue 10161, 24–30 November 2018, Pages 2280-2287
The Lancet

Articles
Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study

https://doi.org/10.1016/S0140-6736(18)32534-0Get rights and content

Summary

Background

A substantial proportion of patients with migraine does not respond to, or cannot tolerate, oral preventive treatments. Erenumab is a novel CGRP-receptor antibody with preventive efficacy in migraine. We assessed its efficacy and tolerability in patients with episodic migraine in whom previous treatment with two-to-four migraine preventives had been unsuccessful.

Methods

LIBERTY was a 12-week, double-blind, placebo-controlled randomised study at 59 sites in 16 countries. Eligible patients were aged 18–65 years and had a history of episodic migraine with or without aura for at least 12 months, had migraine for an average of 4–14 days per month during the 3 months before screening, and had been treated unsuccessfully (in terms of either efficacy or tolerability, or both) with between two and four preventive treatments. Eligible participants were randomly assigned (1:1) to receive either erenumab 140 mg (via two 70 mg injections) or placebo every 4 weeks subcutaneously for 12 weeks. Randomisation was by interactive response technology and was stratified by monthly frequency of migraine headache (4–7 vs 8–14 migraine days per month) during the baseline phase. Cenduit generated the randomisation list and assigned participants to groups. Participants, investigators, people doing various assessments, and the study sponsor were masked to treatment assignment. The primary endpoint was the proportion of patients achieving a 50% or greater reduction in the mean number of monthly migraine days during weeks 9–12. Efficacy was measured in the full analysis set, which included all randomly assigned patients who started their assigned treatment and completed at least one post-baseline monthly migraine day measurement. Safety and tolerability were assessed by recording adverse events and by physical examination, assessment of vital signs, clinical laboratory assessments, and electrocardiography. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT03096834. The trial is closed to new participants, but the open-label extension phase is ongoing.

Findings

Between March 20, 2017, and Oct 27, 2017, 246 participants were randomly assigned, 121 to the erenumab group and 125 to the placebo group. 95 of 246 (39%) participants had previously unsuccessfully tried two preventive drugs, 93 (38%) had tried three, and 56 (23%) had tried four. At week 12, 36 (30%) patients in the erenumab had a 50% or greater reduction from baseline in the mean number of monthly migraine days, compared with 17 (14%) in the placebo group (odds ratio 2·7 [95% CI 1·4–5·2]; p=0·002). The tolerability and safety profiles of erenumab and placebo were similar. The most frequent treatment-emergent adverse event was injection site pain, which occurred in seven (6%) participants in both groups.

Interpretation

Compared with placebo, erenumab was efficacious in patients with episodic migraine who previously did not respond to or tolerate between two and four previous migraine preventive treatments. Erenumab might be an option for patients with difficult-to-treat migraine who have high unmet needs and few treatment options.

Funding

Novartis Pharma.

Introduction

Migraine is a neurological disease that is typically characterised by recurrent attacks of severe, unilateral, pulsating headaches associated with nausea, vomiting, photophobia, and phonophobia.1 As of 2016, migraine is the second leading cause of disability worldwide.2 Episodic migraine is defined as migraine that manifests on fewer than 15 days per month, whereas patients with chronic disease have headache on 15 or more days per month—at least 8 of which have to fulfil migraine criteria or have been successfully treated with migraine-specific medication—for at least 3 months.1, 3

Pharmacological management of migraine includes acute and preventive treatment of attacks. Commonly used preventive treatments for episodic migraine include β blockers (mainly propranolol and metoprolol), antiepileptics (mainly topiramate and valproate), and antidepressants (eg, amitriptyline).3 None of these therapies were specifically developed for migraine,3, 4, 5 and their mode of action in the disease is not clearly defined.3, 5 Efficacy and tolerability are considered to be poor by up to 50% of patients resulting in early discontinuation of treatment.6, 7, 8, 9 As a result, many patients' conditions cannot be managed with available preventives, and patients experience high disability and severely impaired quality of life.2

Research in context

Evidence before this study

We searched PubMed with the terms “episodic migraine”, “CGRP OR calcitonin gene-related peptide”, and “antibody OR antibodies” to identify articles published in English between Jan 1, 2010, and June 18, 2018. We identified 38 articles. Published work suggests that CGRP is involved in the pathophysiology of migraine. Biologics targeting CGRP (eg, erenumab, galcanezumab, fremanezumab, eptinezumab) showed efficacy compared with placebo in phase 2 and 3 trials of episodic migraine. However, efficacy and safety data have not yet been published for patients with episodic migraine in whom multiple previous preventive treatments were unsuccessful. Oral preventive therapies for episodic migraine are associated with low adherence because of poor efficacy or tolerability, or both. Thus, management of patients who have unsuccessfully tried multiple treatments becomes a challenge for physicians. Erenumab is a fully human monoclonal antibody that inhibits the canonical CGRP receptor. It has been approved in the USA by the Food and Drug Administration and in Australia for the preventive treatment of migraine in adults. In phase 2 and 3 studies in chronic and episodic migraine, erenumab was associated with significant reductions in monthly migraine days and use of acute migraine medications compared with placebo. The effects on monthly migraine days were sustained for up to 15 months in an open-label extension study in episodic migraine (4–14 headache days per month).

Added value of this study

In this 12-week, randomised, double-blind, placebo-controlled trial in patients with episodic migraine in whom multiple previous preventive treatments were unsuccessful, the proportion of patients with a 50% or greater reduction in the mean monthly number of migraine days from baseline was significantly higher in the erenumab 140 mg group than in the placebo group. In line with previously reported evidence, the tolerability and safety profiles of erenumab were similar to those of placebo, and no patients developed binding or neutralising antibodies during the double-blind treatment phase. These results suggest that erenumab is a potential treatment for difficult-to-treat episodic migraine in patients who have previously unsuccessfully tried multiple preventive medications.

Implications of all the available evidence

Erenumab 140 mg is a well tolerated and potentially effective preventive treatment for patients with episodic migraine, even in those in whom multiple other migraine preventives had either low efficacy or low tolerability.

CGRP is a neuropeptide that has an important role in migraine pathophysiology10 and is a target for migraine preventive therapies.11, 12 Erenumab is a fully human monoclonal antibody that inhibits the canonical CGRP receptor.13 At 4-weekly doses of 70 mg and 140 mg, erenumab efficaciously reduced monthly days with migraine and migraine-specific medications in episodic14, 15 and chronic16 migraine. A subset of the participants in these studies had previously unsuccessfully tried other preventive treatments.17 In this study, we aimed to compare the efficacy and tolerability of erenumab with placebo in a well defined group of patients with episodic migraine who had previously not responded adequately to two-to-four preventive treatments, or who could not tolerate these treatments.

Section snippets

Study design and participants

LIBERTY was a 12-week, randomised, double-blind, placebo-controlled, phase 3b study done at 59 sites in 16 countries across Europe and Australia. A summary of patient enrolment by country is in the appendix. Eligible patients were aged 18–65 years and had a history of episodic migraine with or without aura18 for at least 12 months. They also fulfilled the criteria for migraine in the third edition of the international classification of headache disorders, and had to have had migraine symptoms

Results

Between March 20, 2017 (first patient first visit), and Oct 27, 2017 (last patient last visit of the double-blind treatment phase), 333 patients were screened for eligibility, and 246 were randomly assigned: 121 to the erenumab group and 125 to the placebo group (figure 1). Three participants (two in the erenumab group and one in the placebo group) were excluded from the full analysis set and safety analysis for protocol deviations—specifically, they did not receive study drug. Six patients

Discussion

LIBERTY is, to our knowledge, the first study to show that a CGRP-directed therapy could have preventive efficacy in patients with episodic migraine in whom multiple previous preventive treatments have been unsuccessful. At 12 weeks, significantly more patients in the erenumab group than in the placebo group had a 50% or greater reduction from baseline in the mean number of monthly migraine days. As in previous large placebo-controlled trials14, 15 in migraine prevention, adverse events

Data sharing

Institutions wishing to analyse data from the study can apply via www.clinicalstudydatarequest.com.

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