Migraine is a primary headache disorder that can cause substantial pain and disability and has a high global burden.1 Chronic migraine, which is defined as headaches occurring for 15 days or more per month for 3 months or more, and migraines occurring 8 days or more per month, in a patient with a previous history of migraine, shares many features with, and can transform from, episodic migraine.2, 3 Migraine therefore constitutes a spectrum of disease frequency and severity that affects quality of life4 and is associated with a range of comorbidities.5, 6
Chronic migraine affects approximately 1−2% of the global population,7 and is the most prevalent type of headache in tertiary care.8 Acute treatment options are available to abort migraine attacks, yet too frequent use of these can lead to medication overuse, a common problem in patients with chronic migraine.8, 9 Based on the high frequency of migraine and effect on quality of life, patients with chronic migraine are good candidates for preventive therapy.10 However, there are few well controlled studies for migraine preventive therapies in patients with chronic migraine, with quality evidence available only for onabotulinumtoxinA,11 topiramate,12, 13 and fremanezumab (TEV-48125).14 Other therapies such as β blockers or amitriptyline are frequently used, despite a lack of evidence in patients with chronic migraine. Oral preventive therapies available at present, including topiramate, β blockers, and amitriptyline, are often not fully efficacious or are poorly tolerated,15 which can lead to low adherence rates.16, 17 One study of 8688 adults with chronic migraine estimated adherence to range from 26% to 29% at 6 months, decreasing to as low as 17% at 12 months.16 This gap in care is underscored by the availability of just one preventive treatment for adults with chronic migraine, onabotulinumtoxinA, which is approved by the US Food and Drug Administration and in receipt of a licence from the European Medicines Agency.18 Thus, a large unmet need remains.
Research in context
Evidence before this study
Preclinical studies dating back nearly three decades first suggested a role for calcitonin gene-related peptide (CGRP) in migraine. There has since been clinical substantiation, with proof-of-concept studies showing that monoclonal antibodies targeting the CGRP pathway have the potential to prevent migraines. A search through the Ovid SP platform using Embase (Jan 1, 1974–Oct 31, 2016) and Ovid Medline In-Process and other non-indexed citations and Epub ahead of print (Jan 1, 1946–Oct 31, 2016) using the search terms “CGRP”, “migraine”, “prevention”, “prophylaxis”, “monoclonal antibody”, and “chronic migraine”, restricted to studies in human beings and in English, identified 50 articles. Of these, five phase 2 studies of monoclonal antibodies targeting the CGRP pathway were identified: galcanezumab (LY2951742) in patients with episodic migraine; eptinezumab (ALD403) in patients with frequent episodic migraine; fremanezumab (TEV-48125) in patients with high-frequency episodic migraine and chronic migraine; and erenumab (AMG 334) in patients with episodic migraine. All studies contributed evidence for the role of CGRP in the pathogenesis of migraine, and all monoclonal antibodies investigated showed no significant adverse event or safety concerns and were seemingly well tolerated.
Added value of this study
The present study is, to the best of our knowledge, the largest phase 2 trial of an antibody targeting the CGRP pathway. It is the sixth published phase 2 trial of a monoclonal antibody targeting the CGRP pathway in patients with migraine, and the second in patients with chronic migraine. Erenumab offers a mechanistically distinct approach compared with all other monoclonal antibodies being developed for the treatment of migraine by targeting the CGRP receptor and not the CGRP ligand. In this population, both doses of erenumab met the primary endpoint of change in monthly migraine days from baseline. Both doses also resulted in significant increases in the proportion of patients achieving at least a 50% reduction from baseline in monthly migraine days, and a significant reduction in the number of days per month that acute migraine-specific drugs were used (secondary efficacy endpoints).
Implications of all the available evidence
This study provides class 1b evidence (American Academy of Neurology Level A; ie, high-quality randomised controlled trial data) that once-monthly subcutaneous injection of either 70 mg or 140 mg erenumab, a fully human monoclonal antibody against the CGRP receptor, could be a potential new preventive therapy in patients with chronic migraine. Areas of future research should aim to identify which patients respond best to therapy and whether factors such as biomarkers, previous preventive treatment history, or presence or absence of medication overuse might predict a therapeutic response.
Calcitonin gene-related peptide (CGRP) is a proinflammatory vasodilating neuropeptide implicated in the pathophysiology of migraine,19, 20, 21, 22, 23 with early studies showing that CGRP levels increase in jugular venous blood during migraine attacks20 and are elevated interictally in the peripheral circulation in patients with episodic migraine23 and chronic migraine.24 By contrast, normal plasma CGRP levels were reported in chronic tension-type headache.25 The CGRP pathway is a promising target for migraine therapies. Small-molecule CGRP receptor antagonists, also known as gepants, have previously shown efficacy for acute treatment of migraine, although concerns with liver toxicity from telcagepant halted clinical development.26 Studies of monoclonal antibodies as preventive therapy for migraine have shown potential with respect to efficacy and safety.14, 27, 28, 29, 30, 31 Erenumab is the only fully human monoclonal antibody in clinical development that potently binds in a competitive and reversible manner (Ki 0·02 nM) to the CGRP receptor with greater selectivity than to other human calcitonin family receptors (eg, calcitonin, amylin, and adrenomedullin).32 The safety and efficacy results of erenumab 70 mg given subcutaneously every 4 weeks in a phase 2 study of patients with episodic migraine were reported in 2016.30 The aim of our study was to assess the safety and efficacy of erenumab 70 mg and 140 mg in patients with chronic migraine.