Erenumab in the Prevention of High-frequency Episodic and Chronic Migraine

Erenumab in Real Life in Italy (EARLY), The First Italian Multicenter, Prospective Real-life Study

Piero Barbanti MD, PhD; Cinzia Aurilia MD; Gabriella Egeo MD, PhD; Luisa Fofi MD; Sabina Cevoli MD, PhD; Bruno Colombo MD; Massimo Filippi MD; Fabio Frediani MD; Francesco Bono MD; Licia Grazzi MD; Antonio Salerno MD; Bruno Mercuri MD, PhD; Antonio Carnevale MD; Claudia Altamura MD, PhD; Fabrizio Vernieri MD


Headache. 2021;61(2):363-372. 

In This Article

Abstract and Introduction


Objective: To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors.

Background:Erenumab is a fully human Ig-2 monoclonal antibody blocking the calcitonin gene-related peptide receptor, indicated for migraine prophylaxis. Phase II and III trials demonstrated that erenumab is effective, safe, and well tolerated in the prevention of episodic and chronic migraine (CM), showing an early onset of action.

Methods: This is a multicenter, prospective, cohort, and real-life study. We considered for enrolment all consecutive patients aged 18–65 affected by high-frequency episodic migraine (HFEM) or CM, with or without medication overuse, visited at nine Italian Headache Centers from December 20, 2018 to September 30, 2019. Each patient was treated with erenumab 70 mg, administered subcutaneously every 4 weeks. Treatment duration was planned to last from 6 to 12 months, depending on the patient's response. The primary endpoint was the change in monthly migraine days (MMDs) at weeks 9–12 compared to baseline. Secondary endpoints included changes in monthly analgesics intake, ≥50%, ≥75%, and 100% responder rates and any variation in the Visual Analog Scale (VAS) and Headache Impact Test scores (HIT).

Results: In total, 372 migraine patients were treated with at least one dose of erenumab 70 mg. At weeks 9–12, erenumab decreased MMDs by 4.5 ± 4.1 days (mean ± SD) in patients with HFEM and by 9.3 ± 9.1 (mean ± SD) days in those with CM compared to baseline. At weeks 9–12 VAS score was reduced by 1.9 ± 1.9 (mean ± SD), HIT score by 10.7 ± 8.8 (mean ± SD), and median monthly analgesics intake passed from 12.0 (interquartile range [IQR] 10.0–14.0) to 5.0 (IQR 3.0–7.0) in HFEM. In CM patients, VAS was reduced by 1.7 ± 2.0 (mean ± SD), HIT by 9.7 ± 10.4 (mean ± SD), and median monthly analgesics intake passed from 20.0 (IQR 15.0–30.0) to 8.0 (IQR 5.0–15.0). At week 12, ≥50% responders were 60/101 (59.4%) for HFEM and 146/263 (55.5%) for CM, ≥75% responders were 17/101 (16.8%) and 59/263 (22.4%) and 100% responders 1/101 (1.0%) and 3/263 (1.1%), respectively. Erenumab responsiveness in HFEM was positively associated with unilateral pain localization (OR: 3.03, 95% CI: 1.24–7.40; p = 0.015), whereas in CM responsiveness was positively associated with and baseline migraine frequency (OR: 1.06, 95% CI:1.02–1.11; p = 0.031), dopaminergic symptoms (OR: 2.01, 95% CI: 1.14–3.52; p = 0.015), and negatively associated with psychiatric comorbidities (OR: 0.43, 95% CI: 0.20–0.93; p = 0.003).

Conclusions: Erenumab 70 mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.


Migraine is characterized by a complex pathophysiology, composite comorbidities and an unsatisfying response to conventional pharmacological treatments, which are often associated with poor tolerability and high discontinuation rates.[1] Since the early 1990s, acute migraine treatment has taken advantage of the selective and specific acute migraine drugs called triptans,[2] which are able to counteract the activation of the trigeminovascular system by targeting the 5-HT1B/1D receptors. Migraine prevention, on the other hand, has relied on drugs with unspecific mechanisms of action, often discovered by serendipity and characterized by inadequate efficacy and frequent adverse events.[3]

Topiramate and onabotulinumtoxinA are the only drugs which have been approved for migraine prevention in the last 28 years, while methysergide and pizotifen—two of the most efficacious compounds—are no longer marketed in most countries.[4] Thus, there is a stringent need for new selective, effective and well-tolerated migraine preventing agents.

In this scenario, the identification of the crucial migraine pathogenic role of the calcitonin gene-related peptide (CGRP), a 37-aminoacid neuropeptide widely distributed in both the central and the peripheral nervous system, represented a substantial advance in the development of more tailored treatments.[5] The antagonism to CGRP or its receptor is currently the most promising therapeutic strategy in migraine. Small molecules antagonizing the CGRP receptor, called gepants, proved effective in the treatment of migraine, although their clinical development was initially discontinued due to liver toxicity. More recently, ubrogepant and rimegepant—that is, two new gepants—are being investigated for acute treatment in phase III trials without any safety concern, whereas atogepant and rimegepant are being tested in the prevention of migraine.[6–9] In addition, monoclonal antibodies (mAbs) targeting CGRP (galcanezumab, eptinezumab, and fremanezumab) or the CGRP receptor (erenumab), are the first selective and specific agents for migraine prevention.[5–10]

Erenumab—a fully human Ig-2 mAb which blocks the CGRP receptor—is a first-in-class CGRP inhibitor approved by the US Food and Drug Administration and the European Medicines Agency for migraine prevention.[11] Phase II and III, randomized, placebo-controlled trial (RCTs) demonstrated that erenumab is effective in the prevention of episodic and chronic migraine (CM) with an early onset of action, regardless of the presence of medication overuse (MO), aura, anxiety, depression, or menstrual-related migraine.[12,13] Erenumab showed also an established safety and tolerability profile, low incidence of immunogenicity, no apparent increase in the risk of cardiovascular adverse events, no interactions or synergistic cardiovascular effects with triptans, and no impact on contraceptive treatments.[14]

In our first single-center pioneering real-life study, we reported high effectiveness and tolerability in high-frequency episodic migraine (HFEM: ≥8 monthly migraine days, MMDs) and in CM.[15] Here, we report the results of the first 3 months of treatment with erenumab in the ongoing 12-month EARLY (Erenumab in Real Life in Italy) study, a large Italian multicenter, prospective, cohort, real-life trial carried out in 372 consecutive patients affected by HFEM or CM.