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

Abstract

Klatt, J. (2018). 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. Lancet.Abstract: 299 words excluding Current word count: 4621 (including Research in 24 context) 25 Manuscript LIBERTY-primary manuscript Re-submission draft 2 Summary 26Background: A significant proportion of patients does not respond to, or cannot tolerate, current 27 oral migraine preventives. Erenumab is a novel CGRP-receptor antibody with preventive 28 efficacy in migraine. Here we assessed its efficacy and tolerability in patients with episodic 29 migraine who had previously failed 2-4 migraine preventives (efficacy failure: no meaningful 30 reduction in headache frequency after administration of approved preventive for migraine for at 31 least 2-3 months based on patient history and medical judgment). 32Methods: LIBERTY (NCT03096834) was a 12-week, double-blind, randomised study. 33Participants with migraine symptoms from 4-14 days/month (28-day interval) across the three 34 months prior to screening and during the baseline period were randomised (1:1) to receive 35 erenumab 140 mg or placebo every four weeks subcutaneously for the 12-week double-blind 36 treatment phase. The primary endpoint was proportion of patients achieving ≥50% reduction in 37 monthly migraine days during Weeks 9-12. Additionally, safety and tolerability were also 38 assessed by recording adverse events and by physical examination, vital signs, clinical laboratory 39 assessments, and electrocardiogram. 40 Findings: Of 246 randomised participants (n=121 for erenumab 140 mg and n=125 for placebo), 41 240 completed the double-blind phase. Of these, 95 (38·6%), 93 (37·8%), and 56 (22·8%) had 42 previously failed two, three, and four preventives, respectively. At Week 12, the ≥50% responder 43 rate was observed in 36 (30·3%) patients on erenumab versus 17 (13·7%) patients on placebo 44 (odds ratio, 95% confidence interval [CI]: 2·7 [1·4, 5·2]; p=0·002). The tolerability and safety 45 profiles of erenumab were comparable to placebo. The most frequent treatment-emergent 46 adverse events was injection site pain (7 [5.9%] with erenumab 140 mg, 7 [5.6%] placebo).47 Interpretation: Erenumab was effective in patients with episodic migraine who previously did 48 not respond to/tolerate 2-4 migraine preventives. Erenumab might be an option for patients with 49 difficult-to-treat migraine who have high unmet needs and limited treatment options.50 Funding: Novartis Pharma AG 51 52 LIBERTY-primary manuscript Re-submission draft 3 Research in context 53Evidence before this study 54 We searched PubMed to identify articles published in English language between January 1, 55 2010, and June 18, 2018, using the search terms "episodic migraine", "CGRP OR calcitonin 56 gene-related peptide", and "antibody OR antibodies". The search retrieved 38 articles. Published 57 literature suggests that CGRP is involved in the pathophysiology...

Targeting CGRP for the Prevention of Migraine and Cluster Headache: A Narrative Review

“…In EM subjects who failed 2‐4 preventives, erenumab decreased MMD by 1.6 days (placebo adjusted), acute medication use by 1.8 days (placebo adjusted), and had a low placebo response rate (0.2 days) . Significantly more erenumab, than placebo‐treated subjects, achieved ≥50% reduction in MMD (30% vs 14%).…”

“…In a subgroup analysis from EVOLVE‐1, EVOLVE‐2, and REGAIN studies on subjects who failed onabotulinumtoxinA, galcanezumab showed a change in MMD change of 5.3 (240 mg), 3.9 (120 mg), and 0.9 (placebo) days . It is worth mentioning that migraine subjects who have failed preventives have a much lower placebo response than those who have not . Based on the complimentary mechanism of action, it is certainly hopeful that CGRP functional blockade can elicit an additive and perhaps even a synergistic effect with current migraine preventives.…”

A Randomized Phase 2 Study of Erenumab for the Prevention of Episodic Migraine in Japanese Adults

“…[7][8][9][10] Erenumab has also demonstrated efficacy in the prevention of chronic migraine, 11 including patients who had failed previous preventive migraine treatments. To date, 3 global, randomized, double-blind, placebo-controlled, clinical studies have demonstrated the efficacy of erenumab in the prevention of episodic migraine, including patients who had failed previous preventive migraine treatments.…”

Novel Medications for the Treatment of Migraine

“…65 Patients who received erenumab had a −2.9 days change in monthly migraine days (MMD), vs −1.8 days for placebo. 67,68 Both trials also found that erenumab treatment led to significant reduction in the number of days of acute migraine-specific medication (ergots or triptans) use. 66 By months 4 through 6, patients in the 70 mg group had a −3.2 days change in MMD, and patients in the 140 mg group had a −3.7 days change (−1.8 days for placebo).…”

“…66 By months 4 through 6, patients in the 70 mg group had a −3.2 days change in MMD, and patients in the 140 mg group had a −3.7 days change (−1.8 days for placebo). 67 Patients received either erenumab 140 mg or placebo every 4 weeks. In both trials, AEs were similar to placebo, with the most frequently reported AEs being upper respiratory tract infection, injection site pain, constipation, and nasopharyngitis.…”