title: Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial.
abstract: BACKGROUND
  The calcitonin gene-related peptide (CGRP) pathway is a promising target for preventive therapies in patients with migraine. We assessed the safety and efficacy of AMG 334, a fully human monoclonal antibody against the CGRP receptor, for migraine prevention.
  
  
  METHODS
  In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients aged 18-60 years with 4 to 14 migraine days per month were enrolled at 59 headache and clinical research centres in North America and Europe, and randomly assigned in a 3:2:2:2 ratio to monthly subcutaneous placebo, AMG 334 7 mg, AMG 334 21 mg, or AMG 334 70 mg using a sponsor-generated randomisation sequence centrally executed by an interactive voice response or interactive web response system. Study site personnel, patients, and the sponsor study personnel were masked to the treatment assignment. The primary endpoint was the change in monthly migraine days from baseline to the last 4 weeks of the 12-week double-blind treatment phase. The primary endpoint was calculated using the least squares mean at each timepoint from a generalised linear mixed-effect model for repeated measures. Safety endpoints were adverse events, clinical laboratory values, vital signs, and anti-AMG 334 antibodies. The study is registered with ClinicalTrials.gov, number NCT01952574. An open-label extension phase of up to 256 weeks is ongoing and will assess the long-term safety of AMG 334.
  
  
  RESULTS
  From Aug 6, 2013, to June 30, 2014, 483 patients were randomly assigned to placebo (n=160), AMG 334 7 mg (n=108), AMG 334 21 mg (n=108), or AMG 334 70 mg (n=107). The mean change in monthly migraine days at week 12 was -3·4 (SE 0·4) days with AMG 334 70 mg versus -2·3 (0·3) days with placebo (difference -1·1 days [95% CI -2·1 to -0·2], p=0·021). The mean reductions in monthly migraine days with the 7 mg (-2·2 [SE 0·4]) and the 21 mg (-2·4 [0·4]) doses were not significantly different from that with placebo. Adverse events were recorded in 82 (54%) patients who received placebo, 54 (50%) patients in the AMG 334 7 mg group, 54 (51%) patients in the AMG 334 21 mg group, and 57 (54%) patients in the AMG 334 70 mg group. The most frequently reported adverse events were nasopharyngitis, fatigue, and headache. Serious adverse events were reported for one patient in the AMG 334 7 mg group (ruptured ovarian cyst) and one patient in the AMG 334 70 mg group (migraine and vertigo); these events were judged to be unrelated to AMG 334 treatment. Nine (3%) of 317 patients had neutralising antibodies. No apparent association was recorded between patients with positive anti-AMG 334 antibodies and adverse events. No clinically significant vital signs, laboratory, or electrocardiogram findings were recorded.
  
  
  CONCLUSIONS
  These results suggest that AMG 334 70 mg might be a potential therapy for migraine prevention in patients with episodic migraine and support further investigation of AMG 334 in larger phase 3 trials.
  
  
  BACKGROUND
  Amgen.
authors.affiliation: Department of Global Development, Amgen, Thousand Oaks, CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dodick
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Silberstein
authors.affiliation: Department of Neurology NIHR-Wellcome Trust King's Clinical Research Facility, King's College London, London, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Goadsby
authors.affiliation: Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Reuter
authors.affiliation: Department of Neurology, Danish Headache Center and Department of Neurology, Rigshospitalet, Faculty of Medical and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Messoud
authors.initials: M
authors.lastname: Ashina
authors.affiliation: Michigan Head Pain and Neurological Institute, Ann Arbor, MI, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Saper
authors.affiliation: Clinvest Research, Banyan Group, Headache Care Center, Springfield, MO, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Cady
authors.affiliation: Department of Biostatistics, Amgen, Thousand Oaks, CA, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Chon
authors.affiliation: Department of Global Development, Amgen, Thousand Oaks, CA, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: Department of Global Development, Amgen, Thousand Oaks, CA, USA. Electronic address: rlenz@amgen.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000517:prevention & control*; D017063:Outcome Assessment, Health Care
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007155:Immunologic Factors; C000605816:erenumab