title: Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study.
abstract: BACKGROUND
  Calcitonin gene-related peptide (CGRP) is a validated target for the treatment of episodic migraine. Here we assess the safety, tolerability, and efficacy of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of high-frequency episodic migraine.
  
  
  METHODS
  In this multicentre, randomised, double-blind, placebo-controlled, phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had migraine headaches 8-14 days per month. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1; stratified by sex and use of concomitant preventive drugs) after a 28 day run-in period to three 28 day treatment cycles of subcutaneous 225 mg TEV-48125, 675 mg TEV-48125, or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Patients reported headache information daily using an electronic diary. Primary endpoints were change from baseline in migraine days during the third treatment cycle (weeks 9-12) and safety and tolerability. The secondary endpoint was change relative to baseline in headache-days during weeks 9-12. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered at ClinicalTrials.gov, number NCT02025556.
  
  
  RESULTS
  Between Jan 8, 2014, and Oct 15, 2014, we enrolled 297 participants: 104 were randomly assigned to receive placebo, 95 to receive 225 mg TEV-48125, and 96 to receive 675 mg TEV-48125. The least square mean (LSM) change in number of migraine-days from baseline to weeks 9-12 was -3.46 days (SD 5.40) in the placebo group, -6.27 days (5.38) in the 225 mg dose group, and -6.09 days (5.22) in the 675 mg dose group. The LSM difference in the reduction of migraine-days between the placebo and 225 mg dose groups was -2.81 days (95% CI -4.07 to -1.55; p<0.0001), whereas the difference between the placebo and 675 mg dose group was -2.64 days (-3.90 to -1.38; p<0.0001). LSM differences in the reduction of headache-days were -2.63 days (-3.91 to -1.34; p<0.0001) between the placebo group and 225 mg dose group and -2.58 days (-3.87 to 1.30; p <0.0001) between the placebo group and the 675 mg dose group. Adverse events occurred in 58 (56%) patients in the placebo group, 44 (46%) patients in the 225 mg dose group, and 57 (59%) patients in the 675 mg dose group; moderate or severe adverse events were reported for 29 (27%) patients, 24 (25%) patients, and 26 (27%) patients, respectively.
  
  
  CONCLUSIONS
  TEV-48125, at doses of 225 mg and 675 mg given once every 28 days for 12 weeks, was safe, well tolerated, and effective as a preventive treatment of high-frequency episodic migraine, thus supporting advancement of the clinical development programme to phase 3 clinical trials.
  
  
  BACKGROUND
  Teva Pharmaceuticals.
authors.affiliation: Research and Development Department, Teva Pharmaceuticals, Frazer, PA, USA. Electronic address: marcelo.bigal@tevapharm.com.
authors.forename: Marcelo E
authors.initials: ME
authors.lastname: Bigal
authors.affiliation: Department of Neurology, Mayo Clinic, Phoenix, AZ, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dodick
authors.affiliation: The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Rapoport
authors.affiliation: Department of Neurology, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Silberstein
authors.affiliation: Statistics Department, Teva Pharmaceuticals, Frazer, PA, USA.
authors.forename: Yuju
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Statistics Department, Teva Pharmaceuticals, Frazer, PA, USA.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Yang
authors.affiliation: Research and Scientific Affairs Department, Teva Pharmaceuticals, Frazer, PA, USA.
authors.forename: Pippa S
authors.initials: PS
authors.lastname: Loupe
authors.affiliation: Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Rami
authors.initials: R
authors.lastname: Burstein
authors.affiliation: Headache Institute and St Luke's-Roosevelt Hospital Center, New York, NY, USA.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Newman
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lipton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015740:Calcitonin Gene-Related Peptide / Q000276:immunology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016239:MEDLINE / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000517:prevention & control*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; C000604315:fremanezumab; D015740:Calcitonin Gene-Related Peptide