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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: Teva Pharmaceuticals.