title: Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study.
abstract: BACKGROUND
  Migraine remains poorly treated, with few effective preventive drugs available. We assessed the safety and efficacy of LY2951742, a fully humanised monoclonal antibody to calcitonin gene-related peptide, for migraine prevention.
  
  
  METHODS
  We did a randomised, double-blind, placebo-controlled, phase 2 proof-of-concept study at 35 centres in the USA. Patients aged 18-65 years with four to 14 migraine headache days per month were randomly assigned (1:1) to LY2951742 or placebo by a computerised randomisation scheme. LY2951742 (150 mg) or placebo were given as a subcutaneous injection once every 2 weeks for 12 weeks. The primary endpoint was the mean change in number of migraine headache days per 28-day period assessed at 9-12 weeks. Safety was assessed over 24 weeks, including the 12-week treatment period and the subsequent 12 weeks after study drug administration. Patients and treating investigators were masked to treatment allocation. Analyses were by intention to treat. A mixed-effects model of repeated measures was used, including patient baseline value, treatment, visit, and treatment-by-visit interaction as fixed effects, and patients as random effects. Safety measures were analysed according to the treatment received. This study has been completed and is registered with ClinicalTrials.gov, NCT01625988.
  
  
  RESULTS
  Between July 31, 2012, and Sept 18, 2013, 218 patients were randomly assigned to LY2951742 (n=108, but one patient withdrew before treatment) or placebo (n=110). The mean change from baseline to week 12 in the number of migraine headache days was -4·2 (SD 3·1; 62·5% decrease) in the LY2951742 group compared with -3·0 (SD 3·0; 42·3% decrease) in the placebo group (least-squares mean difference -1·2, 90% CI -1·9 to -0·6; p=0·0030). Adverse events that occurred more frequently with LY2951742 than with placebo included injection site pain, erythema, or both (21 [20%] of 107 vs seven [6%] of 110), upper respiratory tract infections (18 [17%] vs ten [9%]), and abdominal pain (six [6%] vs three [3%]). There were two serious adverse events reported in the treatment arm and four in the placebo arm, none of which were deemed to be related to the study drug.
  
  
  CONCLUSIONS
  These results provide preliminary evidence that LY2951742 might be beneficial in migraine prevention and provide support for the role of calcitonin gene-related peptide in the pathogenesis of migraine. Further controlled studies are needed to assess the safety and efficacy of monoclonal calcitonin gene-related peptide antibodies for the preventive treatment of migraine.
  
  
  BACKGROUND
  Arteaus Therapeutics.
authors.affiliation: Department of Neurology, Mayo Clinic, Phoenix, AZ, USA. Electronic address: dodick.david@mayo.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Dodick
authors.affiliation: NIHR Wellcome Trust Clinical Research Facility, Kings College London, London, UK; Department of Neurology, University of California, San Francisco CA, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Goadsby
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Craniofacial Pain Center, Tufts University School of Dental Medicine, Boston, MA, USA; Headache and Face Pain Program, Tufts Medical Center, Boston, MA, USA.
authors.forename: Egilius L H
authors.initials: EL
authors.lastname: Spierings
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Scherer
authors.affiliation: Arteaus Therapeutics, Cambridge, MA, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Sweeney
authors.affiliation: Arteaus Therapeutics, Cambridge, MA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Grayzel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors* / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000517:prevention & control*; D010919:Placebos; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D010919:Placebos; D015740:Calcitonin Gene-Related Peptide