title: A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis.
abstract: BACKGROUND
  The aim of this study was to evaluate the safety, pharmacokinetics, and clinical response of brodalumab (AMG 827), a human, anti-IL-17 receptor A (IL-17RA) monoclonal antibody in subjects with moderate-to-severe rheumatoid arthritis (RA).
  
  
  METHODS
  This phase Ib, randomized, placebo-controlled, double-blind multiple ascending dose study enrolled subjects with moderate to severe RA (≥ 6/66 swollen and ≥ 8/68 tender joints). Subjects were randomized 3:1 to receive brodalumab (50 mg, 140 mg, or 210 mg subcutaneously every two weeks for 6 doses per group; or 420 mg or 700 mg intravenously every 4 weeks for two doses per group) or placebo. Endpoints included incidence of adverse events (AEs) and pharmacokinetics. Exploratory endpoints included pharmacodynamics, and improvements in RA clinical metrics.
  
  
  RESULTS
  Forty subjects were randomized to investigational product; one subject discontinued due to worsening of RA (placebo). The study was not designed to assess efficacy. AEs were reported by 70% (7/10) of placebo subjects and 77% (22/30) of brodalumab subjects. Three serious AEs were reported in two subjects; there were no opportunistic infections. Brodalumab treatment resulted in inhibition of IL-17 receptor signaling and receptor occupancy on circulating leukocytes. No treatment effects were observed with individual measures of RA disease activity. On day 85 (week 13) 37% (11/30) of brodalumab subjects and 22% (2/9) of placebo subjects achieved ACR20; 7% (2/30) brodalumab subjects and 11% (1/9) of placebo subjects achieved ACR50; and 0% (0/30) brodalumab subjects and 0% (0/9) of placebo subjects achieved ACR70.
  
  
  CONCLUSIONS
  Multiple dose administration of brodalumab was tolerated in subjects with active RA. There was no evidence of a clinical response to brodalumab in subjects with RA.
  
  
  BACKGROUND
  ClinicalTrials.gov, NCT00771030.
authors.forename: David A
authors.initials: DA
authors.lastname: Martin
authors.forename: Melvin
authors.initials: M
authors.lastname: Churchill
authors.forename: Luis
authors.initials: L
authors.lastname: Flores-Suarez
authors.forename: Mario H
authors.initials: MH
authors.lastname: Cardiel
authors.forename: Daniel
authors.initials: D
authors.lastname: Wallace
authors.forename: Richard
authors.initials: R
authors.lastname: Martin
authors.forename: Kristine
authors.initials: K
authors.lastname: Phillips
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Kaine
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.forename: David
authors.initials: D
authors.lastname: Salinger
authors.forename: Erin
authors.initials: E
authors.lastname: Stevens
authors.forename: Chris B
authors.initials: CB
authors.lastname: Russell
authors.forename: James B
authors.initials: JB
authors.lastname: Chung
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000627:therapeutic use; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D003371:Cough / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004351:Drug Resistance; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D053722:Receptors, Interleukin-17; C571216:brodalumab; D008727:Methotrexate