title: MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study.
abstract: OBJECTIVE
  To assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX).
  
  
  METHODS
  In this phase IIa, proof-of-concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for >or=6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1-83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897-treated group compared with that in the placebo-treated group.
  
  
  RESULTS
  MLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent-to-treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897-treated patients and placebo-treated patients (35% versus 33%, respectively; P=0.72). Results were similar for the per-protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (>or=90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1alpha internalization assay).
  
  
  CONCLUSIONS
  MLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study.
authors: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Clarissa E
authors: CE
authors: Vergunst
authors: Danielle M
authors: DM
authors: Gerlag
authors: Lisa
authors: L
authors: von Moltke
authors: Michael
authors: M
authors: Karol
authors: Tim
authors: T
authors: Wyant
authors: Xuedong
authors: X
authors: Chi
authors: Ellen
authors: E
authors: Matzkin
authors: Timothy
authors: T
authors: Leach
authors: Paul P
authors: PP
authors: Tak
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; C515300:CCR1 protein, human; D054389:Receptors, CCR1; D008727:Methotrexate