title: Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis.
abstract: OBJECTIVE
  Interactions between C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) and their ligands, including CCL2 and CCL5, mediate fibrogenesis by promoting monocyte/macrophage recruitment and tissue infiltration, as well as hepatic stellate cell activation. Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. CVC's anti-inflammatory and antifibrotic effects were evaluated in a range of preclinical models of inflammation and fibrosis.
  
  
  METHODS
  Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC's antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alcoholic steatohepatitis (NASH) and renal fibrosis. Study assessments included body and liver/kidney weight, liver function test, liver/kidney morphology and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses.
  
  
  RESULTS
  CVC significantly reduced monocyte/macrophage recruitment in vivo at doses ≥20 mg/kg/day (p < 0.05). At these doses, CVC showed antifibrotic effects, with significant reductions in collagen deposition (p < 0.05), and collagen type 1 protein and mRNA expression across the three animal models of fibrosis. In the NASH model, CVC significantly reduced the non-alcoholic fatty liver disease activity score (p < 0.05 vs. controls). CVC treatment had no notable effect on body or liver/kidney weight.
  
  
  CONCLUSIONS
  CVC displayed potent anti-inflammatory and antifibrotic activity in a range of animal fibrosis models, supporting human testing for fibrotic diseases. Further experimental studies are needed to clarify the underlying mechanisms of CVC's antifibrotic effects. A Phase 2b study in adults with NASH and liver fibrosis is fully enrolled (CENTAUR Study 652-2-203; NCT02217475).
authors.affiliation: Tobira Therapeutics, Inc., South San Francisco, CA, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Lefebvre
authors.affiliation: Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Graeme
authors.initials: G
authors.lastname: Moyle
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, United States of America.
authors.forename: Ran
authors.initials: R
authors.lastname: Reshef
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States of America.
authors.forename: Lee P
authors.initials: LP
authors.lastname: Richman
authors.affiliation: AIDS Research Consortium of Atlanta, Atlanta, GA, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: Thompson
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Hsin-L
authors.initials: HL
authors.lastname: Chou
authors.affiliation: Stelic Institute & Co., Inc., Tokyo, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Hashiguchi
authors.affiliation: Plato BioPharma, Inc., Westminster, CO, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Plato
authors.affiliation: Charles River Laboratories Montreal ULC, Montreal, QC, Canada.
authors.forename: Dominic
authors.initials: D
authors.lastname: Poulin
authors.affiliation: Plato BioPharma, Inc., Westminster, CO, United States of America.
authors.forename: Toni
authors.initials: T
authors.lastname: Richards
authors.affiliation: Stelic Institute & Co., Inc., Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoneyama
authors.affiliation: Tobira Therapeutics, Inc., South San Francisco, CA, United States of America.
authors.forename: Helen
authors.initials: H
authors.lastname: Jenkins
authors.affiliation: Independent Consultant, Kailua-Kona, HI, United States of America.
authors.forename: Grushenka
authors.initials: G
authors.lastname: Wolfgang
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
mesh_terms: D000818:Animals; D065100:CCR5 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002633:Chemotaxis; D005355:Fibrosis; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors; D013454:Sulfoxides
chemical_list: D065100:CCR5 Receptor Antagonists; D007093:Imidazoles; D054390:Receptors, CCR2; D013454:Sulfoxides; C506967:cenicriviroc