2. Academic Validation
  3. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis

Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis

  • PLoS One. 2016 Jun 27;11(6):e0158156. doi: 10.1371/journal.pone.0158156.
Eric Lefebvre 1,  Graeme Moyle 2,  Ran Reshef 3,  Lee P Richman 4,  Melanie Thompson 5,  Feng Hong 6,  Hsin-L Chou 6,  Taishi Hashiguchi 7,  Craig Plato 8,  Dominic Poulin 9,  Toni Richards 8,  Hiroyuki Yoneyama 7,  Helen Jenkins 1,  Grushenka Wolfgang 10,  Scott L Friedman 6
Affiliations

Affiliations

  • 1 Tobira Therapeutics, Inc., South San Francisco, CA, United States of America.
  • 2 Chelsea and Westminster Hospital, London, United Kingdom.
  • 3 Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, United States of America.
  • 4 Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States of America.
  • 5 AIDS Research Consortium of Atlanta, Atlanta, GA, United States of America.
  • 6 Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
  • 7 Stelic Institute & Co., Inc., Tokyo, Japan.
  • 8 Plato BioPharma, Inc., Westminster, CO, United States of America.
  • 9 Charles River Laboratories Montreal ULC, Montreal, QC, Canada.
  • 10 Independent Consultant, Kailua-Kona, HI, United States of America.
PMID: 27347680 DOI: 10.1371/journal.pone.0158156
Abstract

Background & aims: 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).

Figures
Products