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PLoS One. 2016 Jun 27;11(6):e0158156. doi: 10.1371/journal.pone.0158156. eCollection 2016.

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

Author information

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.

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).

PMID:
27347680
PMCID:
PMC4922569
DOI:
10.1371/journal.pone.0158156
[Indexed for MEDLINE]
Free PMC Article

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