Journal Article

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

Wolfgang, Grushenka, Poulin, Dominic, Hashiguchi, Taishi, Chou, Hsin-l, Reshef, Ran, Moyle, Graeme, Lefebvre, Eric, Richards, Toni, Jenkins, Helen, Plato, Craig, Yoneyama, Hiroyuki, Hong, Feng, Friedman, Scott L., Richman, Lee P., Thompson, Melanie

2016

Overview

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. 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. 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. 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).

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acquired immune deficiency syndrome / Adults / AIDS / Analysis / Animal models / Animals / Biology and Life Sciences / CC chemokine receptors / CCR2 protein / CCR5 protein / CCR5 Receptor Antagonists - administration & dosage / CCR5 Receptor Antagonists - pharmacology / CCR5 Receptor Antagonists - therapeutic use / Cell activation / Chemokine receptors / Chemokines / Chemotaxis / Collagen / Collagen (type I) / Collagens / Cytokines / Deposition / Disease control / Drug dosages / Drug therapy / Fatty liver / FDA approval / Fibrosis / Gastroenterology / Gene expression / Hepatology / Imidazoles - administration & dosage / Imidazoles - pharmacology / Imidazoles - therapeutic use / In vivo methods and tests / Infiltration / Inflammation / Insulin resistance / Kidney Diseases - drug therapy / Kidney Diseases - pathology / Kidneys / Ligands / Liver / Liver diseases / Macrophages / Macrophages - drug effects / Male / Medicine / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Monocyte chemoattractant protein 1 / Monocytes / Monocytes - drug effects / Non-alcoholic Fatty Liver Disease - drug therapy / Non-alcoholic Fatty Liver Disease - pathology / Peritonitis / Pharmacokinetics / Pharmacology / Rats / Rats, Sprague-Dawley / Receptors / Receptors, CCR2 - antagonists & inhibitors / Recruitment / Research and Analysis Methods / Risk factors / Rodents / Sulfoxides / Thioacetamide