Background: Hepatic fat accumulation modulates innate immunity causing recruitment of bone marrow derived macrophages/activation of Kupffer cells, resulting in inflammatory changes associated with the development of insulin resistance and NASH. Monocyte recruitment/infiltration into the liver is mediated by C-C chemokine receptor 2 (CCR2). CCR5 promotes obesity-induced insulin resistance/hepatic steatosis in murine models. Cenicriviroc (CVC) is an oral CCR2/CCR5 antagonist in Phase 3 development for NASH. We evaluated effects of CVC on inflammatory cytokines and HbA1c in NASH subjects.
Methods: Adults with NASH and liver fibrosis were randomized 1:1 to CVC 150 mg or placebo (PBO) [Phase 2 CENTAUR study]. Cytokines and metabolic parameters were assessed.
Results: In 289 randomized adults (mean age 54 years, mean BMI 33.9 kg/m2, 52.0% diabetes), CCL2 significantly increased from baseline (BL) in CVC vs. PBO. For CVC, hs-CRP, IL-6, IL-8 and IL-1β decreased from BL; HbA1c decreased for CVC at all time points but increased for PBO at Days 180 and 360 (Table). Changes were consistent over time and more pronounced in those with advanced liver fibrosis.
Conclusions: CVC was associated with elevation of CCL2 and decreased hs-CRP/inflammatory cytokines, suggesting strong target engagement and a therapeutic impact on the inflammatory milieu associated with insulin resistance that may be reflected in lower HbA1c.
A.D. Coviello: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Allergan, Bristol-Myers Squibb Company, GENFIT. Speaker's Bureau; Self; Novo Nordisk Inc. R.W. Charlton: Employee; Self; Allergan. E.B. Martins: Employee; Self; Allergan. Stock/Shareholder; Self; Allergan. J. Yuan: None. N. Alkhouri: Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Other Relationship; Self; Allergan, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal. M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc.