Background: Nonalcoholic steatohepatitis (NASH) is considered the hepatic manifestation of type 2 diabetes and can progress to advanced fibrosis (AF), associated with significant increase in morbidity and mortality. CVC is an oral C-C chemokine receptor 2/5 antagonist being evaluated to treat liver fibrosis in adults with NASH. This study describes antifibrotic effects seen in the Phase 2b CENTAUR study overall and those with AF (F3) specifically.
Methods: Adults with confirmed NASH, nonalcoholic fatty liver disease activity score ≥4, and liver fibrosis Stages F1-3 (NASH CRN) received CVC 150 mg daily (Arm A) or placebo (PBO; Arm C) for 2 years; Arm B received PBO in Year (Y)1 and CVC in Y2. Liver biopsies were assessed blind at baseline (BL), Y1, and Y2 by a central pathologist. Improvement in fibrosis and serum inflammatory markers were assessed in subjects with evaluable biopsies at BL, Y1, and Y2 (modified intent-to-treat [mITT] population).
Results: Of 289 adults randomized (mean age 54 years, mean BMI 33.9 kg/m2, 52.0% diabetes), 28.6% (36/126) vs. 19.0% (24/126) achieved ≥1-stage fibrosis improvement at Y1 in CVC vs. PBO arms (mITT) overall. Of 97 AF subjects at BL (mean age 57.8 years, mean BMI 34.1 kg/m2, 69.0% diabetes), 38.3% (18/47) vs. 28.0% (14/50) achieved this endpoint in CVC vs. PBO arms (mITT). Overall, 60.0% (18/30) in Arm A vs. 30.0% (3/10) in Arm C maintained benefit at Y2 (mITT). In AF subjects, 85.7% (12/14) in Arm A vs. 60.0% (3/5) in Arm C maintained benefit at Y2 (mITT). Greater reductions in hs-CRP, fibrinogen, IL-6, IL-8, and IL-1β were observed with CVC. In AF subjects, these changes were more pronounced. Overall and with AF, adverse events were comparable for CVC and PBO; no deaths occurred.
Conclusion: CVC was well tolerated and provided antifibrotic benefit in adults with NASH and fibrosis, especially those with AF. Most subjects achieving ≥1-stage fibrosis improvement at Y1 maintained benefit at Y2, with reductions in inflammatory biomarkers, supporting the ongoing Phase 3 study of CVC in NASH.
N. Alkhouri: Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Other Relationship; Self; Allergan, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal. R.W. Charlton: Employee; Self; Allergan. E.B. Martins: Employee; Self; Allergan. Stock/Shareholder; Self; Allergan. H. Landgren: Employee; Self; Allergan. A.D. Coviello: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Allergan, Bristol-Myers Squibb Company, GENFIT. Speaker's Bureau; Self; Novo Nordisk Inc. 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.