Abstract
IntroductionNonalcoholic steatohepatitis (NASH) is a sub-classification of nonalcoholic fatty liver disease (NAFLD) characterized by increased risk of progressive liver fibrosis. Cenicriviroc (CVC) is a novel, orally administered, potent chemokine 2 and 5 receptor antagonist currently in development for the treatment of liver fibrosis in adults with NASH. Methods and analysisEfficacy and safety of CVC will be comprehensively evaluated in a global, Phase 3, multicenter, randomized, double-blind, placebo-controlled study (AURORA, NCT03028740) of subjects with NASH and Stage F2 or F3 fibrosis. Approximately 2000 adults (Part 1, 1200 subjects; Part 2, 800 additional subjects) aged 18–75 years with histological evidence of NASH with Stage F2 or F3 fibrosis (NASH Clinical Research Network classification system) will be randomized 2:1 to CVC 150 mg or placebo orally once daily. Primary efficacy endpoints will include the proportion of subjects with ≥1-stage improvement in liver fibrosis and no worsening of steatohepatitis at Month 12 relative to screening (Part 1), and time to first occurrence of any adjudicated event: death; histopathologic progression to cirrhosis; liver transplant; Model of End-Stage Liver Disease score ≥ 15; ascites; hospitalization due to liver decompensation (Part 2). Patient-reported outcomes will assess changes in health outcomes from baseline (Chronic Liver Disease Questionnaire - NAFLD; Work Productivity and Activity Impairment in NASH; 36-Item Short Form Health Survey version 2). Adverse events will be assessed throughout the study. As there are currently no approved treatments indicated for NASH, the AURORA CVC Phase 3 study addresses an unmet medical need.
Highlights
Nonalcoholic steatohepatitis (NASH) is a sub-classification of nonalcoholic fatty liver disease (NAFLD) characterized by increased risk of progressive liver fibrosis
Up to 44% of individuals with NAFLD will progress to nonalcoholic steatohepatitis (NASH) [6,7,8], which is characterized by steatosis, hepatocellular ballooning, and lobular inflammation, and can progress to cirrhosis and hepatocellular carcinoma [9,10,11]
In Part 1, at baseline (Day 1), eligible subjects will be assigned to treatment arms (2:1 CVC or placebo) using permuted block randomization stratified by NASH Nonalcoholic steatohepatitis Clinical Research Network (CRN) fibrosis stage (F2 or F3) and the presence or absence of documented type 2 diabetes mellitus (T2DM) (“yes” or “no”)
Summary
Nonalcoholic fatty liver disease (NAFLD) is a common, often “silent” liver disease associated with metabolic disorders [1] It is characterized by accumulation of fat in the liver (steatosis), unrelated to excessive alcohol consumption [2,3,4,5]. CVC has shown a favorable safety and tolerability profile in > 1200 subjects [34], including those with cirrhosis and hepatic impairment [33,35] Following these promising Phase 2 results, the AURORA Phase 3 study aims to evaluate and confirm the efficacy and safety of CVC for the treatment of liver fibrosis in adults with NASH
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