TITLE:
NASH Cirrhosis: A Systematic Review of Phase 2B Trials
AUTHORS:
Bipneet Singh, Sruthi Ramanan, Waryaam Singh, Gurleen Kaur, Palak Grover, Nidhishri Sridhar
KEYWORDS:
PPAR, Icona, Tandem, Harmony, Falcon
JOURNAL NAME:
Open Journal of Gastroenterology,
Vol.15 No.4,
April
8,
2025
ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease in the United States. It includes a spectrum of conditions, from simple steatosis to more severe forms such as nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Recently, NAFLD has been redefined as metabolic dysfunction-associated fatty liver disease (MAFLD) to better reflect its association with metabolic dysregulation. Moreover, people with MAFLD can have a component of alcohol use, making MAFLD and alcoholic liver disease, 2 ends of a spectrum. It also moves away from the stigma of terminology previously used. This summary reviews the findings from recent phase 2b clinical trials that assess the efficacy and safety of various drugs targeting NAFLD and NASH. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search included databases like PubMed, Embase, Cochrane Library, and Google Scholar, focusing on studies published within the last five years. Eleven randomized controlled trials (RCTs) met the inclusion criteria. For PPAR Agonists, the EMMINENCE trial evaluated a PPAR agonist, but did not meet its primary endpoints. In contrast, the NATIVE trial assessed lanifibranor and found significant improvements. FGF-21 and FGF-19 analogs were investigated in several trials with mixed results. The Harmony trial on efruxifermin (an FGF21 analog) reported significant improvements in fibrosis, highlighting its potential in treating NASH. However, the Alpine 2/3 and Alpine 4 trials on aldafermin (an FGF19 analog) did not demonstrate significant efficacy in fibrosis reduction. These mixed outcomes suggest that while FGF-based therapies hold promise, their effectiveness needs further research. Belapectin, a galectin-3 inhibitor, did not show significant benefits. TANDEM trial assessed the combination of tropifexor (TXR) and cenicriviroc (CVC), showing safety and tolerability with notable reductions in liver enzyme levels (ALT, AST, GGT). FXR agonists like tropifexor modulate bile acid metabolism and inflammatory pathways, while CCR inhibitors like cenicriviroc target chemokine receptors involved in hepatic inflammation and fibrosis. The combination therapy approach may offer synergistic benefits in managing NASH. The reviewed trials underscore the complexity of NAFLD and NASH treatment, with multiple therapeutic targets. PPAR agonists like lanifibranor show promise, particularly in resolving NASH. The variability in the efficacy of FGF-based therapies highlights the need for further research to identify the most effective agents and patient profiles.