Copyright ©The Author(s) 2018.
World J Gastroenterol. Oct 21, 2018; 24(39): 4436-4447
Published online Oct 21, 2018. doi: 10.3748/wjg.v24.i39.4436
Table 1 Conditions which have been associated with hepatocellular carcinoma development in the non-cirrhotic liver[6,7]
Type 1 glycogen storage disease
Α1 antitrypsin
Type 1 hypercitrullinemia
GenotoxinsAflatoxin B1
CongenitalAlagille syndrome
Congenital hepatic fibrosis
Sex hormonesAnabolic steroids
Hepatic adenoma transformation
VascularHepatic vascular pathology, e.g., Budd Chiari
Table 2 Summary of some of the antifibrotic agents being actively pursued in clinical trials, outlining mechanism and key outcomes to date
BMS-986263/ND-LO2-s0201siRNA that inhibits HSP47, reducing type 1 collagen synthesisA lipid nanoparticle containing siRNA that inhibits HSP47. Vitamin A conjugated to the nanoparticle surface target facilitating targeted delivery to HSC and preclinical studies suggest disruption of collagen synthesis which may reverse fibrosis. A phase 1 study has demonstrated tolerability[94]
SimtuzumabInhibition of Lysyl oxidases (LOX) mediated collagen cross linking reduces the breakdown of collagen by proteases such as MMPsSimtuzumab is a humanized monoclonal antibody. It binds to LOXL2 and acts as an immunomodulator. However in a large phase 2 clinical trial in patients with NASH fibrosis the results were disappointing and focus has been diverted to LOXL1 inhibition where expression appears constant in carbon tetrachloride induced fibrosis in mouse models[95,96]
SelonsertibInhibits apoptosis signal-regulating kinase 1 which in the setting of oxidative stress activates pathways which lead to fibrosisIn patients with NASH has shown promise that it may lead to a reduction in fibrosis in a phase 2 trial where it was given with and without Simtuzumab and compared to Simtuzumab alone[97,98]
CenicrivirocDual antagonist of C-C motif chemokine receptor (CCR) types 2 and 5Demonstrated anti-fibrotic activity in animal models of liver fibrosis. In a phase 2 study improvements were seen in noninvasive markers of hepatic fibrosis. Antagonism of CCR2 reduces pro-inflammatory monocytes and macrophages. CCR5 antagonism impairs the activation of HSCs
EmricasanInhibitor of apoptotic and inflammatory caspasesEmricasan in the murine NASH model attenuated HSC activation. In phase 2 clinical trials for the regression of hepatic fibrosis caused by HCV infection after liver transplantation, the study didn’t reach its primary endpoint but the results from a phase 2 trial in NASH are awaited[102]
GR-MD-02Targets galectin-3Phase 3 studies are already planned for GR-MD-02. Phase 1 and 2 have been completed in the NASH cohort. Preclinical data showed some reversal of fibrosis and a reduction in portal pressures in cirrhosis[103]
ErlotinibEpidermal growth factor (EGF) receptor inhibitorIn preclinical models the FDA approved inhibitor regressed fibrosis in some animals and blocked the development of HCC. A pilot phase1/2 trial is underway[104]