Carcinogenesis on the background of liver fibrosis: Implications for the management of hepatocellular cancer

Table 2 Summary of some of the antifibrotic agents being actively pursued in clinical trials, outlining mechanism and key outcomes to date

Drug	Mechanism	Comment	Ref.
BMS-986263/ND-LO2-s0201	siRNA that inhibits HSP47, reducing type 1 collagen synthesis	A 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]
Simtuzumab	Inhibition of Lysyl oxidases (LOX) mediated collagen cross linking reduces the breakdown of collagen by proteases such as MMPs	Simtuzumab 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]
Selonsertib	Inhibits apoptosis signal-regulating kinase 1 which in the setting of oxidative stress activates pathways which lead to fibrosis	In 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]
Cenicriviroc	Dual antagonist of C-C motif chemokine receptor (CCR) types 2 and 5	Demonstrated 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
			[99-101]
Emricasan	Inhibitor of apoptotic and inflammatory caspases	Emricasan 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-02	Targets galectin-3	Phase 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]
Erlotinib	Epidermal growth factor (EGF) receptor inhibitor	In 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]