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Cheng et al. Advances in liver fibrosis

metabolic risk factors is central in the management this agent announced it discontinued testing of
to improved liver fibrosis in NAFLD patients. A weight simtuzumab, as it failed to show efficacy in Phase
reduction of 10% or more by aggressive lifestyle 2 trials of NASH as well as primary sclerosing
modification appears to resolve fibrosis in most if not cholangitis. [128] More recent data also support that the
all cases (at least with mild-moderate fibrosis). [119,120] hepatic expression of the apoptosis signal-regulating
Thiazolidinediones [peroxisome proliferator-activated kinase 1 (ASK1) marker, phosphorylated-P38 (p-P38),
receptor (PPAR)-γ agonists] such as pioglitazone correlates with fibrosis stage in patients with NAFLD. [129]
and rosiglitazone are insulin sensitizers and were Therefore, selonsertib, an oral molecule that inhibits
found to be effective to reduce fibrosis in two meta- ASK1, together with simtuzumab, was found to be
analyses; [121,122] but the finding was not confirmed when effective to regress liver fibrosis in NASH patients with
more recent and bigger studies were included in the stage 2 or 3 fibrosis. Selonsertib alone is currently
analysis. [123] The largest study of pentoxiphylline and evaluated in NASH patients with advanced fibrosis and
also a recent study of obeticholic acid both showed a cirrhosis (Clinicaltrials.gov Identifier NCT03053050
significant reduction of fibrosis, [124] the magnitude was and NCT03053063) [Table 3].
not pathologically significant (far less than one fibrosis
stage by the non-alcoholic steatohepatitis (NASH) Cenicriviroc is a C-C chemokine receptor type 2 and
Clinical Research Network system. [125] type 5 (CCR2/CCR5) antagonist, which interrupts
the inflammatory cascade in NASH that leads to
In terms of pharmacological agents, there has been fibrogenesis. In animal models, the drug has been
much interest in anti-fibrotic therapy in NAFLD as shown to have anti-inflammatory and anti-fibrotic
fibrosis is one of the strongest prognostic markers activity. [130,131] In an ongoing two-year Phase 2b trial
for NAFLD. Lysyl-oxidase like 2 (LOXL2) is involved with cenicriviroc, it significantly improved liver fibrosis
in a relatively late step in hepatic fibrogenesis, the for at least one stage at 48 weeks when compared to
crosslinking of extracellular matrix proteins such as placebo (20% vs. 10%; P = 0.023). [132] Galectins are cell
collagen and elastin. [126] Simtuzumab, a humanized surface glycoproteins that can mediate cell migration,
monoclonal anti-LOXL2 antibody was once evaluated matrix interaction and inflammatory signals. GR-
in Phase 2 trials in nonalcoholic steatohepatitis (NASH) MD-02 and GM-CT-01, two galectin inhibitors, bind to
patients with significant fibrosis and cirrhosis. [127] terminal galactose residues in glycoprotein and reduce
Nonetheless, the pharmaceutical company developed fibrosis in animal NASH. [133] GR-MD-02 has favorable

Table 3: Active clinical trials in the clinical trials.gov on anti-fibrotic treatments
Clinicaltrials.gov Drug Phase Disease Target sample size Status
NCT01965418 Fufang Biejia Ruangan 4 Chronic hepatitis B 100 Recruiting
NCT02241616 Entecavir + Fuzheng Huayu + 4 Chronic hepatitis B 350 Recruiting
TCM Granule
NCT00956098 Oltipraz 2 Chronic hepatitis B or C 81 Completed
NCT02138253 IDN-6556 2 Chronic hepatitis C 60 Ongoing, finished recruitment
(POLT-HCV-SVR)
NCT02744105 Dietary Supplement: Spirulina N/A Chronic hepatitis C (in 60 Ongoing, finished recruitment
beta-thalassemia)
NCT02217475 Cenicriviroc 2 NASH fibrosis 200 Ongoing, finished recruitment
NCT03059446 Cenicriviroc 2 NASH fibrosis 200 Recruiting by invitation
NCT03028740 Cenicriviroc 3 NASH fibrosis 2000 Recruiting
(AURORA)
NCT02530138 Synbiotic 2/3 NASH fibrosis 42 Recruiting
NCT02686762 Emricasan 2 NASH fibrosis 330 Recruiting
NCT02704403 Elafibranor 3 NASH fibrosis 2000 Recruiting
(RESOLVE-IT)
NCT02548351 Obeticholic Acid 3 NASH fibrosis 2000 Recruiting
(REGENERATE)
NCT03053050 Selonsertib 3 NASH advanced fibrosis 800 Recruiting
(STELLAR 3)
NCT03053063 Selonsertib 3 NASH cirrhosis 800 Recruiting
(STELLAR 4)
NCT01899859 GR-MD-02 1 NASH cirrhosis 31 Completed
NCT02462967 GR-MD-02 2 NASH cirrhosis 156 Ongoing, finished recruitment
NCT02806011 Livercellgram 2 Alcoholic cirrhosis 50 Recruiting by invitation
NCT01452308 Simtuzumab 2a Any 20 Completed
NASH: non-alcoholic steatohepatitis
162 Hepatoma Research ¦ Volume 3 ¦ August 08, 2017