Table 3.
Summary of the treatments in development for NAFLD (#) and ALD (§).
| Compound | Classification | Effect | Mechanisms of action |
|---|---|---|---|
| Cenicriviroc # | CCR2-CCR5 dual antagonist | Fibrosis regression Improvement of grade-2 ballooning (42) |
Reduction high-sensitivity C-reactive protein, IL-6, IL-1ß, and fibrinogen Reduction of monocyte activation through CCR2-CCR5 blockade (42) |
| Selonsertib #,§ | ASK-1 inhibitor | Fibrosis regression No effect on steatohepatitis No effect on metabolic parameters (43) |
Reduction p38 and JNK phosphorylation (44) Inflammatory signaling pathways blockade Macrophage activation impairment (43) |
| Elafibranor # | Dual PPARα-δ agonist | Resolution of NASH without worsening of fibrosis Regression of fibrosis (if response to treatment) Improvement of serum lipids Improvement of glycaemic control Reduction of calculated overall cardiovascular risk (45) |
PPARα: Control of fatty acid transport and β-oxidation Dampening of inflammatory response (47, 48) PPARδ: M2 polarization of KC (49) |
| Lanifibranor | Pan-PPAR agonist |
Improvement of liver histology Anti-fibrogenic effect Improvement of insulin sensitivity and serum triglycerides Improvement of body weight and adiposity index (46) |
Decreased expression of inflammasome components (50) PPARγ: Promotion of adipocyte differentiation (51) Increase of glucose uptake and reduction of triglycerides (52, 53) Increase of anti-inflammatory cytokines (54) |
| Obeticolic acid #,§ | Bile acid FXR agonist | Improvement of fibrosis Improvement of steatohepatitis (55, 56) Decrease of HDL No improvement of glycaemic control (55) |
Targets KC Decrease of TNF-α and LPS Decrease of MCP-1 and IL-10 (57) |
| BAR501 # | GPBAR-1 agonist |
Reduction of steatosis Reduction of inflammation Improvement of fibrosis (58, 59) |
Release of GLP-1 Modulation of macrophage phenotype (58, 59) |
| BI 1467335 # | VAP-1 inhibitor | Reduction of liver injury (60) | Reduction of leucocyte infiltration in the liver during fibrogenesis (60) |
| Tipelukast # | Leukotriene receptor antagonist |
Anti-inflammatory and anti-fibrotic properties Decrease of serum triglycerides (61) |
Down-regulation of inflammation-related genes (including CCR2 and MCP-1) (61) |
| JKB-121 # | TLR-4 receptor antagonist |
Prevention of LPS-induced inflammatory liver injury in MCDD model No benefit on human liver disease (62) |
Stimulation of KC activation (62) |
| Emricasan #,§ | Pan-caspase inhibitor |
Effective in preclinical models of liver injury (including NAFLD and ALD) (63) Decrease of transaminases in viral hepatitis (64) |
Interference with the signaling cascade of the NLRP-3 inflammasome (63) |
| GR-MD-02 # | Galectin-3 inhibitor | Reduction of portal pressure Reduction of occurrence of esophageal varices (65) |
Interference with fibrogenesis (66) |
| HepaStem # | Liver-derived mesenchymal stem cells | Reduction in NAS and fibrosis in mouse model of NASH (67, 68) |
Inhibition DC differentiation Inhibition of TNF-α production Promotion hepatocyte regeneration (67) |
| G-CSF § | G-CSF | Mobilization of hematopoietic stem cells Improvement of liver function and survival in AH |
Stimulation of neutrophil function Mobilization of hematopoietic stem cells Induction of liver regeneration (69–71) |
| DUR-928 § | Small molecule epigenetic regulator | Anti-fibrotic and anti-inflammatory properties (72) | Reduction of MCP-1 and TNF-α (72) |
NAFLD, Non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; ALD, Alcoholic liver disease; AH, alcoholic hepatitis; CCR, C-C chemokine receptor; ASK, apoptosis signal-regulating kinase; PPAR, peroxisome proliferator-activated receptor; FXR, farnesoid X receptor; GPBAR, G protein-coupled bile acid receptor; VAP, Vascular adhesion protein-1; TLR, Toll-like receptor; G-CSF, Granulocyte-colony stimulating factor; IL, interleukin; KC, Kupffer cells; TNF, tumor necrosis factor; LPS, lipopolysaccharide; MCP, monocyte chemoattractant protein; GLP, glucagon-like peptide; NLRP, nucleotide oligomerization domain-like receptor family pyrin domain containing protein; DC, dendritic cells. Preclinical data are indicated in cursive; HDL, high-density lipoprotein; MCDD, methionine/choline- deficient diet.