New Drugs for Hepatic Fibrosis

Abstract

The morbidity and mortality of hepatic fibrosis caused by various etiologies are high worldwide, and the trend is increasing annually. At present, there is no effective method to cure hepatic fibrosis except liver transplantation, and its serious complications threaten the health of patients and cause serious medical burdens. Additionally, there is no specific drug for the treatment of hepatic fibrosis, and many drugs with anti-hepatic fibrosis effects are in the research and development stage. Recently, remarkable progress has been made in the research and development of anti-hepatic fibrosis drugs targeting different targets. We searched websites such as PubMed, ScienceDirect, and Home-ClinicalTrials.gov and found approximately 120 drugs with anti-fibrosis properties, some of which are in phase Ⅱ or Ⅲ clinical trials. Additionally, although these drugs are effective against hepatic fibrosis in animal models, most clinical trials have shown poor results, mainly because animal models do not capture the complexity of human hepatic fibrosis. Besides, the effect of natural products on hepatic fibrosis has not been widely recognized at home and abroad. Furthermore, drugs targeting a single anti-hepatic fibrosis target are prone to adverse reactions. Therefore, currently, the treatment of hepatic fibrosis requires a combination of drugs that target multiple targets. Ten new drugs with potential for development against hepatic fibrosis were selected and highlighted in this mini-review, which provides a reference for clinical drug use.

Keywords: HSCs; anti-hepatic fibrosis drug; hepatic fibrosis; inflammation; oxidative stress.

FIGURE 1

Structural formula of new drugs with anti-hepatic fibrosis effects. (1) Cenicriviroc is a dual antagonist of CCR2/5, which also inhibits both HIV-1 and HIV-2, and displays potent anti-hepatic fibrosis activity. (2) Elafibranor is a double agonist of PPARα/δ, and both animal experiments and clinical trials have found that it has anti-hepatic fibrosis activity. (3) Emricasan is an irreversible pan-caspase inhibitor, which is currently in a phase 2 clinical trial to test its efficacy in treating liver injury and fibrosis, although its clinical trial results are controversial. (4) Liraglutide is a GLP-1 receptor agonist used clinically to treat type 2 diabetes, which functions by ameliorating the progression of NAFLD in patients with T2DM. (5) Obeticholic acid is a potent, selective, and orally active FXR agonist; FXR has been shown to reduce inflammatory mediator expression in HSCs via the induction of PPARγ, suggesting that FXR is an ideal target for the treatment of hepatic fibrosis. (6) Pentoxifylline is an orally active non-selective PDE inhibitor, with anti-inflammatory and anti-proliferation effects. PDE has a strong anti-fibrosis effect but needs more in-depth research. (7) Pirfenidone has broad-spectrum anti-fibrosis effects and is the first drug to demonstrate some efficacy for IPF, which was approved by the FDA in 2008. The mechanism of action of Pirfenidone may be related to the reduction of TGF-β-induced signal transduction pathways. (8) Sorafenib is a multikinase inhibitor of Raf-1, B-Raf, and VEGFR-2, an inhibitor of tyrosine protein kinases that targets the Raf/Mek/Erk pathway. Animal experiments have shown that Sorafenib has anti-fibrosis effects, and the mechanism may be related to inhibiting the TGF-β1/Smad3 pathway.

FIGURE 2

Main targets of new drugs against hepatic fibrosis. Hepatic fibrosis can be induced by various factors, including HBV, HCV, alcohol, obesity, and NFALD, all of which can stimulate the normal liver to induce an inflammatory response. Various cells in the liver, mainly hepatocytes, macrophages, and HSCs, secrete inflammatory cytokines (mainly IL-1β, IL-6, and TNF-α) after receiving stimulation. A large number of inflammatory cytokines continuously stimulate HSCs, inducing activation, proliferation, and the secretion of many fibrosis cytokines, including α-SMA, TGF-β, collagen-I, and Collagen-Ⅲ, which are important components of the ECM. The chronic accumulation of ECM eventually leads to hepatic fibrosis. Inhibiting the activation and proliferation of HSCs and reducing the accumulation of ECM are the most important methods to reverse hepatic fibrosis. Numerous recent studies have found many targets for inhibiting the process of hepatic fibrosis, which has led to the development of novel therapeutic drugs, mainly activators of PPAR α/δ, agonists of FXR, antagonists of CCR2/5, Galectin-3 inhibitor, GLP-1 analog, inhibitors of VEGFR-2/PDGF-β, LOXL2 inhibitor, Pan-caspase inhibitor, a Phosphodiesterase inhibitor, and TGF-β signaling inhibitors.

FIGURE 3

Potential candidates for hepatic fibrosis and their mechanisms of action. Inhibiting the activation and proliferation of HSCs is an important method for the prevention and treatment of hepatic fibrosis. Various representative drugs have emerged for different targets. (1) PPARs are members of the nuclear receptor superfamily, and the PPAR agonist Elafibranor can inhibit liver fibrosis through direct anti-inflammatory effects and indirect improvement of the oxidative stress state. (2) Additionally, a representative FXR receptor agonist, Obeticholic acid, has been shown to reduce liver inflammation and promote ECM degradation to alleviate hepatic fibrosis. (3) Simtuzumab is a monoclonal antibody currently being developed by Gilead for NASH, cirrhosis, and advanced hepatic fibrosis blocking of LOXL2. LOXL2 is a protease that modifies the ECM by promoting the cross-linking of collagen fibers and is believed to play an important role in tumor progression and fibrosis. (4) Emricasan is an irreversible pan-caspase inhibitor, which can reduce the activity of caspases to improve the inflammatory environment and inhibit HSC activation. (5) The GLP-1R agonist Liraglutide can inhibit the formation of ECM and reduce the liver inflammatory response and fibrosis process. (6) Belapectin is a galectin-3 antagonist, which can alleviate hepatic fibrosis and portal hypertension in rats and was found to be safe and well-tolerated in a phase I trial. (7) The CCR2/5 antagonist Cenicriviroc can improve hepatic fibrosis by inhibiting liver inflammation. Cenicriviroc is not only effective for early hepatic fibrosis but also feasible for maintenance treatment in patients with advanced fibrosis. (8) Pentoxifylline is a non-specific PDE inhibitor, which can increase intracellular cAMP concentration and plays an anti-hepatic fibrosis role by inhibiting TNF-α production. (9) Attenuating TGF-β-induced signal transduction pathways can inhibit hepatic fibrosis, such as via Pirfenidone (10) Sorafenib can inhibit VEGFR-2 and PDGF-β to alleviate hepatic fibrosis.