New progress of farnesol X receptor agonist in the treatment of nonalcoholic steatohepatitis

Xue Rui, fan Jiangao, Xinhua Hospital Affiliated to Medical College of Shanghai Jiaotong University

Nonalcoholic steatohepatitis is a chronic progressive liver disease characterized by hepatocyte steatosis, ballooning, inflammation and fibrosis. With the increasing prevalence of obesity, type 2 diabetes and metabolic syndrome, non-alcoholic steatohepatitis has become the most common cause of chronic hepatitis and end-stage liver disease in the world. Nonalcoholic steatohepatitis is a key link in the disease spectrum of nonalcoholic fatty liver disease. About 25% of patients with nonalcoholic steatohepatitis can progress to nonalcoholic steatohepatitis, and more than 30% of patients with nonalcoholic steatohepatitis have the potential to develop cirrhosis or hepatocellular carcinoma, However, no specific drugs have been approved for the treatment of nonalcoholic steatohepatitis. Therefore, it is very important to study the pathogenesis and potential drug therapeutic targets of nonalcoholic steatohepatitis.

In recent 20 years, it has been found that bile acids, as signal molecules, bind to receptors and play a central role in the occurrence, progression and regression of nonalcoholic fatty liver disease / nonalcoholic steatohepatitis. In 2015, the mid-term results of flint test "obecholic acid can reduce the activity score (NAS) and fibrosis degree of nonalcoholic fatty liver disease in patients with nonalcoholic steatohepatitis by activating farnesol X receptor" triggered the crazy research on new farnesol X receptor agonists by scholars all over the world. Farnesol X receptor is a nuclear receptor, which is expressed in liver, small intestine, colon, kidney, adrenal gland and ovary, especially in liver and intestine. After activation, farnesol X receptor participates in the occurrence and development of nonalcoholic fatty liver disease by regulating bile acid homeostasis, lipid metabolism, inflammatory response, liver fibrosis and liver regeneration.

Obecholic acid is the first farnesol X receptor agonist to enter the phase II clinical trial of new drug development for nonalcoholic steatohepatitis. The results of phase II clinical flint test showed that obecholic acid significantly improved the liver histological performance of patients with nonalcoholic steatohepatitis. It is the first experimental drug to reduce the NAS score and the degree of fibrosis and improve the liver histological performance. The results of the subsequent phase III regenate clinical trial showed that there was a significant difference in reducing the degree of fibrosis in patients with nonalcoholic steatohepatitis complicated with moderate and severe fibrosis compared with the placebo group, but it did not reach the end point of the regression of nonalcoholic steatohepatitis. In view of adverse reactions such as dose-dependent pruritus and potential atherogenic risks (increased blood LDL cholesterol and decreased HDL cholesterol), the U.S. Food and Drug Administration pointed out in its official reply in June 2020 that the expected benefits of obecholic acid in the treatment of nonalcoholic steatohepatitis did not exceed its potential risks, So far, the U.S. Food and drug administration has not officially approved obicholic acid for the treatment of nonalcoholic steatohepatitis.

A recent IIa clinical trial of a unique non bile acid farnesol X receptor agonist met-409 showed that compared with other farnesol X receptor agonists, met-409 significantly reduced liver fat content, and the incidence and severity of pruritus and high blood LDL cholesterol in the low-dose group (50mg) were significantly lower than those in other experimental drug treatment groups. When the average relative LFC decreased by more than 30%, the incidence of pruritus in the low-dose group was 16%, and the level of low-density lipoprotein cholesterol increased by 9%. The reason for the increase of met-409 treatment index and enhanced efficacy may be that its unique chemical structure can induce different receptor conformations and gene expression profiles. However, some patients in met-409 group had a transient asymptomatic increase in alanine aminotransferase within 4-8 weeks of treatment, and 31-50% of patients treated with met-409 had a relative decrease of more than 30% in the 12th week of treatment. In the future met-409 clinical trial, we need to pay attention to additional monitoring of alanine aminotransferase and other liver markers, and pay attention to the reduction of liver fat reflected by magnetic resonance proton density fat fraction during short-term treatment, which does not mean that continuous treatment can certainly alleviate non alcoholic steatohepatitis and reverse fibrosis. In addition, due to the differences in trial design of clinical trials of different farnesol X receptor agonists in the treatment of nonalcoholic steatohepatitis, the clinical trial data can not be simply compared. Finally, head-to-head direct comparison is needed to clarify the potential differences of different farnesol X receptor agonists. The activation of farnesol X receptor can reduce cirrhotic portal hypertension, repair intestinal mucosal barrier and reduce intestinal bacterial translocation. Therefore, the application of farnesol X receptor agonists may bring liver benefits to patients with pre cirrhotic or cirrhotic nonalcoholic steatohepatitis.

In conclusion, compared with the existing candidate drugs, the structurally optimized farnesol X receptor agonist has a wider therapeutic index and higher efficacy, and may solve the major unmet needs. The risk-benefit ratio of farnesol X receptor agonists can be improved through structural optimization, but the optimal dose after balancing the advantages and disadvantages needs to be explored in larger and longer studies. At present, the main challenge is to optimize the structure of farnesol X receptor agonist and determine the optimal dose, so as to reduce side effects while maintaining deterministic liver histological improvement and clinical efficacy, which is a dilemma to be solved.

Main references

1． Kremoser C. FXR agonists for NASH: How are they different and what difference do they make?  J Hepatol, 2021, 75: 12-15.

2. Harrison SA, Bashir Mr, Lee K-J, et al. A structurally optimized farnesol X receptor agonist, met409, reduced life fat content over 12 weeks in patients with non-alcoholic sterohepatitis. J Hepatol, 2021, 75: 25-33