Assessing the Use of Non-Invasive Biomarkers in Drug Development for Pre-Cirrhotic Nonalcoholic Steatohepatitis

Authors:: Poster Author(s)

Tian, Xiaofan, FDA/CDER (Student); Li, Shen (Steven), FDA/CDER (Mentor)

Center:: Contributing Office

Center for Drug Evaluation and Research

Abstract

Poster Abstract

Background

Nonalcoholic steatohepatitis (NASH) is a chronic and progressive liver disease that can lead to adverse clinical outcomes including cirrhosis, hepatocellular carcinoma and even death. Currently, there is no FDA-approved medication for the treatment of NASH. One of the key hindrances to drug development for NASH is its long clinical course along with the lack of validated non-invasive biomarkers as surrogate endpoints. Currently, histological outcome detected by liver biopsy is the only FDA-recommended surrogate efficacy endpoint. However, liver biopsy is an invasive procedure associated with bleeding, pain, and risk of infection. It is also associated with high cost and long trial duration, making it a cumbersome procedure to include in clinical studies.

Objective

The objective of this study is to assess the correlation of non-invasive biomarkers with histological endpoints to better predict and evaluate drug efficacy for pre-cirrhotic NASH.

Methods

A comprehensive search was conducted on clinicaltrials.gov to gather a list of published phase 2 and phase 3 studies in pre-cirrhotic NASH. A total of 12 studies were included for analysis after accounting for sample size, trial duration, and outcome measures.

Results

A negative correlation is observed with the change of liver-specific biomarkers (i.e., ALT and AST) and response rate for NASH resolution. Moreover, biomarkers reflective of extracellular matrix turnover (i.e., CK-18 M30, CK-18 M65, and ELF score) are negatively correlated with response rate for both NASH resolution and fibrosis improvement. Adiponectin, a metabolic modulator, shows a positive correlation with the two histological endpoints. On the other hand, non-specific biomarkers (e.g., body weight, glycemic parameters, and lipid panel) fail to show a strong correlation with the histological outcomes as they are subject to the influence of many covariates.

Conclusion

Overall, data suggest that the investigation of non-invasive biomarkers should focus on markers specific to the pathology of NASH over non-specific biomarkers. A combination of biomarkers might be essential for the evaluation of NASH activity and fibrosis stages. Future investigation with a larger sample size is warranted to better elucidate and confirm the correlation.