Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development

Area of Science:

• Hepatology
• Biomarker Development
• Drug Discovery

Background:

• Assessing antifibrotic drug efficacy in clinical trials is challenging due to slow liver fibrosis progression.
• A significant unmet need exists for predictive biomarkers of fibrosis progression.

Purpose of the Study:

• To develop a fibrosis progression signature (FPS) as a surrogate biomarker to predict future fibrosis progression.
• To validate the FPS in diverse liver disease cohorts and assess its utility in antifibrotic drug development.

Main Methods:

• A 20-gene fibrosis progression signature (FPS) was defined and validated in hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) cohorts.
• The FPS was used to evaluate antifibrotic drug responses in ex vivo liver tissue cultures and a clinical trial.
• A serum protein-based surrogate FPS was developed and tested in compensated cirrhosis patients.

Main Results:

• The 20-gene FPS accurately predicted fibrosis progression in independent cohorts (AUC=0.86).
• BCL2 was identified as a potential therapeutic target, and combination antifibrotic therapies were identified.
• FPS modulation correlated with fibrosis improvement in patients treated with cenicriviroc, suggesting pathway-specific responses.
• A 7-protein serum FPS predicted decompensation in cirrhosis patients.

Conclusions:

• The fibrosis progression signature (FPS) is an etiology-agnostic biomarker for predicting long-term liver fibrosis progression.
• The FPS can significantly inform and accelerate antifibrotic drug development for liver diseases.