Bile Acids-Based Therapies for Primary Sclerosing Cholangitis: Current Landscape and Future Developments.

Area of Science:

• Hepatology and Gastroenterology
• Drug Discovery and Development
• Immunology

Background:

• Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease with no approved therapies.
• Ursodeoxycholic acid (UDCA) is commonly used but lacks evidence for improving transplant-free survival.
• The pathogenesis of PSC involves cholangiocytes and immune dysregulation.

Purpose of the Study:

• To review current and emerging therapeutic strategies for PSC.
• To highlight novel drug candidates targeting various pathways implicated in PSC.
• To emphasize the importance of targeting bile acid metabolism and gut microbiota.

Main Methods:

• Review of preclinical and clinical studies on PSC therapeutics.
• Analysis of drug classes including FXR agonists, FGF19 analogues, and PPAR agonists.
• Exploration of agents targeting GPBAR1 (TGR5), gut microbiota, and fibrotic pathways.

Main Results:

• Several drug classes are under investigation, with FXR agonists being the most prominent.
• Targeting bile acid metabolism, including ASTB/IBAP inhibitors and FGF19 analogues, is a key area.
• Modulating GPBAR1 (TGR5) on cholangiocytes and addressing gut dysbiosis are promising avenues.

Conclusions:

• A diverse range of novel therapeutic agents are in development for PSC.
• Targeting specific molecular pathways and the gut-liver axis holds significant promise for future treatments.
• Further research is crucial to establish the efficacy and safety of these emerging therapies for PSC.