PSC Therapeutic Horizon 2025 | New Treatments for Primary Sclerosing Cholangitis | Dr. Bilal Bobat

Overview

This lecture by Dr. Bilal Bobat provides a comprehensive review of the current understanding and emerging therapeutic landscape for Primary Sclerosing Cholangitis (PSC), a rare progressive cholestatic liver disease with significant unmet medical need and historically limited treatment options.

Key Clinical Topics

• Epidemiology, pathogenesis, and natural history of PSC
• Limitations of existing therapies, including ursodeoxycholic acid (UDCA)
• Nuclear and membrane receptor-based therapies (FXR and FGF19 analogs)
• Antifibrotic agents and novel bile acid derivatives
• Gut microbiome and gut-liver axis as therapeutic targets
• Immunomodulatory approaches and their limitations

Key Learning Points

• PSC definition: A chronic progressive inflammatory disorder causing cholestasis through damage to intra- and/or extrahepatic bile ducts, ultimately resulting in biliary cirrhosis
• Epidemiology: Global incidence of 0.4–2 per 100,000; prevalence of 1 per 100,000; 60–70% male predominance; mean diagnosis age 30–40 years; median transplant age 48 years
• IBD association: Up to 70% of PSC patients have concurrent IBD; conversely, only 4–5% of IBD patients have PSC
• No established medical therapy: No agent has demonstrated clear mortality or transplant-free survival benefit in PSC
• Ursodeoxycholic acid (UDCA): Current guidance supports dosing at 13–23 mg/kg/day; high doses exceeding 23 mg/kg/day are associated with worsening fibrosis and increased malignancy risk and should be avoided
• UDCA response monitoring: Continue therapy if alkaline phosphatase (ALP) drops by ≥40% or falls to <1.5× upper limit of normal (ULN) within 12 months; consider withdrawal if targets unmet
• Malignancy risk: Patients with PSC face elevated risk of cholangiocarcinoma, hepatocellular carcinoma, and colorectal adenocarcinoma
• Nor-ursodeoxycholic acid (NorUDCA): A UDCA derivative with enhanced cholangiohepatic shunting; induces a bicarbonate-rich choleresis; anti-inflammatory and antifibrotic; first agent to show benefit in a phase three trial (NUC-3 trial)
• Elafibranor (PPAR-α/γ agonist): Targets immune regulation, cholestasis, and fibrosis; studied in the ELMWOOD phase two trial
• Obeticholic acid (OCA): FXR agonist showing 14–25% ALP reduction in phase two; fibrosis endpoint not met; phase three not currently planned; further uncertainty following COBALT trial results leading to OCA withdrawal in PBC
• Aldafermin: FGF19 analog showing improved fibrosis markers despite static ALP, raising questions about appropriate trial endpoints in PSC
• Bepirovirsen (Betratinib): TGF-β inhibitor with antifibrotic properties; phase two trial showing early improvements in ALP, liver stiffness, and quality of life
• Nidufexor/Neboglamine (CCL24 inhibitor): Monoclonal antibody blocking the CCL24–CCR3 axis, inhibiting fibroblast differentiation; CCL24 highly expressed in PSC biopsies; studied in the SPRING phase two trial (76 patients)
• Bezafibrate: Available off-label in some regions; used for pruritus relief and showing ALP reduction when combined with UDCA; renal and muscle-related side effects require monitoring

Clinical Data & Study Results

• Epidemiologic study (Hepatology, 2013 — Netherlands cohort): Median time to liver transplant or PSC-related death was approximately 13 years in liver transplant centre patients and 20 years in non-transplant centre patients
• NUC-3 trial (NorUDCA): Dose-dependent ALP reduction up to **