Liver Lineup: Breakthroughs in Cholestatic Liver Disease in 2025

As the calendar turns to 2026, cholestatic liver disease is among the most active and rapidly evolving areas in hepatology. In this special edition episode of Liver Lineup, recorded as part of HCPLive's This Year in Medicine series, hosts Nancy Reau, MD, and Kimberly Brown, MD, break down the most consequential updates of the year across primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH), highlighting data that may reshape both near-term management and longer-term treatment strategies.

A major theme was the persistent underutilization of second-line therapy in PBC. Despite well-established criteria for inadequate biochemical response to ursodeoxycholic acid, real-world data continue to demonstrate many eligible patients are not escalated to additional treatment.

Reau emphasizes newer FDA-approved PPAR agonists have expanded options for patients, removing prior safety barriers that limited use of older agents in advanced disease. As treatment goals evolve toward deeper biochemical response, the hosts say closing this implementation gap remains a critical educational priority.

Additionally, interim results from extension studies for elafibranor and seladelpar indicate sustained alkaline phosphatase and bilirubin response over several years, suggesting improvements rather than late loss of efficacy. While liver stiffness measurements showed stability rather than dramatic regression, other fibrosis-related biomarkers highlight potential antifibrotic benefits with longer follow-up. Brown noted that in chronic liver disease, stabilization itself may meaningfully translate into improved long-term outcomes.

Across multiple studies, PPAR agonists showed sustained reductions in pruritus and fatigue, 2 of the most burdensome symptoms in PBC. Of note, improvements in fatigue appeared independent of pruritus relief or biochemical response, reinforcing the concept that symptom burden does not always mirror disease severity. The discussion raised the possibility that symptom-driven treatment strategies may eventually play a larger role, even if they are not yet reflected in guidelines.

Beyond PBC, Reau and Brown note that emerging therapies for PSC have generated cautious optimism. Phase 2 data for elafribanor demonstrated rapid and sustained reductions in alkaline phosphatase, alongside improvements in itch and fibrosis-related markers.

Although PSC’s heterogeneity complicates the interpretation of surrogate endpoints, Reau highlights the significance of seeing consistent biochemical signals in a disease long defined by therapeutic nihilism. Additional early-stage data targeting inflammatory chemokine pathways with nebokitug further underscored growing interest in mechanism-driven approaches for PSC, even if clinical applicability remains distant.

The conversation then transitioned to autoimmune hepatitis, where treatment options have remained largely unchanged for decades. A novel immunomodulatory agent, zetomipzomib, demonstrated steroid-free biochemical remission in a subset of patients with refractory disease.

Both hosts emphasize the unmet need among patients who cannot be adequately controlled with steroids and antimetabolites and suffer the long-term consequences of chronic corticosteroid exposure.

Collectively, advances in 2025 reflect a cholestasis landscape in transition: durable second-line therapies in PBC, early momentum in PSC, and the first glimmers of innovation in AIH. As Reau and Brown underscore, the challenge now lies not only in advancing the pipeline, but in translating progress into routine clinical practice.

Editors’ note: Relevant Disclosures for Reau include AbbVie, Gilead, Salix, Arbutus, and VIR. Relevant disclosures for Brown include Mallinckrodt Pharmaceuticals, Gilead, Salix, Intercept, Ipsen, and Madrigal.

References

1. Cuoto C, Cancado G, Ferraz ML, et al. TREATMENT OUTCOMES AND UNDERUTILIZATION OF SECOND-LINE THERAPIES FOR PRIMARY BILIARY CHOLANGITIS IN LATIN AMERICA: A CALL TO BRIDGE THE GAP. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

2. Levy C, Akarca U, Alvares-da-Silva MR, et al. Long-term treatment with elafibranor leads to biochemical and symptomatic improvements for at least 3 years in patients with primary biliary cholangitis. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

3. Pratt D, Lawitz EJ, Bowlus CL, et al. Seladelpar Is Associated With a Sustained Reduction in Cholestatic Markers and a Consistent Safety Profile in Patients With Primary Biliary Cholangitis Treated up to 48 Months in the Ongoing, Open-Label ASSURE Study. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

4. Bowlus CL, Levy C, Abouda G, et al. Long-term data of elafibranor in primary sclerosing cholangitis: Interim safety and efficacy data from the ongoing open-label extension of the ELMWOOD phase II trial. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

5. Bowlus CL, Barclay S, Joshi D, et al. Safety and activity of nebokitug over 48 weeks in patients with primary sclerosing cholangitis: Open-label extension results from the SPRING Study. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

6. Kremer A, Jones D, Levy C, et al. Changes in fatigue and pruritus in patients with primary biliary cholangitis treated with elafibranor are largely independent from improvements in serum biomarkers. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

7. Lammert C, Anand N, Bade D, et al. Zetomipzomib, a First-in-Class Selective Immunoproteasome Inhibitor, Demonstrates Steroid Sparing Biochemical Remission in Patients with Relapsed or Insufficiently Responding Autoimmune Hepatitis in a Randomized, Double-blind, Placebo-controlled, Phase 2a Study. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.