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Key Updates on PBC Management
Key Updates on PBC Management From ACG and AASLD 2025

Released: December 24, 2025

Nancy Reau
Nancy Reau, MD
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Key Takeaways
  • New data presented at the 2025 ACG and AASLD meetings support the long-term, sustained efficacy and safety of the PPAR agonists seladelpar and elafibranor for second-line treatment of PBC.
  • The IBAT inhibitors volixibat and linerixibat showed significant, sustained reductions in pruritus and improvements in quality-of-life measurements.

There were several impactful presentations focused on primary biliary cholangitis (PBC) presented at the 2025 American College of Gastroenterology (ACG) and American Association for the Study of Liver Diseases (AASLD) meetings. 

We now have 2 PPAR agonists approved for second-line therapy for people who did not achieve biochemical remission with ursodeoxycholic acid or in whom therapy was limited by intolerance. This is important because approximately 40% of people with PBC have inadequate response to first-line therapy.

Sustained Efficacy With New PPAR Agonists
Both new PPAR agonists have shown rapid reductions in alkaline phosphatase, but it is important to show that this response is sustained and the agents are safe. Although it will take time to demonstrate that these biochemical measures are associated with long-term outcomes, we can look at other surrogates such as elastography and serum biomarkers associated with fibrosis. 

It was exciting to learn that both PPAR agonists showed sustained efficacy. Data were presented with up to 36 months of treatment with seladelpar. It remained effective with sustained improvement in markers of cholestasis.  At 36 weeks, 67% of patients had achieved a composite biochemical response (alkaline phosphatase [ALP] <1.67x upper limit of normal, ALP decrease ≥15% from baseline, and total bilirubin normalization), and approximately 33% achieved a deep response (normalization of both total bilirubin and ALP), showing that this is a great option for patients who have not responded to ursodeoxycholic acid.

Despite enrolling people with cirrhosis, there were no new safety signals. The drug was well tolerated with improvements in itching, which is incredibly impactful for patients.

Of equal importance, people receiving seladelpar had improvements in liver stiffness, with 27% of those with a baseline liver stiffness measurement (LSM) of 16.9 kPa or higher moving to <10.7 kPa. Those who had progression by LSM were more likely to have had higher baseline alkaline phosphatase, emphasizing the importance of recognizing inadequate biochemical response early. 

Elafibranor, also a PPAR agonist, similarly achieved rapid biochemical response that was sustained. At 182 weeks of treatment, 72% of participants achieved a biochemical response and nearly 20% normalized ALP.  Although LSM and enhanced liver fibrosis scores were stable, there was improvement in N-terminal type III collagen propeptide (PRO-C3), which is a marker of fibrogenic activity. Improved levels suggest a favorable impact on fibrosis. By contrast, PRO-C3 increased in those receiving placebo.

Furthermore, there was improvement in both fatigue and pruritus. There were no new safety signals and no CPK elevations.

Both studies support the use of PPAR agonists for long-term treatment of PBC, with improvement not just in markers of disease activity, but also in disease associated symptoms. 

Potential Treatments for Itching and Fatigue

Itching and fatigue are consistently reported in people with PBC and are highly impactful on quality of life.  Unfortunately, these disease-associated symptoms may not improve with ursodeoxycholic acid and do not correlate with disease activity.  People can be incapacitated by the disease even if the liver injury is mild.

In a real-world study using US claims and laboratory data of people with PBC, pruritus was a significant contributor to healthcare resource utilization and costs. People with PBC-associated pruritus had higher utilization of outpatient and emergency room visits and inpatient stays. They also had higher prescription counts.

Traditionally, these symptoms had few treatment options. Ileal bile acid transit (IBAT) inhibitors are a new class of agents being investigated for cholestatic itching.

Earlier interim data from the VANTAGE study showed that individuals receiving the IBAT volixibat had less pruritus, and newly presented data demonstrated improved patient-reported outcomes, as measured by PROMIS scores, in both fatigue and sleep after 28 weeks.

GLISTEN is a phase III, randomized, double-blind, placebo-controlled study of 238 patients with PBC and moderate to severe pruritus receiving the IBAT inhibitor linerixibat. At Week 24, the agent was associated with significant reduction in potential pruritus mediators vs placebo, which correlated with reductions in pruritus and was sustained over the treatment period. Linerixibat also modulated C4 and FGF-19 levels as expected.  Furthermore, these effects were reversible upon linerixibat treatment discontinuation

In conclusion, data from ACG and AASLD give hope to our patients with PBC who have not yet achieved biochemical remission or are struggling with disease-associated symptoms. 

Your Thoughts
Given that both the PPAR agonists and the IBAT inhibitors appear to improve symptoms of PBC (namely pruritus), how do you think healthcare professionals should approach second-line treatment selection in the real world, if and when the IBATs become widely available? Leave a comment to join the discussion!

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