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PBC FAQs
PBC Questions and Cases: The Place of Newer Therapies

Released: May 01, 2025

Expiration: April 30, 2026

Aparna Goel
Aparna Goel, MD
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Key Takeaways
  • Considerations for starting second-line therapy for PBC should focus on ALP assessment at 6 or 12 months after treatment with UDCA for high-risk and low-risk groups, respectively.
  • Newer PPAR agonists show promising effects on lowering ALP as second-line therapies, and we look forward to longer-term data on liver-related outcomes.

Newer therapies for treatment of primary biliary cholangitis (PBC), such as elafibranor and seladelpar, have the potential to improve not just disease progression, but also extrahepatic symptoms. To understand more about the current treatment landscape of PBC, including the place of these newer therapies, here are my answers to learner questions from a recent educational activity.

Do you ever use initial combination therapy for people with PBC who have risk factors for progression?
The second-line therapies—obeticholic acid, elafibranor, and seladelpar—are indicated for persons who do not have a response to or are intolerant to first-line ursodeoxycholic acid (UDCA), but researchers are still exploring early initiation of combination therapy with UDCA and these second-line agents.

Until we see enough safety and efficacy data from these studies, I would adhere to guideline-recommended treatments. The current treatment guidelines are to start with UDCA monotherapy, then assess the biochemical response at 12 months, or for those at higher risk, at 6 months. Then, a determination can be made as to whether the patient might require combination treatment with a second-line therapy.

How long should you wait to see an effect with UDCA before moving on to second-line combination therapy? What threshold do you use?
For people with a low risk of progression, such as those with a liver stiffness of <10 kPa, I usually wait 12 months to see if UDCA treatment is sufficient to achieve the goal of alkaline phosphatase (ALP) <1.67 times the upper limit of normal (ULN).

However, I also consider ALP level as early as 6 months, especially in people with advanced fibrosis. This is based on data from the Global PBC Study Group cohort. In that study, among a subgroup of people with ALP >1.9 times the ULN at 6 months, only 11% met the treatment goal of ALP <1.67 times the ULN at 12 months. In other words, 89% of people with high ALP were still above the treatment goal after 12 months of UDCA treatment.

If you are going to consider starting second-line combination therapy earlier, the threshold to use is ALP >1.9 times the ULN at 6 months, especially for those at high risk for progression. That provides the best chance of reaching the eventual treatment goal of ALP <1.67 times the ULN.

Having said that, there is some evidence that ALP normalization, rather than just reaching <1.67 times the ULN, is associated with better outcomes. A deep response is better than an adequate response.

What factors do you consider when choosing between elafibranor and seladelpar?
Although not studied head-to-head, the efficacy rates and side effect profiles for the peroxisome proliferator-activated receptors (PPARs) elafibranor and seladelpar are quite similar. The big difference in the mechanism of action is that elafibranor has dual alpha/delta agonism, whereas seladelpar has selective delta agonism.

However, with elafibranor, you need to be mindful of whether a person is also receiving a concomitant statin. Elafibranor is also contraindicated in pregnancy and breastfeeding, so that must be carefully considered when prescribing to women of childbearing age.

When should you monitor creatine kinase levels after starting PPARs?
After starting second-line elafibranor or seladelpar, I check creatine kinase levels at 1, 3, and 6 months. It is especially important to monitor creatine kinase levels if a person is receiving a concomitant statin.

Is there evidence for reversing early F2 or F3 fibrosis scores with PPARs?
That is a very good question, but we do not have an answer to that yet. These therapies were approved based on the surrogate endpoints of biochemical response criteria, such as ALP reduction. We know from UDCA studies that reducing ALP is associated with improved mortality and liver transplant, so we believe that this biochemical response will mirror liver-related outcomes. However, we need to see these data in long-term, real-world studies.

Fibrosis regression is a very slow process, and most of our data for elafibranor and seladelpar are limited to 1-3 years. We do see some stability in FibroScan measurements and stability in Enhanced Liver Fibrosis measurements with these drugs, but I think it is too early to see if there is a signal for improvement in fibrosis. Hopefully in the near future, we will have 5-year and 7-year data to help answer this question.

What are some logistical considerations for getting access to second-line therapies?
First, I have found that insurance companies have been reasonable at approving second-line therapies if the person’s ALP levels have not achieved their treatment goal after a year of first-line therapy.

Some insurance companies have asked me to try obeticholic acid first before using PPARs. However, that requires effective management of any pruritus before starting, as pruritus could worsen with obeticholic acid treatment. PPARs, by contrast, do not worsen pruritus and may actually improve it.

Finally, while awaiting insurance authorization for PPARs, there are ways to obtain these agents for your patients for 1 or 2 months.

Your Thoughts
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