Understanding the Role of PPAR Agonists in PBC Care, with Aparna Goel, MD

In 2024 alone, the field of hepatology saw the addition of 2 new second-line treatment options for primary biliary cholangitis (PBC) with the FDA accelerated approvals of elafibranor (Iqirvo) and seladelpar (Livdelzi).1,2

A chronic and progressive autoimmune liver disease affecting intrahepatic bile ducts, PBC treatment has historically relied on ursodeoxycholic acid. While this continues to be the only first-line therapy, many patients do not respond to or are unable to tolerate it, underscoring the need for more treatment options to prevent progression to cirrhosis and eventual liver failure as well as to improve symptoms most negatively impacting patients, including pruritus and fatigue.

For additional insight into the importance of second-line therapies for ursodeoxycholic acid nonresponders and the role peroxisome proliferator-activated receptor (PPAR) agonists play in their care, the editorial team of HCPLive Hepatology spoke with Aparna Goel, MD, an associate professor of medicine at Stanford University and a transplant hepatologist in the division of gastroenterology and hepatology at Stanford University Medical Center.

HCPLive Hepatology: Can you explain the historical treatment landscape for PBC and why second-line therapies are so important?

Goel: Treatment for PBC has relied on Ursodiol, or ursodeoxycholic acid, as first-line therapy for a very long time, but we know that about 40-50% of patients will have an inadequate response or will be intolerant to it. That leaves about half of our PBC patients who are not meeting our therapeutic target goals of alkaline phosphatase levels and that's the population that has an unmet need for second-line therapy.

HCPLive Hepatology: 2024 was an exciting year for second-line therapies in PBC. Can you tell me a little bit about seladelpar and elafibranor and, in general, what is known about the PPAR class’s benefit for the treatment of PBC?

Goel: We've actually been using PPARs for the management of PBC for quite a long time. Bezafibrate and fenofibrate are also PPARs, and bezafibrate is not available in the US but is available in multiple places around the world. There's really good data to suggest that there are pretty dramatic benefits in our patients with PBC, with really high rates of alkaline phosphatase reductions, normalization of alkaline phosphatase, and improvements in itch with PPARs.

We've used fenofibrate off-label, and it's even in the guidelines to be considered as off-label therapy for patients who are nonresponders to ursodeoxycholic acid. So PPARs have had a place in the treatment landscape of PBC, we just haven't had any that are FDA-approved for the treatment of PBC in the US until 2024.

2024 was really exciting because we saw the approval of both seladelpar and elafibranor. Seladelpar is a selective PPAR delta agonist, and elafibranor is a dual PPAR alpha and delta agonist. There are different regulatory functions that these PPAR isoforms play in the liver, the cholangiocytes, and the Kupffer cells, but in general, we know that this class of drugs regulates bile acid synthesis, lipid metabolism, and fatty acid oxidation. It's involved in anti-inflammatory benefits and potentially anti-fibrotic benefits as well.

We've seen some great results that led to the approval of both drugs in 2024. I think we have a lot more to learn about what other benefits there might be besides alkaline phosphatase reduction, but they’re great options to have for second-line therapy.

Editors’ note: Goel has no relevant disclosures.

References

1. Brooks A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed March 24, 2025. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc

2. Brooks A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. HCPLive. August 14, 2024. Accessed March 24, 2025. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis