Understanding Elafibranor and Seladelpar for PBC, 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 clinical impact of having elafibranor and seladelpar as treatment options for PBC and what’s next in PBC research, 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: Clinically, what has been the impact of now having these new second-line therapies as options to offer patients?

Goel: It's great to have options for our patients. When we have 3 different approved second-line therapies that we can offer our patients who are not responding to Ursodial as well as we want them to, it's all about going through the historical data and looking at what long-term data we have for these drugs, what the efficacy rates are, what the side effect profile is, and understanding what other medications they are on that might impact that which drug you try to use, if they have concomitant itch or not, if they have significant fatigue or not.

It's very nuanced in terms of which medicine you might recommend, but I think it's important for us to review all these medications with our patients. Our patients are excited, I think many patients love seeing their alkaline phosphatase levels reach normal values. For the first time in decades, some of them are getting to normal values with the addition of second-line therapy that they can tolerate.

Beyond the biochemical response that patients are seeing with these drugs, I think both of them have also shown potential benefits in terms of improvements in pruritus and improvements in fatigue. It's really nice to be able to see that impact for our patients in terms of their quality of life as well.

HCPLive Hepatology: Are there any drugs or trials in PBC that you're most looking forward to seeing more of in 2025?

Goel: PBC has definitely been saturated with new second-line therapies. There’s actually another PPAR currently being studied in PBC, saroglitazar, which is a dual PPAR-alpha/gamma agonist, so we'll have to see the results of that.

In terms of PBC, I think what is exciting to see on the horizon is what the long-term benefits of these medications are going to be. It's not just about improving alkaline phosphatase levels, but are we confident that the improvement in the alkaline phosphatase levels is the equivalent of an improvement in liver-related health? Are we preventing transplantations? Are we improving rates of hepatic decompensation? Only with time will we truly be able to determine that.

We also need to understand more about the side effect profile of these medications. There was an increased risk of fractures for both seladelpar and elafibranor in the studies, so I think really understanding what the PPARs are doing to the bones will be interesting.

We need to better understand these drugs’ impact on quality of life. These are exploratory endpoints that were studied in both of the trials, and while there were signals for improved itch and improved fatigue, I think we have to understand what the mechanism is there and how we can potentially use these medicines to help patients with these symptoms, even if their alkaline phosphatase levels might not be incredibly abnormal.

There's a big push in PBC of not just treating to mild elevations of alkaline phosphatase, but really pushing to normal values. I said 40-60% of the population of those with PBC are nonresponders, but that's if we look at an alkaline phosphatase threshold of 1.5 or 1.67 times up the limit of normal. If we look at anyone that's above normal after a year of Ursodial, that number probably goes up to closer to 70%, maybe even 75%. I think there's a big population of patients who will benefit from bringing their alkaline phosphatase levels down to normal, and it’s important to understand the clinical impact of that and what the benefit is for our patients.

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