Sonal Kumar, MD, MPH: PPAR Agonists in PBC, Advances in Second-Line Therapy

The primary biliary cholangitis (PBC) treatment landscape has undergone dynamic changes in the past few months with the addition of a pair of new US Food and Drug Administration (FDA)-approved second-line therapies in elafibranor (Iqirvo) and seladelpar (Livdelzi).

While ursodeoxycholic acid (UDCA) has long been the mainstay of treatment for PBC and continues to be the only first-line therapy, many patients do not respond to or are unable to tolerate UDCA, 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.

Previously, the only FDA-approved second-line therapy was obeticholic acid (Ocaliva), a farnesoid X receptor (FXR) agonist that reduces bile acid synthesis and promotes bile acid outflow. Since June, the FDA has approved 2 more second-line therapies for PBC in combination with UDCA in adults who have an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA: elafibranor and seladelpar. Both are peroxisome-activated receptor (PPAR) agonists that have demonstrated significant alkaline phosphatase (ALP) reduction in clinical trials, cited by the FDA as the basis for both accelerated approvals.

For more on the PPAR class and its potential in PBC, the editorial team of HCPLive Hepatology spoke with Sonal Kumar, MD, MPH, an assistant professor of medicine and director of clinical hepatology at Weill Cornell Medical College.

HCPLive: Can you describe the PPAR class and what is known about their use in PBC?

Kumar: PPARs come in a variety of different forms with different pathways, and the new ones that have been approved for primary biliary cholangitis have been shown to play a role in bile acid metabolism the inflammatory pathways that we see in PBC. Now the exact mechanism is not 100% known, but we know through clinical trials they have been shown to reduce alkaline phosphatase and normalize bilirubin to a significant degree, and improvement in these markers has been associated with improved outcomes and survival. Elafibranor is a dual PPAR alpha/delta and seladelpar is considered a delpar, or a PPAR delta.

HCPLive: Looking at elafibranor and seladelpar in particular, how do they compare to each other, and what is the significance of their recent accelerated approvals?

Kumar: Obviously, there has been no head-to-head comparison, so you can't really compare the 2 to each other. I would say that seladelpar is just PPAR delta, so it's a single PPAR pathway, whereas elafibranor is dual. Both have been shown to improve alkaline phosphatase and are thought to affect the inflammatory pathways and bile acid metabolism that are thought to play a role in primary biliary cholangitis. This is a novel mechanism of action in terms of FDA approvals in PBC. Ocaliva, which has been approved for the past 8 years or so, is an FXR agonist, so it works in a completely different way. I will say that fibrates such as fenofibrate, which have been used off-label, and bezafibrate used in Europe, are also considered PPARs, but do not affect the same PPAR pathways that elafibranor and seladelpar do.

HCPLive: When seladelpar was granted accelerated approval, it was coined as the “first and only treatment to demonstrate statistically significant reductions across key biomarkers, ALP normalization and pruritus versus placebo.” Can you explain some of the key clinical trial findings for elafibranor, specifically as they pertain to its impact on itch?

Kumar: So for elafibranor, one of their secondary endpoints was the effect of the drug on pruritus, which is one of the most common symptoms that we see in PBC. There are different tools that we have available to assess for pruritus in patients, and one of the tools, the primary tool that the FDA uses for assessing pruritus, is this Worst Itch NRS Score. It actually was not developed for PBC, but it is a tool that we can use to assess for pruritus and it has been well-validated as a way to assess for changes in itch.

The other 2 tools that were used, which are basically just questionnaires for the patients, are the 5-D itch scale and the PBC-40. Those 2 have been developed for PBC, but the Worst Itch NRS, the WI-NRS score, as I said, is not specific to be used in PBC, but it is what the FDA has recognized as the primary modality for assessing pruritus. And so when elafibranor looked at their secondary endpoints for pruritus, it did not meet statistical significance in terms of improvement in pruritus using that WI-NRS score, but there was a trend towards improvement. It just didn't meet statistical significance, and because it didn't meet statistical significance, the other 2 tools that we can use, the 5-D itch and PBC-40, we can't report that there was statistical significance in those. But, there was an improvement in pruritus using the latter 2 tools, which, again, were developed for PBC.

Editors’ Note: Kumar has relevant disclosures with Cymabay, Intercept, Ipsen, Novo Nordisk, and Gilead.

References

1. ^{Brooks, A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed August 23, 2024. 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 August 23, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis}