Robert Gish, MD: Advancements in Therapeutic Development, Combination Therapy in PBC

Robert Gish, MD

Credit: Robert G Gish Consultants, LLC

Recent years have seen a growing interest in the development and study of different therapeutic approaches in the treatment of primary biliary cholangitis (PBC), as evidenced by the recent US Food and Drug Administration approval of elafibranor (Iqirvo) and various other agents in development for the chronic cholestatic autoimmune disease.¹

Ursodeoxycholic acid (UDCA) is the first-line treatment in PBC, although there is a growing interest in combination therapy integrating second-line treatments. Prior to the approval of elafibranor on June 10, 2024, obeticholic acid (OCA) was the only second-line option. Now, with 2 on-label options for second-line therapy and a third on the horizon with an FDA decision for seladelpar expected in August, the growing armamentarium of treatments being explored and garnering regulatory approval for PBC are fundamentally reshaping care for these patients.^1,2,3

For insight into recent and ongoing developments in the treatment of PBC and what the future may hold, the editorial team of HCPLive Hepatology spoke with Robert Gish, MD, principal of Robert G Gish Consulting LLC and medical director of the Hepatitis B Foundation.

HCPLive Hepatology: We’ve seen a considerable amount of interest in the ongoing development and study of therapeutic approaches leveraging different MoAs in PBC. Can you describe how this reflects the unmet need in PBC and why this pipeline development with elafibranor was merited?

Gish: PBC used to be a disease that was uniformly fatal and would present with cholestatic disease, end-stage liver disease, jaundice, and that's where it got the name primary biliary cirrhosis. But, over the years, we diagnosed patients much earlier and intervened earlier, and we've slowed disease with the medication ursodeoxycholic acid, which is first-line therapy. The big gap there is somewhere around 40% of people with PBC are not being treated with any medication whatsoever. Everybody who has PBC should be on ursodeoxycholic acid, in my opinion. There's a perception that this is a very slowly progressing or nonprogressive disease and it's not urgent to treat people or many people don't need treatment. This, of course, needs to be corrected through further education.

We have a good second-line therapy called OCA, obeticholic acid, and this medication has also been documented to stabilize disease, improve liver enzymes, and improve liver function. Liver enzymes are different than liver function, of course, with alkaline phosphatase and GGT being the dominant biomarkers we use in PBC for disease progression, risk of disease progression, and following patients. The higher the enzymes, the more likely patients are going to progress and the more likely they are to progress rapidly. We want liver enzymes and liver function to be decreased on therapy, and importantly, if possible, normalized. That's really the best endpoint for these treatments.

There's also a side effect profile with OCA, which is itching. Some patients avoid the medication and some providers don't want to use the medication because dealing with itching is a lot of work. We need to make our patients' quality of life better, but it's a step therapy, and sometimes people are on 2 or 3 medicines to manage the itching that's there. If you take all the patients who have progressive disease or are at risk of progressive disease, 1 out of 5 patients are on OCA and really should be treated with one of the second-line medications.

We have the emergence and recent approval of elafibranor. This is a paroxysmal proliferation agent that changes the biochemistry in the liver, changes inflammation in the liver. We're hoping at some point we can prove that it reverses fibrosis. That has not been proven yet, but stabilizing disease is clear. It met its primary endpoint, which is what the FDA and regulatory agents use in terms of improvement of alkaline phosphatase and normalization of bilirubin, if the bilirubin is elevated.

I think this will fill a gap because elafibranor is neutral to positive in terms of itch management. In general, it does not cause worsening of itching or new onset itching in PBC patients. There's a trend, although not statistically significant, that it may improve itching in some patients, so this would make it a favorable medication in people with PBC who have itch, who are concerned about itching, or concerned about itching being worse.

Elafibranor has a different mechanism of action than OCA, which is an FXR agonist. FXR changes bile acid metabolism, inflammation, fibrosis signaling, and the PPARs work through a different pathway, improving enzymes, improving liver inflammation, improving biomarkers. We're going to predict from the data that we've seen with this family of second-line drugs that it's going to stabilize disease in the majority of patients and hopefully, in the future, we'll prove that it can reverse fibrosis.

We're also expecting the approval of seladelpar to take place at the end of the summer. Seladelpar is a delta PPAR agonist, and it also has met its phase 3 endpoints of improving alkaline phosphatase and normalizing bilirubin. It also has an advantage in terms of anti-itch. So seladelpar is in the loop, and that's going to give us 3 options that will be on label for second-line therapy.

HCPLive Hepatology: The development of new agents is driven in large part by increases in understanding of pathophysiology. Why is it important to continue to examine the effects of an agent like OCA on these markers?

Gish: What we really need in the PBC world is long-term data with what we call hard endpoints. That's a little bit of a harsh word, because we want to prevent death, cirrhosis, and transplant. There is real-world data that OCA does prevent those outcomes, and it's real-world data that we are going to have to depend on to show these long-term benefits in all of these agents. We do have real-world data with UDCA showing that it changes outcomes, but it's not enough. That's why we need second-line agents, and it's good that we're going to have a choice of second-line agents.

But again, back to real-world data, if you look at different studies, we're looking at outcomes that are favorable for patients. I have a mantra that I tell my providers and my patients that no patient should be going to transplant and no patient should develop end-stage liver disease. We now have a whole armamentarium of medications to treat PBC, and we need to raise awareness and increase treatment.

HCPLive Hepatology: Moving forward, how do you think the advent of new agents will change the discussions around combination therapy approaches among patients with PBC?

Gish: Whenever there's a new medication that comes to market, there is a new emphasis on education. We call it disease-state education. There's also a new emphasis on promotional talks from companies bringing the medication out. Also, the new agents, with the company support, direct education through CME programs. We have a lot of different methods to get the message to the community about diagnosing PBC, staging PBC, intervention for PBC with medications. Of course, one of our biggest issues is improving quality of life.

HCPLive Hepatology: What agents or trials, not limited to PBC but across hepatology as a whole, are you most looking forward to in the second half of 2024?

Gish: There are 2 big areas I'd like to emphasize. One is fatty liver, which goes under a variety of names, including MASLD, MASH, and MAFLD. We just had a recent medication that was approved for fatty liver, resmetirom, and I'm expecting to have a lot more data now on fatty liver treatments in the next 6 to 12 months. The other very exciting area is hepatitis B. There are over 30 medications in development for hepatitis B that we think will lead to a much higher rate of functional cure in the next 5 to 7 years. In the next 6 to 12 months, we think there's going to be a lot of interesting phase 2 and phase 3 data that's really going to make this prediction realistic.

Editors’ note: Transcript was edited for clarity using AI.

Editors’ note: Gish has relevant disclosures with AbbVie, Gilead, Abbott, Arrowhead, Genentech, Janssen, Lilly, Pfizer, Bristol-Myers Squibb, and others.

References:

1. ^{Brooks, A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed June 19, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc}
2. ^{US Food and Drug Administration. FDA approves Ocaliva for rare, chronic liver disease. May 31, 2016. Accessed June 19, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-ocaliva-rare-chronic-liver-disease}
3. ^{Brooks, A. Seladelpar NDA Submitted to FDA for Primary Biliary Cholangitis. HCPLive. December 15, 2023. Accessed June 19, 2024. https://www.hcplive.com/view/seladelpar-nda-submitted-to-fda-for-primary-biliary-cholangitis}