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Key PBC Studies From AASLD 2025
CME/CE Information Summary

Activity

Progress
1 2 3
Course Completed
Activity Information

Nurse Practitioners/Nurses: 0.25 Nursing contact hour

Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™

Released: January 06, 2026

Expiration: January 05, 2027

Nancy Reau
Nancy Reau, MD

Dr. Nancy Reau (University of Chicago): Welcome to this educational program titled Keeping Up with New Developments in PBC. I'm Dr. Nancy Reau, Professor of Medicine at Rush University Medical Center in Chicago. This specific Medical Minute will be focusing on key PBC studies from AASLD 2025. Please be sure to check out the other Medical Minutes in this series along with Clinical Thought commentaries and podcasts on the CCO website.

 

[00:00:52]

 

The learning objectives today are to apply new advances in PBC to clinical practice and to formulate patient management strategies based on up-to-date understanding of new and emerging agents for PBC, including mechanisms of action, clinical data safety, and place in therapy.

 

[00:01:15]

 

We're going to start first by talking about treatment goals.

 

[00:01:18]

 

There have been some moving goal posts. In the past, we looked at reduction of alkaline phosphatase, specifically to less than 1.67x the upper limit of normal, but now this is pushing towards deep remission or normalization of alkaline phosphatase. We also previously talked about a normal bilirubin, but it's been recognized that subnormal or a bilirubin less than 0.6x the upper limit of normal is now a better prognostic sign. And then we always want to make sure that we are discussing symptoms, as quality of life is very important to our patients. So the goal of lifelong therapy is to prevent progression of liver disease and to improve disease-associated symptoms.

 

[00:02:02]

 

That takes us to our first investigational therapy for PBC. So the PPARs are new. They've been around for almost a year now for second-line therapy, primarily cholangitis, and we have two, seladelpar and elafibranor.

 

They're slightly different in mechanism of action. So although there are pan-PPARs, such as bezafibrate, seladelpar is a delta-specific PPAR, and elafibranor is a dual agonist from delta and alpha. This means that they both affect the bile acid and cholesterol synthesis, as well as some lipid management. But the delta seems to be a little more specific for inflammatory signals, as well as fibrosis.

 

[00:02:52]

 

So when we're looking at these new therapies, it's really important to know what long-term outcome is. As we get something new, we recognize if it works early, but you really want to make sure that that efficacy is long-lasting and that that efficacy translates into those quality of life or disease progression aspects that we think are so important for our patients.

 

[00:03:16]

 

So the first study that we're going to cover is the RESPONSE and ASSURE study. This is looking at seladelpar. Just as a reminder, individuals that participated in the study could have well-compensated cirrhosis. They were either intolerant or had not had adequate response to ursodeoxycholic acid. This RESPONSE trial was looking at a double-blind, placebo-controlled trial. And then ASSURE is the crossover or the continuation of that seladelpar. And this study now is looking at the long-term efficacy and safety signals all the way up to 48 months of exposure.

 

[00:03:54]

 

So it's really encouraging to see that the composite biochemical response, which is the combination of improvement in alkaline phosphatase of at least 15% from baseline, as well as going lower than the 1.67x the upper limit of normal, and bilirubin normalization was maintained. So you can see from this graphic that very early, about 60% of individuals achieved this biochemical response, and this was well-maintained over the 36-month period.

 

Deep response was described as total bilirubin normalization, as well as a normalization of alkaline phosphatase. And here early, about 17% of individuals achieved that. And that actually increased a little bit over the duration of the study and then was well-maintained.

 

So it's important to remember that about 40% of individuals do not respond to first-line therapy. And here we're capturing the majority of those individuals that did not respond, of which about a third achieved deep biochemical response.

 

[00:04:59]

 

Reminding the clinician that you're going to see an alkaline phosphatase improvement very early in our responders.

 

So you can see that precipitous drop all the way at one month, and then this is nicely well-maintained over the 36-month period.

 

[00:05:16]

 

Now, safety is as important as efficacy, and there were no new adverse events. It's important to remember because patients with more advanced disease could participate. There are going to be some liver-related adverse events, and there was a handful of decompensating events like variceal hemorrhage, hepatorenal syndrome, but these were really felt to be in a minority and not to be treatment-related to the agent. There was only one individual with myalgia and no renal-related events.

 

[00:05:49]

 

Pruritis is a really important complication of this, or an association of this disease, and very life-impactful for our patients. And you can see in the study that patients didn't very early have an improvement in their pruritis, and this was also well-maintained throughout the duration of the trial.

 

[00:06:11]

 

When we're looking at long-term efficacy, we use alkaline phosphatase and bilirubin as surrogates for histology, or even if not histology, long-term outcomes. But this study also was started to capture liver stiffness measurements by elastography, and it was really nice to see that those individuals that had low stiffness maintained that, and some of the individuals that had increased liver stiffness measurements actually had improvement of their stiffness over the duration of the trial.

 

It was much easier to improve if your alkaline phosphatase was normal or lower. So you can see that in the baseline characteristics, alkaline phosphatase was a little bit of a marker for success. If you had greater than 2x the upper limit of normal at baseline, those individuals did have a lower chance of achieving biochemical remission, as well as improvement in histologic endpoints or surrogates for histology. But that does not mean that they worsened.

 

[00:07:19]

 

So, next we're going to turn to ELATIVE. This is looking at 182-week efficacy for our other PPAR agonist, elafibranor.

 

And similar in trial design, this recruited individuals who were either treatment intolerant or had inadequate efficacy with ursodeoxycholic acid alone. They had a double-blind, placebo-controlled period, and then they had an open-label extension phase. And then we are looking at the 182-week interim data.

 

This is also looking at a composite biochemical response of alkaline phosphatase improvement, less than 1.67x the upper limit of normal, as well as a decrease of 15%, at least, from baseline and normalization of bilirubin. And secondary endpoints also achieved or looked at that deep biochemical response or alkaline phosphatase normalization.

 

[00:08:16]

 

Similar to the seladelpar data, biochemical response occurred early.

 

You can see 42% at four weeks. And this was nicely maintained over the 182 weeks, actually increasing to 72%. So, similar to our other study, as a reminder, about 40% of individuals do not achieve a biochemical response with ursodeoxycholic acid alone. And at 182 weeks, we're now capturing 72% of those non-responders. When you look at alkaline phosphatase normalization, this is much harder to achieve. And the numbers were much smaller, but still about 20% of individuals had achieved alkaline phosphatase normalization at that 182-week marker.

 

[00:09:02]

 

Now, we want to use not just a surrogate like alkaline phosphatase, but also measure other markers of fibrosis. And here, they looked at liver stiffness measurement by elastography ELF, which is a nice serum blood test that looks at markers of fibrosis, and then PRO-C3, which is a fibrotic marker. Liver stiffness and ELF definitely were stable through the duration of the trial, and there was a significant improvement in PRO-C3, declining by that 182-week marker.

 

So these are all very, you know, positive towards a prevention of progression, and maybe even improvement in liver fibrosis.

 

[00:09:49]

 

Fatigue and pruritus were also clinically improving in this study. So you can see that using standard scales to assess for fatigue and itching, there was, you know, a decline very early and well-maintained throughout the clinical trial in both itching as well as fatigue.

 

[00:10:11]

 

So the key takeaways. Seladelpar was associated with a rapid and sustained effect on biomarkers of cholestasis, pruritus, and also improvement in liver stiffness measurements at 36 months. The majority of participants did achieve a complete biochemical response, and about a third achieved a deep response at 36 months.

 

Elafibranor also associated with a rapid and sustained effect on biomarkers of cholestasis, as well as stabilization or reduction in those fibrosis markers at 182 weeks, and there were sustained improvements in both fatigue as well as itching.

 

[00:10:48]

 

Because itching is such a significant complication for our patients with PBC, our next trials are really looking at investigational therapies for pruritus.

 

These may not be as impactful on disease progression, but as that significant marker of quality of life, that itching, our IBAT inhibitors, our ileal bile acid inhibitors, are felt to be a really important tool to address pruritus.

 

[00:11:16]

 

This is Vantage. This is looking at changes in pruritus on volixibat. This is a Phase II trial that started with a first dose selection, and then taking that 20 mg dose, going into an open-label extension. This is really looking at week 28 data, looking at the itch, and itch was measured by the itch questionnaire, and then they also looked at health-related quality of life endpoints using PROMIS.

 

[00:11:52]

 

It's nice to see that both fatigue as well as sleep improved on the IBAT inhibitor significantly compared to placebo, and they did combine the 20 mg and 80 mg groups, even though that we know that 20 mg is going to go forward.

 

[00:12:10]

 

So key takeaways.

 

This IBAT inhibitor was associated with improvements in fatigue and sleep at week 28, and the investigators did conclude that improvements in pruritus might result in improvements in fatigue and sleep. So it may not be that these are independent, but rather a reflection that the fact that the individual is not so itchy, they're able to get better sleep, which is going to improve fatigue.

 

Part two of Vantage is ongoing, so we look forward to more data at hopefully AASLD in 2026 and ESL of 2026.

 

[00:12:45]

 

The next IBAT inhibitor is in GLISTEN. This is linerixibat, and this study was a Phase III trial looking at PBC-related pruritus. Here they had a placebo-controlled period for 24 weeks, and then this then extended over into a longer-duration study looking at both safety and tolerability.

 

The primary endpoint was a baseline change from week 24 in the monthly itch score as measured by a numerical rating scale.

 

[00:13:18]

 

So most of us recognize that we don't do these things in clinic, but these are really important tools when you're looking at something for efficacy in a clinical trial. So although we don't really understand completely why patients are itching, there are multiple putrogens or markers of pruritus.

 

In this study, looking at some of the markers that are associated with itching, as well as markers that should either increase or decrease if you achieve bile acid inhibition. So this was associated with a reduction in FGF-19, total serum bile acids, as you would expect, ATX and IL‑31, and an increase in C4, all of which are favorably associated with effects of a bile acid inhibitor or improvements in pruritus.

 

[00:14:10]

 

And you can see that the pruritus as the primary endpoint improved significantly over placebo.

 

[00:14:20]

 

And so the key takeaways are that linerixibat affects key mediators of cholestatic pruritus, thus improving itch. It inhibits the bile acid reuptake from the small bowel, which as you would expect, results in a reduction of FGF-19 and increased C4, as well as the other markers such as total serum bile acids, ATX and IL-31. These effects are maintained over the 24 weeks that it was used. They were reversible. So when you'd stop the treatment, they returned kind of to where you would expect in a person who was not on an IBAT inhibitor. And the investigators concluded that the agent reduced total serum bile acids, leading to downstream effects on the mediators of cholestatic pruritus.

 

[00:15:10]

 

So I want to thank you for joining us today, and please go online for more CCO coverage of PBC.

 

[END OF TRANSCRIPT]