Alan Bonder, MD, on New Therapies for Pruritis in Liver Disease

Dr Bonder recaps news from the European Association for the Study of the Liver meeting on new therapies being investigated for the relief of pruritis in patients with primary biliary cholangitis. 

Alan Bonder, MD, is medical director of liver transplantation at Beth Israel Deaconess Medical Center and associate professor of medicine at Harvard University Medical School in Boston, Massachusetts.

TRANSCRIPT:

Welcome everyone. I am Dr. Alan Bonder. I am the medical director of liver transplantation at Beth Israel Deaconess Medical Center in Boston, Massachusetts. And this is my second video about talking about updates in autoimmune liver disease presentations at EASL, which was presented back in May of 2025.

So this is the first video that I will basically rely on presenting patient-related outcomes on trials. Specifically, I will just dedicate this to trials devoted to treat the patient's complaint of itching. So as we're aware, itching is one of the main symptoms that really affect patients with PBC. And I think it's really important to understand that data, we have new data related to new medications that hopefully will be in the market very soon.

So the first data I want to talk about is the GLISTEN trial. The GLISTEN trial is an IBAT inhibitor linerixibat presentation's name was Impact of Linerixibat for the Treatment of Cholestatic Pruritus in Participants With PBC.

The key eligibility criteria was, you know, someone had to have moderate to severe itching with a NRS score more than 4. They were allowed to use other medications to treat itching, but at least they have to be in a stable dose for 8 weeks. They were excluded actually either on OCA or IBAT inhibitors, or they had more advanced liver disease, which had total bilirubin more than 2.

So this is a study with a randomized in a fashion of 1:1:1:1, where patients either got placebo or linerixibat 40 milligrams twice a day. And then there was a blind day crossover period after 24 weeks where patients who were on the placebo got linerixibat 40 or in the linerixibat got placebo for another 12 weeks. And then there was a follow up for another 2 weeks. Basically, the primary endpoint was changes from baseline and monthly itch score over 24 weeks.

When you look at patient baseline characteristics, I would say the duration of PBC, the duration of pruritus, the severity of the pruritus was very similar. When you look at the biochemistries profiles, all of them were familiar. And when you look at concomitant meditations, also it was a pretty similar characteristic in both the placebo and the linerixibat study. So when you look at the intention to treat, the weekly itch score over time, we saw the patients on the linerixibat 40 milligrams twice a day had a sustained and a better response to weekly itch scores. This basically lasted for the 6 months of trial and then persisted through the trial. So you can see in a graph presented at EASL that even starting at week 3 or 4, you see a pretty nice kind of downslope of the graph that persisted all the way to the 24 weeks of therapy. And you can see this flips when those patients who were in the blinded crossover arms were basically crossed from the linerixibat to the placebo group.

So this is also very exciting, you know, the adverse events were diarrhea and bloating, but this is the largest randomized control trial for itching so far. Rapid and strong reduction in pruritus was seen in the linerixibat treatment. We still see a placebo effect is very strong, but you know, it is important to focus on the efficacy of the treatment, especially in the trial that assess the symptoms. We have more data on how the mechanism look like, although we should look then, for example, bile acids and IL-31 in the future. The safety profile was promising. And I think overall the results were promising and hopefully will result in a first approved medication just to treat the itching.

The other medication that was used is volixibat, another IBAT inhibitor, and this is the result of the trial VANTAGE. This is a phase 2B adaptive randomized placebo control trial for the treatment of cholestatic pruritis patients with PBC. Pretty similar eligibility criteria, primary endpoints, again, main change in daily itch scores using an HRO questionnaire. And there are also some secondary outplants, for example, adverse events, change in serum bile acids, and also the quality of life. The way the trial was designed is basically the part 1, where you basically had a placebo versus volixibat 20 and volixibat 80 , and then you went into the open label extension and there's a part 2, when everyone completed and it's in the enrolling part what you actually looked at placebo versus volixibat about for 20 milligrams a day.

Again patient characteristics were pretty similar. And then when we look at the adult itch RO over time, we see a significant difference with the volixibat, both 20 and 80 milligrams, compared to placebo. You can see again that, you know, even at early weeks and then persistent for the entire trial for 24 weeks, 28 weeks, you can see that the duration of therapy is very important. And in this study specifically, we've seen other markers of pathophysiology of itching. We are seeing levels of IL-31 coming down with the therapy of the IBAT inhibitor.  And we also see changes in the you know, health care quality of life questionnaires. So patients who were treated both in the IBAT inhibitor arm 20 and 80 milligrams had better outcomes and quality from fatigue and sleep part of their questionnaires.

So I think how am I going to summarize this study? Well, it's a significant small interim analysis, but we are seeing that the IBAT inhibitors improved quality of life. We are seeing that reduction in itching is very strong, but also we are seeing that correlates with other markers of itching, such of bile acids and IL-31. Also, we are seeing improvement in fatigue, not only with the related to itching, but as other part of the quality of life questionnaires. Also, we are seeing results comparable, even better than the other IBAT inhibitors. And then, you know, finally, the dose, we don't need a higher dose, 20 milligrams used in the PPARB study was really effective treating the treating the itching. So again, in summary, these two studies really show promising results treating symptoms and improving quality of life in patients with PBC.