Next, I'd like to invite Dr. Aparna Goel, who is an associate professor of medicine at Stanford University in the division of gastroenterology and hepatology. And she will provide today's cholestatic liver disease debrief. All right. Thank you to the organizers for inviting me to give the cholestasis debrief this year. It is a very exciting time for cholestatic liver disease, and it's an honor to be here. The journey for cholestasis, this meeting was very broad and comprehensive. So I will try to do my best to highlight the key abstracts. I want to thank all of the presenters, even if your work wasn't highlighted today in my meeting. And I think some of the satellite symposium, you saw the very long lines for lunch. So I think it was a very interesting programming. So I also want to thank all the folks that shared their slides with me in preparation for the debrief. This is really quickly what I'll try to cover in the 20 minutes that we have. We'll go ahead and get started with primary biliary cholangitis. So as you all know, PBC is a chronic autoimmune liver disease that's characterized by the destruction small and medium-sized intrapartic bile ducts, predominantly affecting middle-aged women. In this year, we've seen the accelerated approval of two novel therapies for second-line therapy for PBC, alofibrinol and saladelpar in the US. But before we understand how we're going to incorporate these novel therapies into our practice, we have to really understand how we're currently practicing in managing PBC. And this was examined by Dr. Ronca in the Fibrate-OCA Study, a global snapshot of PBC around the globe. So in this study, this was a retrospective multi-center study that involved 40 centers across Europe, Japan, South America, North America. PBC patients who began second-line therapy treatment with fibrates or betucolic acid were included. And clinical biochemical treatment data diagnosis and at the start of second-line therapy was captured in addition to adverse events and treatment changes. There were a total of 1,785 patients included in this study, 917 initiated on a betucolic acid and 868 on fibrates, two-thirds of which was bezofibrate. And nearly half of the patients that started on bezofibrate were from centers that had restricted access to a betucolic acid. 17 patients were started on combination therapy. And I think this waterfall plot really beautifully demonstrates the journey of our PBC patients that are started on second-line therapy and something that we have to really keep in mind as we start to incorporate the new therapies that have been approved, the new PPARs that have been approved. So during the course of treatment, 10% of patients that were on a betucolic acid had to add a fibrate. And 2.5% of patients that were on a fibrate added a betucolic acid. And I think notably, the discontinuation rates for both of these medications is actually quite high, 33% in the betucolic acid group and 20% in the fibrate group for various reasons. So this really highlights that the management of PBC requires dynamic adjustments to second-line treatments and that there are high discontinuation rates that underscore the need for us to understand or create better allocation tools for which patients will respond best to which therapies. Now second, another big area of discussion has been what our treatment goals for PBC should be. Historically, we've used a criteria of an alkaline phosphatase cutoff of 1.5 to 1.6, seven times upper limit and normal, and a normobilirubin to define adequate treatment response. But the question is whether or not normalization of alkaline phosphatase and normobilirubin should be the actual threshold. This was examined by Dr. Reddy using the target PBC cohort, which is a longitudinal cohort registry of PBC patients across multiple sites in the United States. And patients were included if they had a recorded start date for UDCA, they had no second-line therapy at any point, and an adequate response to UDCA was defined by the Paris 2 criteria and patients had no prior decompensating events. So in this study, patients were stratified into two groups, those that were defined as having a deep response, defined as either normalization of alkaline phosphatase or total bilirubin less than 0.67 times upper limit and normal, and those with an adequate response defined by the Paris 2 criteria. And the primary outcome was complication-free survival. As you can see here, there were 232 patients that were included in this study. 82% of patients that had a deep alkaline phosphatase response also had a total bilirubin that was less than 0.67, 0.6 times upper limit and normal, and about 50% of the cohort had advanced fibrosis. There was a significant decrease in the hazard ratio of developing serious complications in both the deep alkaline phosphatase and the deep bilirubin response groups, and it really appeared, as you can see with the Kaplan-Meier curves, that this improvement or this improvement in survival or complicating events was really driven by the folks that had advanced fibrosis. So the authors conclude that patients with advanced fibrosis in particular are likely to benefit from more aggressive therapy to achieve normalization of alkaline phosphatase and a deep bilirubin response. So something to keep in mind as we see patients with PBC and really understanding risk stratification early in the course of their therapy and how to individualize treatment response as we have novel therapies. But is there a benefit to treatment if the alkaline phosphatase target cannot be achieved? And I think this is an important question. Dr. Codley presented data to answer this in the abstract, looking at obeticholic acid inflammatory markers from the POIS study. And reminder that this was a study with obeticholic acid that included 216 patients. There were 143 patients that were treated with obeticholic acid in either the titration arm or the 10 milligram arm. There were a total of 77 incomplete responders to obeticholic acid in the POIS study. And the specific biomarkers that they used included FGF19, CRP, IgM, CK18, FIB4, and APRI scores. And what they found was a difference in median percentage compared to the baseline in both groups that received obeticholic acid, either the titration group or the 10 milligram group. And there was also a trend toward improved fibrosis scores using APRI. So perhaps in patients that can't achieve a composite endpoint for alkaline phosphatase, there may still be benefit to obeticholic acid. Now with the newly approved PPARs, is there a benefit or is it safe to use PPARs in PBC patients with cirrhosis? Dr. Villamil reported the efficacy and safety of celadelpar in patients with PBC and compensated cirrhosis from the phase three response trial that's been previously published. And just a reminder that the response was a phase three study with PBC patients that had an inadequate response to UDCA or that were intolerant to UDCA. And patients were randomized in a two to one fashion to receive either celadelpar 10 milligrams or placebo. There were 27 patients with cirrhosis that were included in this initial phase three study, 18 that received celadelpar and nine that received placebo. So the study is small but it does give us some insights into the safety of this drug in patients with cirrhosis. In terms of response, in general, patients that had cirrhosis had a similar reduction alkaline phosphatase that was sustained through the study. And the percentage decline was actually quite similar to that seen in patients that did not have cirrhosis. And bilirubin levels remain relatively stable throughout the study in addition to INR and MELD scores. The safety profile in patients with cirrhosis was very similar to that seen in without cirrhosis. And importantly, there were no patients that had cirrhosis that discontinued celadelpar due to AEs. So the authors conclude that celadelpar decreased cholestatic and liver injury markers similarly to that seen in patients without cirrhosis. And it appeared safe and well tolerated in patients that had compensated cirrhosis. Is the biochemical response that we see with PPARs, there's been data presented up to 52 weeks, that was previously published, but is the response durable? And this is the last one that we'll review in PBC. So Dr. Cowley answers this in the presentation, looking at the long-term efficacy of alofibinor from the ELATIV trial. And remember, similarly to the prior study designed for response, ELATIV was a randomized study looking at patients with PBC that had an intolerance to or inadequate response to UDCA and were randomized two to one to receive alofibinor, which is a PPAR alpha-delta agonist. So there were 138 patients that were entered into the open-label extension of this trial, and 93 of which were continued from alofibinor from the double-blind phase, and 45 that crossed over from the placebo arm. And those that continued alofibinor, shown on the left there you can see, had an ongoing sustained improvement in their, or ongoing sustained reduction in their alkaline phosphatase and the patients that crossed over from the placebo arm into alofibinor at week 52 had similar declines in their alkaline phosphatase that was seen in the double-blind placebo control study. So let's shift gears to primary sclerosing cholangitis, a disease, a fibroblurative disease of the larger bile ducts that predominantly affects middle-aged men that usually have concomitant inflammatory bowel disease. An important area in PSC research is understanding other biomarkers to use and exploring and validating surrogate endpoints because we know that the alkaline phosphatase has suboptimal performance. So I'd like to highlight two studies on this topic. The first is an analysis from the phase three premise study that looked at associations between biomarkers and the MRI-derived ANALI scores. This was presented by Dr. Tronner. So the ANALI score has been proposed to potentially predict disease progression in PSC. In this study, they evaluated baseline associations between the ANALI score and other non-invasive biomarkers in patients with PBC, and they also evaluated the ANALI score for the prediction of PSC-related events. A reminder that the ANALI score is a score that's generated by looking at liver dysmorphia, intrapartic biliary dilation, and portal hypertension from MRI findings. And it's calculated with these findings in a score that's greater than two suggests higher-risk disease. The phase three premise study included 419 adult patients with PSC, some that were in the placebo arm and some that received ciliofexor. And at baseline, you can see that the ANALI score was significantly associated with ELF score and liver stiffness measurements, and a higher ANALI score was associated with cholangitis events during the study. An ANALI score greater than two at baseline was associated with increased ELF score and increased liver stiffness measurements. And these associations, when they looked at the individual components of ANALI, these associations were really driven by dysmorphia and portal hypertension, and not by the presence of intrapartic biliary dilation. So the authors conclude there was also an association with ANALI score and liver enzyme measurements as well. So the authors conclude that ANALI score, or the components of it, could become possible non-invasive biomarkers for selection into really trying to consolidate the phenotype of PSC patients that we select into our PSC trials, or potentially looking for outcomes in PSC trials as well. Another study evaluated transient elastography as a prognostic indicator in PSC. This was presented by Dr. Leung. This was a single center study, a real world use of liver stiffness measurements, looking at as a dynamic prognostic indicator over a 10 year period. There were 403 patients with PSC, and there were 84 composite events during this study period with over 1,300 liver stiffness measurements. And the authors found that for every log increase in liver stiffness measurement, that there was almost a four and a half fold increase in the risk of decompensation, transplant, or death. And when they adjusted this analysis for female sex, age at first liver stiffness measurement, and alkaline phosphatase and bilirubin levels, the hazard ratio remained quite elevated still at 3.25. And there's a nice example that I appreciated that was presented in the poster that looks at one single patient, same patient, age, what their alkaline phosphatase levels are, what their bilirubin levels are, same age, and really looks at how their risk of these complication changes based on their liver stiffness measurements. So this study validates findings from prior studies looking at liver stiffness measurements as a prognostic tool for PSC, and it could be incorporated into trial design as well. Now, two novel therapies that I'd like to point out for PSC, which is really exciting. We saw the novel therapies for PBC. There is a lot of work being done in the PSC space as well. The first is Bexotograst, which is an oral inhibitor of alpha V beta six and alpha V beta one integrins. And looking at markers of cholestasis and fibrosis. This was presented by Dr. Cowley. So this dual selective inhibitor of alpha V of these integrins we think is a main mechanistic target in blunting the TGF beta signaling, which we know is activated by the alpha V integrins and thought to play a key driver of fibrosis in PSC. So in the integrin study, patients with PSC and suspected fibrosis were randomized to receive either Bexo or placebo. And this abstract focuses on the final 24 week analysis of the safety and tolerability of Bexo 320 milligrams versus placebo and looks at some exploratory endpoints as well. So there were a total of 27 patients in the Bexo group and nine in the placebo arm, so still a small study. Two thirds of patients were on UDCA and nearly half had IBD. The degree of fibrosis by alpha transient elastography was similar in the two groups. And importantly, treatment emergent adverse events were similar between the Bexo and the placebo treated groups. And there's a few interesting findings here. One was that Bexo did lower alkaline phosphatase values from baseline to week 24 compared to a slight increase that was seen in the placebo group. There was also a numerical difference in cholangitis and pruritus events observed between the two groups. And the itch NRS score was stable from baseline to week 24 in the Bexo group compared to an increase that was noted in the placebo group. And in terms of fibrosis markers, we saw stabilization of ELF scores through week 24. And in those that had a baseline ELF score of greater than 9.8, maybe a slight improvement. There was also similar stabilization noted in the transient elastography scores. And then lastly, there was some MRI tools that were evaluated, or MRI parameters that were evaluated. One was the overall whole liver enhancement in both the Bexo and the placebo groups. And there was improvement in the relative enhancement. And also the time to arrival of contrast to the common bile duct, which was improved in the Bexo group. So what we see is that this is a well-tolerated drug that's shown improvement in alkaline phosphatase and stabilization of symptoms associated with cholestasis and lending support to longer, larger studies using this drug. The other light breaker was studying a novel therapy looking at CM101 in PSC. This was the phase two spring study. This was presented by Dr. Bolas. So CM101 is a humanized monoclonal antibody targeting CCL24, which has been implicated in inflammation and fibrosis. This was a phase two randomized placebo controlled study of CM101 in patients in non-cerotic PSC. And there were 76 patients that were randomized to either receive CM101 or placebo. And the doses of CM101 varied between the randomization arms. Treatment emergent adverse events were mainly mild and distributed similarly across the cohorts. And there were no serious treatment emergent adverse events related to the study drug. So there was a consistent pattern, as you can see here, of a decline in liver biochemistries that was seen in the 20 milligram per kilogram treated group. And those included patients that had advanced fibrosis. And interestingly, you can see that the effect on AST, ALT, and GGT was actually a little greater than the effect on alkaline phosphatase. There was also significant improvement in liver stiffness measurements in patients with moderate to advanced fibrosis treated with CM101. And ELF scores were improved in patients with moderate to advanced fibrosis that received the 20 milligram per kilogram group. And lastly, pruritus scores were lower in the CM101 treated group. So the authors conclude that this is well-demonstrated and that this is well-tolerated and that it demonstrated a dose-dependent anti-inflammatory and anti-fibrotic effect supporting further studies. Now, I want to spend some time just talking about, we talked about disease control for PBC and novel therapeutics for PSC. But I think another important area is looking at the patient as a whole and talking about the management of symptoms, namely cholestatic pruritus and other health-related quality of life impacts. So this, again, should be considered part of our treatment goals when we're looking at cholestatic liver disease. And we know that despite the existence of guidelines and guideline-recommended therapies, that the use of medications and guidelines is actually quite poor. But how big is the unmet need for cholestatic pruritus? So this was answered by Dr. Hirschfeld in his paper that was presented earlier, looking at the phase three GLSEN trial and looking at the baseline characteristics of patients in the phase three trial. So GLSEN, which stands for the Global Lenorixibat-Ish Study of Efficacy and Safety in PBC, is a phase three study of Lenorixibat, which is an IBAT inhibitor, so an ileal bile acid transport inhibitor, and compared to placebo in patients with PBC that have moderate to severe pruritus. So there are 238 patients that are enrolled in this phase three study. What we know is that 25% of patients have normal alkaline phosphatase. So the presence of liver biochemistry abnormalities does not necessarily predict whether or not a patient will have moderate to severe pruritus. And we also saw that 50% of patients were not receiving any therapy for their pruritus at the time of enrollment, and only 9% were receiving bile acid-binding resins. This is despite its guidance as first-line therapies. So these findings really underscore the unmet need for approved treatment for cholestatic pruritus in patients with PBC, but they also highlight the importance of us as providers of really having discussions with our patients in assessing the severity of their cholestatic pruritus. There were several studies that looked at the impact of itch on quality of life. This was presented by Dr. Levy in the ItchE study, and one of the things that, the severity of itch was correlated with several patient-reported questionnaires in 21 patients that were recruited from PBC advocacy groups, and what we saw was that patients that have moderate to severe itch had worse fatigue, cognitive, and social indices, indicating poorer quality of life, again highlighting the importance of understanding pruritus and really treating these patients effectively. Now, how do the newly-approved PPARs impact pruritus? So Dr. Kramer reports the impact of Celadelpar in terms of patients that had moderate to severe pruritus in the response trial, and in patients that had moderate to severe pruritus, there were several categorizations in terms of improvements with PBC-40 itch domains and quality of life as well in 72 patients in this study. So these were 72 patients that had moderate to severe pruritus to begin with that were enrolled in the response trial. 49 were enrolled in the Celadelpar group, and 23 in the placebo group, and we saw that Celadelpar reduced the mean itch intensity, bringing it down from moderate levels down to mild levels using the NRS score, and in those that had severe pruritus, improvements in itch were associated with improved fatigue and improved sleep. And I think perhaps very interestingly in this study, we saw that patients that did not have itch at baseline of study did not develop itch at month 12 if they were enrolled in the Celadelpar arm compared with about a quarter that were in the placebo arm that did develop itch after. So Celadelpar reduced severity of itch to mild levels, and it did cause resolution in nearly 20%, and it may potentiate the development of itch in those that do not have it. And really quickly, looking at IBAT inhibitors in terms of efficacy for the treatment of pruritus in PBC, Dr. Cowley presented the data for Velixibat for cholestatic pruritus, and these were patients that were studied with either Velixibat 20 milligrams, 80 milligrams, or the placebo arm. There were 10 patients in each arms that had an average itch-row score of six to seven. We saw significant reductions in cholestatic pruritus using the itch-row scores in both the 80 and the 20 milligram arms, and these findings will support hopefully future studies looking at the 20 milligram BID group for patients that have pruritus. And then I will skip this because I'm running out of time, and I want to quickly bring up one other big part of her autoimmune hepatitis. I don't think this will be covered in any other piece here, so I'd like to highlight just one key abstract in autoimmune hepatitis, and this is obviously one that didn't have atherapeutic discovery recently, and we've been using the similar drugs for quite some time. This study was presented by Dr. Welch looking at anti-TNF therapy as a mechanistic target for autoimmune hepatitis, and there's two key components to this study. The first was looking at it as a mechanistic proof that's targeting TNF, and the second was looking at a phase two sort of proof-of-concept study for corticosteroid-free induction. So first, biopsies of patients with autoimmune hepatitis were analyzed by mRNA-Seq and correlated with transaminases and histologic features, and this showed that transcription factors for TNF and JAK-STAT pathways were enriched in the AAH cohort in addition to their respective cytokines correlating with disease activity, and the second part of the study was a trial in 12 patients with autoimmune hepatitis that were treated with corticosteroid-free induction therapy with infliximab for 24 weeks at varying doses, and the results of eight of these patients are included and show that there was dramatic reductions in AST, ALT, and liver stiffness at 24 weeks, and all patients, all eight patients, had AST levels and ALT levels that were less than two times upper limit than normal by week 24 of the study, so really maybe supporting potential targeting of TNF as an option for corticosteroid-free induction therapy in AAH, and more to come, hopefully, with that. So we covered a lot, so whirlwind tour for cholestatic liver disease and a glimpse of autoimmune hepatitis. I really think that there's a lot of discovery in happening in this area, and it truly is an exciting time point, so thank you so much for your attention. Thank you. Thank you very much, Dr. Gold. It really is a busy area, isn't it? So it's great to see.

cholestatic liver disease

primary biliary cholangitis

treatment advancements

biomarkers

primary sclerosing cholangitis

autoimmune hepatitis