Thank you, Dr. Price. The next is a cholestatic liver disease debrief to begin with, given by Dr. Gideon Hirshfield from the Toronto Centre of Liver Disease. It's really exciting to see that there's enough cholestatic data to do a debrief. Thank you, Chairs. Thank you, ladies and gentlemen, for staying until the end. I realize that I represent a rare population of patients with liver disease, and today I'm talking between giants, between viral hepatitis and metabolic associated steatotic liver disease. So what I've tried to do in this talk is to give you that helicopter view that I've had from coming to ASLD 2023, and for you to remember that for our rare disease, a lot is going on in the conference and around the conference, in the plenaries, late breakers, but also in the meet the experts, and in small group sessions. And with that, I hope we can show you the journey, and that's what I'm going to demonstrate, the journey across the meeting, which is offering hope to our patients with these liver diseases. This is myself from Toronto, and these are my disclosures. And for all our patients living with cholestatic liver disease, be they the pediatric liver diseases or the adult liver diseases, you know, what we're taking away from this conference and the discussions is the need for a prompt and clear diagnosis, to personalize therapy to the individual, to prevent end-stage liver disease, manage symptoms, challenge inequity, and champion innovation and excellence. And if you think about the disease that we represent, we have no approved therapies for PSC, and only two approved therapies for PBC, and only recently, you know, two approved therapies for ultra-rare pediatric cholestatic liver disease. So we have a long way to go to get to where you've championed for hepatitis B, C, and beyond. So that's why TLM 2023 was so important, because I want to encourage you to think when you see our patients where we don't know what causes PBC or PSC, that effective treatments, which is the goal of all of the hepatologists in this room today, will come when we combine what is presented at this conference. Epidemiology, why me? Why children? Basic science, why the liver? Why the biliary tree? Why is cancer an issue? With clinical science, you know, really how difficult it is to run clinical trials in rare disease, to understand endpoints, and to prove that the new drugs that we desperately want actually make a difference. I'd like to start with a slight diversion on autoimmune hepatitis. I'd say that ASLD 2023 has been absolutely stellar with its efforts on equity, diversity, and inclusion. It's been noticeable the effort put in by the organization, you know, to raise this. And this abstract, therefore, stood out for me, you know, about the high burden of unmet needs in autoimmune hepatitis exacerbated by low socioeconomic status. So when I describe all the exciting science in clinical trials, I want people to recognize that even within our rare populations of liver disease, with autoimmune and cholestatic liver disease, the importance that socioeconomics plays in the outcomes for our patients. And in this study, an electronic invitation to complete an anonymous survey was sent to thousands of people on the Autoimmune Hepatitis Association. A tool was used adapted from lupus, and participants used a Likert scale to indicate their level of need. And low socioeconomic status was defined in a number of ways. But I think it shows quite clearly the high burden of unmet needs in autoimmune hepatitis independent of gender, race, or degree of fibrosis. Okay? And the importance of, you know, low socioeconomic status. And I believe that that knowledge is relevant to just our quality of care that we offer for our patients with AIH, PBC, and PSE on a daily basis, even before we are aspirational for the future. You saw this slide already. But one of the things that we're challenged with in PBC and PSE and other diseases is we don't know the etiology. We rely on inadequate mouse models. But we are recognizing over time, and I've been coming to ASLD for 15 years, to see the change in the presentations that you're seeing at this meeting to moving to more human-based science using new technologies. And although this was shown in the basic science debrief, I want to just highlight it again. Because this is an ultra-rare cholestatic liver disease. But this is demonstrating using human tissue to make patient-specific induced pluripotential stem cells. And how they then become a model to understand the disease and to map out treatments. So, I think this is an example of where we're headed. Again, stepping back to epidemiology, I wanted to highlight this paper for a number of reasons. The associations between liver biomarkers and clinical outcomes in patients with PSE, a retrospective real-world study. We struggle to get enough patients into our cohort studies from specialist centers that we want to use the power of new data. And there's been a lot on artificial intelligence across, you know, ASLD 2023. Again, future gazing. And this study just highlighted to me the opportunity that we have to characterize our patients in the broadest communities being treated in America and beyond. And to learn about them. But equally, to show the limitations that that data shows. So, on the plus side, they're able to identify many thousands of patients with PSE and to track their morbidity and mortality and look at their liver chemistry. On the downside, they're reporting for you alkaline phosphatase, albinon, and total bilirubin. And I'm not going to get you excited about suggesting that that's new news for you about biomarkers of outcome. But I want you to hold on to this kind of data when you then think about how we prove new therapies work in rare diseases. Where, as I'll show you at the end, it's impossible to do outcome studies which are placebo controlled. It's just not possible. We're going to have to marry up with real world data using the data that you generate when you see patients in your clinics. And that moves to the next slide, which says, well if alkaline phosphatase, bilirubin, albumin are known but are not useful enough, what are the technology platforms that we can use on human samples from human cohorts to learn about prognostic biomarkers, but also potentially to identify new therapeutic targets. So in this presentation, I think it was an oral presentation, this is serum proteomics reveal unique association of the chemokine CCL24 with disease related pathways and signatures in PSE. So this is not a therapeutic intervention or study. But again, it is applying to human samples with characterized patients as compared to healthy volunteers, you know, O-link proteomics and identifying associations between this chemokine, which is potentially targetable with stellate cell activation, IL-1 beta, and liver fibrosis. And showing some specificity for these associations. So it's giving us clues to the future biomarkers that we would like to apply and potentially the future therapies. Again, this is not a therapeutic study, but this is a study to demonstrate how little we already understand about the commonest of the autoimmune cholestatic liver diseases, PBC. AMA positive, cholestasis, female predominant, treated with bile acid therapies. In this study, it is a comparison of the metabolome of PBC patients to healthy volunteers. And it shows us new science that we didn't expect. We think of this as cholestatic and autoimmune, but what we saw in the study as reported by Yoon-Jung Choi was widespread dysregulation of metabolic stress pathways are characteristic of PBC. We're seeing different bile acid profiles and different metabolic stress. This again is the beginning of the avenue to then understanding why your patient feels and functions the way they do. Because perhaps some of these signals that we'll pick up may not relate to prognosis, but may relate to quality of life, and that has become a major topic of interest. Now these two slides that I'm going to show you, we're not part of the core program, but we're part of what goes on around ASLD, which is actually very exciting, and it's why ASLD is so successful. These were presented at the PSC forum, you know, a forum really dedicated to trying to help develop more treatments for PSC, and were presented by Dr. Heller from NIDDK. And I'm using this slide that he kindly let me show you to highlight the kind of science we have to apply in humans to understand diseases where we don't know the etiology. And this is a study that's ongoing at the NIH, where patients are going to be deeply phenotyped, including direct portal vein blood sampling. Because that's the link between the bowel and the liver, and what goes on in the portal vein is not the same as what goes on in the periphery. And if all of our work is on the periphery, we aren't going to make those advances to make the differences. So in his study, he's going to look at the liver, systemic circulation, portal vein, microbiome, bile, and bone marrow. And he shared with me work that he's already done in another related viral liver disease. And the reason I show you this is to show you the bile acid signatures are not the same between portal blood and peripheral blood. So we are missing the opportunity to identify new signatures of disease and new pathophysiology because we're not targeting the right samples. And moreover, it's not going to be possible to do this only in a mouse, because mouse bile acids are different, mouse bowel is different, and mouse microbiome is different. And for the diseases, PSC in particular, that gut-liver axis, which again you've heard a lot about during this conference, is absolutely key to our disease understandings. Following on from that, we are now using some of the tools that we have to potentially learn how to treat our patients. This poster was a poster of distinction and stood out because there is ongoing effort across pediatric and adult cholestatic liver disease to develop better treatments for itch. One modality of those treatments are so-called IBAT inhibitors to interrupt the enteropathic circulation of bile acids. This was a poster presentation using data from a phase 2 trial, which underpinned an ongoing phase 3 study of linorexibat in patients with primary biliary cholangitis who itch. And it looked at two biomarkers, you can't measure them yet in clinic, but we understand them from the clinical translational world, autotaxin and FGF19, which are related to pruritus and to the FXR-FGF19 axis. And it was looking to see whether the change in itch could be correlated with changes in autotaxin and FGF19. In this presentation, the change from baseline at week 16 in serum autotaxin and FGF19 in responders and non-responders, it was possible to show that itch responders, the patients who had benefit from the study with itch, but not in the placebo group, had greater reductions in autotaxin. That in linorexibat-treated patients, autotaxin levels were reduced in itch responders. And in individual dose groups, autotaxin but not FGF19 were significantly reduced again in responders versus non-responders. So it identifies a significant reduction in serum levels of a pruritogen and a regulator of bile acid biosynthesis in patients who respond. And that starts to provide a tool to help interpret our future trials of symptoms, which for our patients are very important. This slide then highlights the work on IBAT inhibitors in a very difficult population to reach, women with intrapathic cholestasis of pregnancy, a very, very symptomatic cholestatic liver disease, which is actually relatively common. And this was an attempt to do a clinical trial of an IVAT inhibitor, felixibat. Over 1,000 patients were invited to participate, 26 were agreed to be screened, and 11 were enrolled and four received treatment. So the study had the right intent, but it proved to be nearly impossible to deliver a study in women who are pregnant, despite the unmet need. And yet we can see in this poster four patients who were treated with felixibat, an IVAT inhibitor, and all patients with pruritus, which is characteristic of ICP, had reduction in pruritus from baseline regardless of the felixibat dose, with intermittent relief coinciding with resumption of dosing where doses were interrupted. And the bile acid levels in the deers all reached less than six following felixibat treatment. And you'll know that bile acids are prognostic for fetal outcome in intropathic cholestasis of pregnancy. So again, for a rare disease area, a great effort to study a very difficult population, but very impactful. I then wanted to move on to something that's incredibly hard to study. We talk about the gut-liver axis, and then we recognize the importance, therefore, of nutrition potentially. We don't really understand the microbiome changes, but we're learning from our colleagues in inflammatory bowel disease who are coming to join us in the effort to try and treat primary sclerosing cholangitis. And this is a pilot study from Boston examining a low-sulfur, low-protein diet versus the specific carbohydrate diet in patients with primary sclerosing cholangitis. Now, I just told you how hard it is to do studies in pregnancy. It's even harder to do proper nutrition studies. They are very difficult, in fact, to deliver. And that's the message that's relevant to all of you interested in sarcopenia in nutrition. But this study is based on the hypothesis that dietary sulfur acts as a substrate for hydrogen sulfide, which plays an important role in U.C. pathophysiology and may therefore contribute to PSE development. It's a pilot study, 20 participants, one-to-one, low-protein diet versus the SCD diet, specific carbohydrate diet for eight weeks under diet supervision, opportunity to continue, and looking at essentially this vegan diet versus the SCD diet and looking to see whether or not there are some signals of alkaline phosphatase. I already told you we don't have the best biomarkers. I'm not even sure what the biomarker would be for a nutrition diet, okay? But there were some patients who, on the sulfur-containing diet, were responders in terms of their alkaline phosphatase. This speaks to an opportunity, plus a challenge, to do more nutrition studies in diseases of the gut-liver axis, but also speaks to the challenges and the need for the right biomarkers. We do have second-line treatment in PBC, one of which is approved and one of which is currently used, Bezafibrate and Phenofibrate used off-label. We're now seeing from, again, groups and consortiums of clinicians, because we have to work together to get the right number of patients, efficacy and safety of second-line therapy in PBC. This is just one example of a prospective multicenter, real-world cohort. Looking for our aspiration, of which is to normalize alkaline phosphatase and to have a bilirubin less than 0.6. In the study of 316 patients, the median follow-up of 26 months, they're able to demonstrate the effects of abetacolic acid on biochemistry, on risk scores, and to demonstrate similar responses. This is a 41% poise response, so-called less than 1.67. Hang on to that number, because it's relevant for some of the late breakers I'm going to show you in the real world of OCA, and then demonstrating the addition of a PPAR to improve the biochemical response. Demonstrating to you that already the community, in practice, is targeting a higher response than the regulatory response of the poise criteria. To finish, I'd like to go through some of the late breakers, because, as I said, we're not going to be choosy for PBC and PSC. The fact that we were in the late breaker session is phenomenal, because we really, really want to make a difference. This was a late breaker I had the privilege of presenting on integrin inhibition in primary sclerosing cholangitis. Not easy studies. This was a 12-week interim safety and efficacy analysis of integrin PSC, Bexotogras, which is an oral alpha-V beta-6, alpha-V beta-1 integrin inhibitor. The idea is that you prevent TGF beta activation, and you're therefore anti-fibrotic in a very fibrotic disease. We presented data on three doses and placebo, safety, and some exploratory endpoints, which were not alkaline phosphatase, but which focus on fibrosis and imaging. So you could see in the study that in the placebo group, there was an increase in the ELF score. In the treated group, there was not that increase, and at the 160-milligram dose, it was significantly low in terms of the change. You saw the same at a progression in the Pro-C3, a dynamic marker of collagen turnover, which was not evident in treatment. What was even more unique, other than this fibrosis-enriched population of patients with PBC, was the use of MR technology. Again, we don't have the answer of how to use MR technology in our PSE trials, but we know it's a biliary disease, and we know that we should be looking at the imaging, not just biochemistry, alongside symptoms. We demonstrated using this MR, Godoxate-enhanced MR study, that again, there was deterioration in whole liver-relative enhancement, and there was deterioration in bile flow, which was not evident in the treated group. This shows you, you know, the challenges of doing clinical trials in PSE, and how we have to get safety, signs of efficacy, and then launch into further studies. This was a late-breaker on the use of bezafibrate and betacolic acid. I'm presenting these in alphabetical order, betotagrass, bezafibrate, and then the other two drugs that were late-breakers, and this is again trying to show what's happening in the real world, but using it in a trial setting to combine drugs into one tablet, okay? Adult patients with insufficient response to clinical trials, and they're randomized to get essentially either bezafibrate or bezafibrate and betacolic acid together, and we're looking at percentage change and normalization rate. So this is a very small study. You can see study 213 and study 214 are next to each other, but you can see significant progress in demonstrating normalization and so-called biochemical remission by using a combined approach of FXR agonism, that's betacolic acid, and bezafibrate, which is currently an off-label pan-PPAR agonist. And this was short-term administration of this therapy, which is generally well-tolerated, okay? Low rates of pruritus, and again, it suggests that we can move forward. We'd like to then present the elitive phase 3 trial, and I'm very grateful to Professor Bolas for sharing these two slides with me, okay? This was a very exciting trial now published, okay, published yesterday, and this study aimed to evaluate the efficacy and safety of elefibrinol in adult patients with PBC with an inadequate response or intolerance to UDCase. This is a phase 3 study in PBC. Patients have insufficient response. They're randomized to elefibrinol or placebo. They're followed up for longer than 52 weeks, but the endpoint for the data is at 52 weeks, and then there's an open-label extension, okay? And the primary endpoint is biochemical response, and other endpoints, which I'll show you, provided by Professor Bolas, are around symptoms. So you can see the primary endpoint, that 5 out of 10 patients met the composite endpoint versus the placebo, and in this case, the calculated treatment benefit was 47 percent. So the primary endpoint was met, okay? There were, and then key secondary endpoints, 15 percent of patients treated with elefibrinol achieved normalization. There were clear reductions in alkaline phosphatase. In the predetermined key endpoint relating to PBC worst itch NRS score through week 52, the difference was not significant, so the itch did not change, but when treatment with elefibrinol was looked at in reductions in the PBC 40 itch score, there was an effect on itch of elefibrinol, and similarly for the 5D itch score. So the study authors were able to conclude that elefibrinol led to significant improvement in biochemical response, along with potential antipyretic benefits, and it was a well-tolerated therapy. And again, it speaks to the broadening of our potential therapeutic base for PBC and who knows where beyond for related cholestatic diseases that have similar mechanisms. This was the other late breaker for a phase three clinical trial in PBC, efficacy and safety of cellar delpoint patients with PBC in the response trial, and I thank the sponsors for giving me permission to show these two slides as well. This was a phase three international randomized placebo-controlled study. Very similar inclusion criteria, patients on ERSA or intolerant who have insufficient response at risk of disease progression, stratified for ALPFOS and treatment. Two arms, cellar delpoint 10 milligrams daily and placebo, 12 months is the primary endpoint. Again, patients willingly follow into the open-label study. Primary endpoint, the composite endpoint, two key secondary endpoints, actually very similar to the study I showed you already, normalization, our target, and symptoms, a patient priority. So, again, with the primary endpoint, you can see in this study, six out of 10 patients met the primary composite endpoint. You can see alkaline phosphatase drops were 40% and were 4% in the placebo, and in this study, one in four or 25% of patients normalized their alkaline phosphatase. In the key predefined secondary endpoint of pruritus at six months in patients with moderate to severe itch, there was a statistically significant improvement in itch, and this was evident across the rest of the study and relevant in the whole population. So again, quite exciting for us. Finally, however, I want to bring you back to the real world, okay? You get these drugs which are making progress and treating disease better. How do you then prove that they make our patients live longer? And many of you would have recruited patients to the Cobalt study, which truly was an international study, trying to demonstrate that beta-cholic acid made people live longer. It's a higher risk population than were included in POIS, but essentially the goal was to compare against placebo. All I really want to show you was the challenge of keeping patients on placebo in a long-term disease, a rare disease, where patients know that biochemical efficacy means something to them, and they don't want to be on placebo for eight to 10 years, and then the drug becomes available commercially to them. And you can see the challenge of the patients coming off treatment and coming off placebo. So I think, and I don't have time to go through all the data, you know, this study confirmed to the community at least that you cannot do classical outcome studies. At least it's not easy, and we need to be thinking more creatively, and that comes back to my point about the journey from the lab to the clinic to bring our biomarkers from science to practice. So you know, what ASLD gave us the opportunity to do in this rare disease area was to focus our sort of concepts on the care, and for this I've just got slides on the common PBC, and I'll show you PSC, which was I think ASLD taught all of us diagnose with confidence, think about our treatment choices, please don't forget the importance of symptoms, stratify risk using the knowledge that we have, and think about our current and emerging treatments for PBC, because it's going to look very different in 2024 and 2025. And similarly for PSC, what it showed us was that there's a lot going on in the gut liver axis, and there's a real commitment from everybody at this meeting to make a difference to this very rare population of patients with a very, very impactful outcome. So please think trials, because that is in fact science, and that's what ASLD is so good about. So my key takeaways, to come to an end, new therapies will be anchored in experimental medicine and clinical science. Patients can expect better interventions that improve quality and quantity of life, and ASLD 2024 will be as exciting, Mr Chair, for cholestatic liver disease, plenaries, meet the experts.

Dr. Gideon Hirshfield

Toronto Centre of Liver Disease

cholestatic liver disease

ASLD 2023

rare liver diseases

clinical trials