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Podcast: PBC highlights from the International Liver Congress 2022

Podcast: PBC highlights from the International Liver Congress 2022

Prof. Gideon Hirschfield, Prof. Jörn Schattenberg, Prof. Kris Kowdley, Prof. Ana Lleo

In this podcast series of two episodes, four international experts discuss their take-home messages from the primary biliary cholangitis (PBC) data presented at the International Liver Congress 2022

In the first episode, Prof. Gideon Hirschfield (Canada) and Prof. Ana Lleo (Italy) focus their discussions on treatments currently available, treatment sequencing, management of adverse events, expected future therapeutic options and how to address the unmet clinical need of this rare liver disease.

In the second episode, Prof. Kris Kowdley (USA) and Prof. Jörn Schattenberg (Germany) discuss how to improve diagnosis, the importance of listening to patient needs when assessing treatment options, considerations for treating PBC-related symptoms, differences in PBC diagnosis and treatment guidelines between Europe and the US, and what's coming next for PBC.

Prof. Gideon Hirschfield

Professor of Medicine

Division of Gastroenterology, University of Toronto

Canada

Prof. Jörn Schattenberg

Director, Metabolic Liver Research

University Medical Center Mainz

Germany

Prof. Kris Kowdley

Director, Liver Institute Northwest

Washington State University

United States (US)

Prof. Ana Lleo

Professor of Internal Medicine

Humanitas University, Milan

Italy

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Primary biliary cholangitis highlights from ILC 2022: episode 1

time Podcast | open 20 min | Jun 2022

Subscribe to our podcast series on:

I agree that this educational programme:

Please note:

Podcasts are designed to be heard. If you are able, we encourage you to listen to the audio, which includes emotion and emphasis that is not so easily understood from the words on the page. Transcripts are edited for readability. Please check the corresponding audio before quoting in print.

This programme is supported through an independent educational grant from Ipsen and is an initiative of COR2ED.

The views expressed within this podcast are the personal opinions of the authors. They do not necessarily represent the views of the author’s academic institution, employer or other group or individual.

Gideon Hirschfield:  Hello, and welcome to this exciting podcast on PBC highlights from the International Liver Congress 2022 just finishing in London UK. My name is Gideon Hirschfield.  I’m a hepatologist from the University of Toronto, and I am delighted to be joined here today by Ana Lleo, a Professor of Hepatology from Milan. Ana and I are going to have a conversation about some of the highlights that we took away from this congress, on primary biliary cholangitis. I hope we can have a fair, frank and open discussion.  So Ana, let me start by asking you what kind of convention you had, and then you tell me a little bit about what you learned about some of the first-line treatments for PBC from some of the sessions at ILC.

Ana Lleo:  Hi Gideon.  It’s really a pleasure being here. It has been a really exciting meeting. It is the first meeting face to face we had in a long time, and it was really exciting following all the sessions. We did a lot of work on PBC during this meeting. For sure the first line was highlighted as ursodeoxycholic acid. I think that's something nobody really doubts - the efficacy has been proven, we all use it. The only reminder was to use the correct dose 13-15 milligrams per kilogram per day. I was actually surprised seeing a very nice study that the UK PBC group presented. It was real life experience with a really high number of patients in which they show that actually a very good percentage of patients are under dosed on first line so that the dose adjustment is not always correct.

Gideon Hirschfield:  I agree, and I think one of the interesting things is when we educate about PBC we've got to educate from the beginning, not just from the middle and so from the beginning it's a good diagnosis and it's using ursodeoxycholic acid properly and there's still work to be done. It's better than it was but there's still work to be done.

What did you think about when we should screen for failure to respond to ursodeoxycholic acid?  Do you think it's okay to wait 12 months or do you think that really we should be accelerating that time point?

Ana Lleo:  Well, I think we already have enough data to suggest that the sooner we start second line in non responders or incomplete responders the better. The large cohort studies have identified that predictors at baseline are reliable to identify those patients that don't respond. So it's not clinical practice yet, the guidelines still recommend to assess response at 12 months, which is what most people do, but I think we need to do more studies to validate these indications and see if we can start second line earlier.

So what do you think Gideon about the second line and the treatments that are available at the moment?

Gideon Hirschfield:  First of all, I agree that I think we would like to accelerate the time point when we consider second line treatment. I would just say in one of the sessions, we talked about whether there needs to always be a rush in PBC. So you know, without doubt, I want all patients to get the best treatment, but I also want patients to be adherent, to understand their disease, to feel as if they understand the quality of life aspects of it. So I'm a little bit nervous about a pure escalator approach to PBC. I want something in the middle, where our colleagues around the world really identify insufficient response at the appropriate time.

As regards second and third line treatment it's very, very exciting times. It's very clear that we've agreed that we don't want our patients living with abnormal serum liver tests on ursodeoxycholic acid, or if intolerant to ursodeoxycholic acid, because that clearly is associated with poor outcomes. And it's very exciting that we have licensed second line therapy and clinical trials of new agents, as well as off-label therapies. So we use licensed therapy and there was data at this conference, looking at real world outcomes, looking at how to demonstrate whether a drug, such as a obeticholic acid does improve not only biochemistry but also improves outcome and that's relevant to other second and third-line treatments because they're going to be developed in a very, very similar way. So in our practice what we're doing, of course, is, we have a choice between obeticholic acid, and sometimes off label use of drugs. We’re using licensed approaches first. We're looking at patients at 12 months of treatment on ursodeoxycholic acid and we're looking at their symptom profile to decide how they will tolerate with obeticholic acid.

But we're looking to the future as well, because we know that not everyone responds adequately to obeticholic acid. We know that obeticholic acid does have a side effect profile, including pruritus

And we know that drugs that target the PPAR pathway, whether that’s bezafibrate, fenofibrate or new drugs in development, such as elafibranor, seladelpar, saroglitazar, they have the opportunity to not only tackle disease but also tackle symptoms. So we're identifying the higher risk patients using biochemistry, as we discussed, maybe we're thinking about this at six months not 12 months and then we are adding in second-line treatment, usually for us it's obeticholic acid, I'm not sure what you're doing, and then we are giving patients triple therapy.

Ana Lleo:  Yeah, I guess, we have a slightly different approach so for sure we use the first approved, second line treatment. We probably personalise a little bit more the treatment, and if the patient, for instance, is a non-responder and has pruritus we will go for fibrates first. But it's still up to the clinician to decide which second-line treatment is better. However, I have to admit that the fibrates are still under used and still the guidelines recommend even in Europe, second-line treatment with obeticholic acid so it's still an open question there. I think we still need more data. Actually the combination second-line data was actually exciting. also it's a recent paper that was represented in some of the sessions in which combination of triple therapy actually has shown, very good effects, and I think that's exciting too. So we can offer our patients that do not respond to second line an add-on therapy with fibrates or obeticholic dependent on what you have used before.

Gideon Hirschfield:  An important point, I think, is that most patients living with PBC do not go to super-specialist PBC clinics. And that's the reason the guidelines are so important and it’s guidelines in Europe and the US and they're pretty well aligned. I mean there's some differences about the emphasis on off label therapies. But the point I'm making is that with new licensed therapies coming online it's easier for the guidelines to be clearer and clearer for everybody, so that it doesn't matter where you live with PBC you're going to get the same opportunity for personalised care. One of the challenges of personalised care is making sure that the person making those decisions in conjunction with the patient has sufficient experience and expertise. Of course with off label therapies people feel a little uneasy about using drugs off label, particularly when they worry about side effect profiles. And so I hope in the future, in the next years to come, when we have other therapies approved for PBC that will then allow the guidelines to be clearer and actually what that means is that there's a more uniform standard of care. I think standards of care, something that you highlighted from the UK paper about the opportunity to actually measure what we're doing, not what we're talking about. That's something that came up in the conference in a number of sessions, it's quite easy to talk about where we'd like to be in terms of treatment response in terms of symptoms and studies that looked at symptoms. But we also have to then translate that into what's actually happening in the community, which is actually where the majority of PBC is looked after and in fact I think wherever you live it's the same around the world.

Ana Lleo: Yeah it is it's the same experience, I think we also need to remind that unfortunately, the second line treatments that we have available at the moment cannot be used in advanced cirrhosis and that's a limitation for our patients. If the patient is not a good candidate for transplantation at the moment they are without options.  There is nothing else we can offer them

Gideon Hirschfield: Absolutely. And the second thing is, as a community of people and patients with PBC we mustn't undervalue our disease. We mustn't take the approach that our disease should be treated only with cheap drugs. Drugs have cost and our patients are valuable and preventing liver transplantation and improving quality of life are valid targets.  It's perfectly valid for those treatments to be state of the art. It's not only diseases that you can cure that should have the latest therapies, but chronic diseases like PBC, which have significant impacts on quality of life and, as you said quantity of life are also valuable to the individuals living with it and therefore there's value to having therapeutic development for PBC and other cholestatic liver diseases.

Ana Lleo: Yeah probably we should organise our care and management of patients also with an early referral of most difficult cases to specialised centres. For those cases that probably are at higher risk of complications that need to be listed for transplantation earlier and I know it's not always easy it's not applicable to all countries, but it’s probably the way to offer our patients the best cure giving everyone the same opportunity.

Gideon Hirschfield: I agree, and look, what we're trying to do is get the patients to the right place at the right time, and you know, there was discussion about side effects of treatment side effects of UCDA, side effects of obeticholic acid, side effects of bezafibrate. We will learn about the safety profile of the new drugs. Clearly what we therefore need is individuals looking after patients who've got the experience to use these drugs, because even drugs like ursodeoxycholic acid, I don't know what you think, even that has some side effect profile. It's a safe drug but, in fact, if you listen to patients, patients do tell you some of the things they don't like about UCDA just like they tell you the things they don't like about OCA and just like they tell you the things they don't like about bezofibrate and no doubt they'll tell us the things they don't like about other drugs. It's taking medicines isn't it?

Ana Lleo: Yeah absolutely the same. PBC is a disease in which you can take your time with. Probably some patients report some discomfort in terms of diarrhoea and nausea but I've learned that if you stop treatment and then you restart with a slower approach, increasing the dose as tolerance allows in the end, they end up tolerating the drug very well. And the same thing I think we've learned a lot about management of pruritus with obeticholic acid. So there's still a lot that we can do and learn in management of side effects for our patients.

Gideon Hirschfield: I agree and that’s what personalised care is about - listening to the patient, listening to their symptoms.  We talked a lot about symptoms, I think you'd agree, at ILC and there were studies on symptoms and there were data on trials, where symptoms have been evaluated and those symptoms were not just pruritus but they were fatigue and so a lot of the discussion was just to listen more. As you say, if you listen more then you can adjust what you do and you can use what we have at the moment better.  But in the future that helps us develop drugs which hopefully have less side effects but also address other issues better, such as pruritus, such as fatigue. So I'm not sure what you took away from the conference but I certainly took away that we need to look at the whole problem with PBC not just alkaline phosphatase and look at pruritus, look at fatigue and actually ask clinical trials to look at those as well.

Ana Lleo: Yeah I agree absolutely with you Gideon. We focus a lot on the technicalities of the disease – alkaline phosphatase, the ultrasound, the signs of portal hypertension, which of course it’s very, very important for doctors, but our patients care more about symptoms, because it's what impacts their daily life. So, probably, as we said during the meeting, we need to find ourselves somewhere in between and manage, of course, the biochemistry and the disease but also treat symptoms. I was excited to see data on clinical trials addressing pruritus, addressing fatigue that we will see a lot in the future, and I think it will be a very good option for our patients. So this was very, very interesting.

Gideon Hirschfield: I agree. ILC had a lot of studies looking at ASBT inhibition, in cholestatic pruritus in children and adults, there was discussion about PPARs, you know, in development and already used and pruritus. Then there's this approach to inhibiting NOX inhibition and there was a secondary analysis as you point out looking at sub domains of the PBC-40 and looking at the impact of a new therapy on fatigue in clinical trials. So I think the fact that they're being discussed at ILC demonstrates the recognition of the importance. Of course, some of these therapies which are going to come are going to change both, as you say, the mechanics of the disease, the cholestatic injuries that have been by alkaline phosphatase which is now a surrogate endpoint for treatment need and treatment efficacy, but also improve pruritus, for example, and then maybe drugs that improve pruritus will also improve other quality of life generally.  I think the big question is whether you can pick that up in six to 12 to 18 months of clinical trial and maybe you have to wait longer and that data really will come out in evolution. I mean the evolution of treatment of PBC is we do treat earlier and when we treat earlier we get better outcomes, so when we get better outcomes, we have patients with better quality of life, as well as better biochemistry.

So I think also we should caution people that you can't necessarily expect in all clinical trials to hit on everything in a relatively short duration, because I think you said it yourself Ana, this is a lifelong disease over decades and decades and a clinical trial is a mere snapshot of 12 months of a patient’s experience of living with the disease. Sometimes you know as we've seen with ursodeoxycholic acid it takes decades to get to understand all of the ups and downs of therapies and we're sort of starting to see that, with obeticholic acid which has been on the market now for six years and now we're getting data on outcomes and comparative ways of looking at outcomes, but it takes time doesn't it? We’re a rare disease, and you know it doesn't all just happen in two years and there are big studies. But I do think that the conference was particularly exciting about that point perspective and really highlighted where things may go in the future, and also set quite high expectations for ourselves as treating physicians and for our patients.

Ana Lleo: Yeah I totally agree with you. As you mention, it was also very nice seeing the comparison, the study of the patients treated with obeticholic acid compared with reference cohort of untreated patients that do not respond to UCDA. That gives a lot of hope. It gives a lot of hope to our patients because these treatments work and there are more options for them, and if we identify them early, as you said, we can offer them different therapeutic options in order to avoid complications.

So I think really the future for PBC is bright, there are a lot of possibilities for our patients, both in the treatment of the disease, in management of the complications and management of the symptoms and I'm sure we will see in the near future a management of the disease that offers our patients a broad line of opportunities and treatment

So I don't know what do you think Gideon, but I think this has been a lot of fun. We have actually enjoyed a lot, the meeting, and we have had a lot of fruitful discussions and we've learned a lot about the possibilities that our patients can have and I can't wait to see the next future what it offers and the possibilities that we will have.

Gideon Hirschfield: I agree, and we have the next in person meeting at AASLD and then there'll be another in person at EASL and we've learned that you can use both in-person meetings, Zoom meetings, podcasts, Twitter… all of these things.  And collectively all of those things have been positive and our little disease. Our rare disease can have a light shone on it, and we can see that things will be better for our patients in the future, with a lot of effort from everyone - patients first and foremost.

Ana Lleo: Goodbye then. I hope to see you soon and we will be chatting about this more.

 

 

 

Primary biliary cholangitis highlights from ILC 2022: episode 2

time Podcast | open 20 min | Jun 2022

Subscribe to our podcast series on:

I agree that this educational programme:

Please note:

Podcasts are designed to be heard. If you are able, we encourage you to listen to the audio, which includes emotion and emphasis that is not so easily understood from the words on the page. Transcripts are edited for readability. Please check the corresponding audio before quoting in print.

This programme is supported through an independent educational grant from Ipsen and is an initiative of COR2ED.

The views expressed within this podcast are the personal opinions of the authors. They do not necessarily represent the views of the author’s academic institution, employer or other group or individual.

Jörn Schattenberg:  Hello everyone thanks for tuning in. This is a podcast recapping the recent findings on primary biliary cholangitis during International Liver Congress 2022 just happening in London. My name is Jörn Schattenberg. I'm an academic hepatologist based at the University Medical Center in Mainz, Germany and it's a pleasure and honour to be joined here today by Dr Kris Kowdley, the Director of the Liver Institute Northwest and a clinical professor at the College of Medicine at Washington State University.  Welcome Kris.

Kris Kowdley:  Thank you Jörn.

Jörn Schattenberg:  It's my pleasure to be recapping with you today some key findings related to primary biliary cholangitis from the recent ILC 2022. From a very personal note, at the beginning, I think it was great to be back in person and actually meet that was a real highlight beyond the content of course.

Kris Kowdley:  Yes, I agree, and Jörn, EASL did a wonderful job of putting on the ILC first live conference, so congratulations.

Jörn Schattenberg:  Great thanks - I am glad you enjoyed it.  Let's dive right into topic, because we have a limited time today and there's a lot of stuff to be covered here. Let me start with the diagnosis or the diagnostics around primary biliary cholangitis.  Maybe you can give me a quick idea on what you're doing in your practice today, or maybe some data you've seen at ILC. What's new on diagnostics?

Kris Kowdley:  Very timely question Jörn because, as we know the use of ELISA based, inexpensive antibody tests has sort of provided some confusion, at least in the United States because historically we used to get the results in immunofluorescence or using some sort of immunofixation test where you got the results in a titre for any mitochondrial antibody. Now increasingly we get a number in the US, so you order an AMA test and you get a number that could be 20, 30, 40, 60, 80 etc. And those who are not very experienced actually sometimes can get confused because at low levels of the ELISA antibody there are significant false positive tests. So one of the things I try to encourage people is to put the test in the clinical context. Does the patient have a cholestatic pattern of liver abnormalities? Is there other history of autoimmune diseases? Etc. One nice advance that has happened in the US is through some of the large commercial labs we can now order a PBC panel which allows us to get a more specific test, as well as the PBC-specific ANA test, ie the GP210 and SP100 antibodies which are available at one blood draw.  So this has made a big advance, but certainly the availability of the inexpensive ELISA test has made it easier, on the one hand, to order the test, but also more confusing for practitioners. What do you find in Europe? Is it a similar issue or are people more sophisticated about how they run the AMA test?

Jörn Schattenberg: I think we've been in that arena for some time now and, as you said, I get my referrals as you've just described it. The dilution assays are used and I think there is less of a confusion in Germany, because these have been used for some time now. I think one of the important aspects is that I see a lot of positive AMA tests in the absence of cholestatic pattern of liver injury as you've just described, and I think we have to remember that this is not a test with a very high sensitivity or positive predictive value, meaning that it's not the AMA in the absence of elevated alkaline phosphatase that defines PB . Its is interesting to speculate that this population can potentially progresses to PBC at one point, but those are not patients, we have to consider for treatment at this time, and I think that in the realm of diagnostics that’s something we're seeing as pretty common in clinical care in terms of referral.

Kris Kowdley: Yeah it's an excellent point. In the US, I don't know about in Germany, but there's a reflex to order every test for every liver disease in a patient that presents for workup.  So you get patients with a hepatocellular pattern of injury, no cholestatic pattern who get an AMA test or patients who get an AMA test for workup of unexplained liver test abnormalities and obviously those tests are much more difficult to interpret. But I guess from our standpoint, the more people are thinking about PBC and ordering the test for PBC the better, because you can make a wrong diagnosis – it’s better than making no diagnosis.

So let's move on to talk about some of the new exciting data presented at ILC and there were really a few different buckets, if you will. I think we are seeing now a greater emphasis on quality of life and patient reported outcomes and we're also seeing more work being presented in terms of how to interpret incomplete response to treatment with UCDA. There were a couple of posters that I thought were quite interesting. One poster talked about whether patients should be given a specific exercise program and actually showed some promise in terms of targeted exercise possibly being useful to help patients in terms of their quality of life. Similarly, there is another poster on survey well-being and mindfulness approach to treating PBC and that also I think was quite promising. So one of the things that's interesting, and this was pointed out by Dr Dyson in a very useful session was we focus on biochemical test abnormalities but I think the patients are much more concerned about their symptoms, particularly pruritus and fatigue and the fatigue may be related to pruritus, but may not be related to pruritus. So do you have any comments about some of these posters? I think we're seeing a real focus now on patient-reported outcomes and measuring quality life, and this may represent an important alternative pathway for development of new treatments.

Jörn Schattenberg: I'm aligned with you here, I think we have to remember, we have a highly effective first line therapy. Many patients respond to first line therapy, which is UDCA and has been around for some time. I know you've been very centrally involved in some of these initial trials and it's just great to have that. However, even patients that do respond to UDCA biochemically, we do have a certain underlying impairment in quality of life, as you highlighted, mostly in the arena of fatigue but also pruritus can be a persistent problem. One of the questions is, how intensely do I have to press for the normalization of alkaline phosphatase and I think when we consider second line therapy we're typically looking at the 1.67 cut off of alkaline phosphatase and not necessarily complete biochemical normalization.  But there have been some reports on lower cut offs and I think one of the posters that you mentioned showed us that we do not necessarily have to thrive for complete normalization but it would be important to get the patients in the category below 1.5 ULN of  alkaline phosphatase. This is an area where the data is supported.  

Now other aspect you mentioned, the quality of life and what can we as physicians do to support quality of life for our patients, I found this very interesting that the UK group started advising patients to actually work out and do physical exercise.  There's been a number of studies that have shown or that have linked sarcopenia and muscle loss in particular in progressive disease to increased symptom burden. We know there's more disease progression. So, by implementing an exercise program which was fairly simple and straightforward patients were empowered to do something for their health within their own home - weighted aerobic exercise. Within the study patients were followed-up by weekly telephone calls. To me this is an important element that supports patients adherences and shows the patients that the health care provider care and follow their progress,  motivating them, aiming to lower barriers for implementation. The most striking aspect here is, that these patients have an improvement in the PBC-40 fatigue domain that was detectable even over this short treatment period of 12 weeks. Also, improved sleep quality and the total hours slept improved. By applying a very simple intervention - physical exercise at home with a little bit of supervision and follow up to support, an impact on fatigue but not pruritus was made. Do you have ideas how sarcopenia could affect disease progression in these pateints? In terms of liver disease sarcopenia is a critical aspect and I found it intriguing that patients reported less symptoms.

Kris Kowdley: Yeah I know that was an excellent summary. Thank you for that.  I was particularly struck by this poster that came out of Newcastle where they had interviewed almost 600 patients and I think this really informs clinical trial development so, for example, what they found is the prevalence of fatigue and brain fog were even higher than classically reported. Patients actually prefer electronic symptom reporting and thought that this would standardize data collection much more and a daily treatment for brain fog and fatigue that made respondents consistently even a little bit better was preferable over treatment that improved symptoms for short periods of time.  So patients would like an incremental increase in quality of life that lasted as opposed to ups and downs. And then, with regard to pruritus, patients appeared to clearly prefer a pill form as opposed to the current approaches which, of course, include either taking up to 24 tablets of cholestyramine a day or the powder, which is difficult to ingest. So this was a really useful abstract, for me, because I think this will inform those of us that are trialers and also our industry partners in designing clinical trials.

Jörn Schattenberg: Let me just revisit one abstract briefly, Kris. I think the concerns about data safety and data electronic capturing are great with sponsors and particularly in the EU and, as you said, this is something the patient actually asks for it's something where we really have to focus on and move this forward.

Kris Kowdley: Yeah I think it's a wonderful thing to see that, although we get excited about improvement in biochemical tests, our patients want to feel better and want to improve the quality of their life.

Let's switch gears a little bit and talk about the guidelines and see how the guidelines are changing and the EASL guidelines, I think, are a few years old I'm sure there's a new guideline update in plan.  The AASLD guidelines were written in detail in 2018 and it's now called the guidance as opposed to a guideline and in 2021 there was an update to the AASLD guidelines that suggested that in fact fibrates could be considered as an alternative to obeticholic acid as second line therapy in patients who are either UDCA non responders or incomplete responders or intolerant.  Now of course fibrates are off label at the present time and, at least in the US, they have a warning about use in liver disease and kidney disease, which of course, can be a little bit confusing to our patients. But certainly the body of data about bezofibrate, in particular, which is not available in the US, but available in Japan and Europe and other places, has certainly increased the enthusiasm and also less concerns about safety. What is your stance on the guideline update and do you have any insight or comments on how EASL guidelines and AASLD guidelines may differ?

Jörn Schattenberg: I think your comment on fibrates is timely and it speaks to the necessity to develop second line therapies. The willingness of physicians and patients to actually be subjected to an off label therapy is right down that line, and the class of PPARs is clearly something I'm very excited about. A lot of data has been - as highlighted  by you - generated on the fibrates, bezafibrate in particular from France and Japan and as such there’s a high uptake in Europe. I have to say, on the other hand, it's somewhat bothersome that I cannot prescribe them in label because coverage by payers but also in terms of safety and liability. Overall, this concerns me and I tend to discuss all these aspects intensely with my patients before I would consider off-label treatment with a fibrate in PBC patients. Having said that, even bezofibrate in Germany is not always available so sometimes physician switch to other fibrates that have not even been studied, such as fenofibrate. But then again, how strong is the evidence supporting their use? Overall I'm very excited to see PPARs to be effective also in terms of symptom burden and I think it's something we're going to see more data emerging.

In terms of differences with guidelines, I think, Europeans have been a little bit more liberal on off label treatment and the US has followed in that arena.  I don't see big differences, maybe some notions in terms of social, cultural aspects but nothing ground-breaking.

Kris Kowdley: Yeah so it sounds like your point of view, Jörn, is similar to mine, which is you would consider using a fibrate, but it's not as easy, at least in Germany, as it may be in France to prescribe it and you would like to see more data with regards to safety and efficacy and, of course, a number of both pan PPARs, as well as specific, targeted agonist to delta and alpha delta are currently in phase three trials, so that would, I think, be very informative to us.

So I'm going to kick it back to you here to comment on the new approach to treatment that is being developed, which I think is good for patients. We have some data on linerixibat which was in the GLIMMER study, a phase 2b study for pruritus in PBC and what's interesting is we're now seeing studies being developed really focused on the symptom burden as opposed to biochemical response and this was shown as a poster and really informed the phase three trial, which is currently recruiting.  What are your thoughts about the IBAT inhibitors and do you see a role for them in combination with traditional ‘disease modifying agents’?

Jörn Schattenberg: Kris, this is an exciting field because it introduces a totally new MOA to this disease and I think it's great to see more companies venturing into this field mainly because based on the burden the patient really experiences and beyond the pruritus which is mainly addressed by those studies.  The linerixibat poster shows a nice response in terms of itch scales, for example, you get a pretty fast uptake here and an improvement.  The authors analysed scores, the monthly itch score for example showing an improvement. Beyond that, I think one of the quality of life posters we discussed in the beginning the aspect of sleep disturbances in these patients was highlighted.  I’m optimistic that this will read through and actually help improve the quality of life in our patients. 

The other study I want to mention briefly is a post hoc analysis presented by David Jones on the setanaxib which is a NADPH oxidase inhibitor and here fatigue was specifically assessed and the authors could show a benefit from treatment.   

So for me as a clinician it's exciting to see new MOAs emerge in this field that will supplement standard of care, even in those patients that might be responsive to first line therapy but have a continued impairment in quality of life. In my opinion, sleep disturbances are currently not studied strong enough, while the focus is more on pruritus that leads to a more obvious quality of life impairment. There is more to be learned.

Kris Kowdley: Yeah that's a great summary and, of course, with some of the newer agents, we are quite enthusiastic that they may not only modify disease but also may improve pruritus so that's certainly awaited with enthusiasm.

So let's move on to the last few minutes here and talk a little bit about your personal view, and I’ll share my personal view, regarding what are our endpoints in treating patients? I thought that having been part of the global PBC study group, I certainly can be accused of being biased, but I certainly think that the GLOBE score and the contributions of the global PBC study group has really changed how we approach PBC and played a role in the approval of obeticholic acid as second line treatment, based on alkaline phosphatase reduction.  We're now seeing a change in the thinking, and I fully subscribe to this, which is why do we stop when we have a alkaline phosphatase down to less than 1.67 times ULN and bilirubin less than upper limit of normal. Maybe we should be aiming for deep remission or biochemical remission and we have multiple drugs now that can help us achieve this.  What are your thoughts in the closing minutes about your view towards what should be our goals of treatment?

Jörn Schattenberg: This is great Kris and I think for an orphan disease it was so important to see a surrogate that is linked to outcome, and as you highlighted the GLOBE score clearly did that. The question is, do we have enough evidence to support bringing the alkaline phosphatase to normal levels or even below. Obviously normalizing of bilirubin has been linked to a benefit and from my perspective I aim for normalization of bilirubin and the mechanism you're going to achieve that is by turning off hepatic or cholestatic inflammation and secretory defects: this might require additional treatment.  Bringing the alkaline phosphatase down to let's say below 100 in patients that have previously not well responded and are far advanced could be beneficial. But on the other hand alkaline phosphatase are also linked to disease stage and we are seeing increasing ALP in advanced disease stages. It can be difficult to achieve this in a cirrhotic patient, when it's related to disease activity, but rather the structural changes in the liver from cirrhosis. A different look at this could be to define absence of symptoms as a treatment goal and I'm aligned with you that we should take any measure to lower the symptom burden in these patients.

Kris Kowdley: No, I agree, and just in closing, there was an interesting abstract that was a poster that suggested the benefit of alkaline phosphatase reduction to less than 1.5 was only seen in patients that had a bilirubin of greater than 0.6, so bilirubin of less than 0.6 seemed to be more important to drive outcomes, as opposed to alkaline phosphatase less than 1.5.

Well it's been a great discussion, and I think we've been given the privilege of reviewing all the PBC abstracts. I'll turn it over to you for closing remarks.

Jörn Schattenberg: Well, thanks, Kris for joining me in this today and thank you for your insightful comments on the abstracts.  It's been a good chat and thank you to all the listeners for tuning in today.  Have a good day.

Kris Kowdley: Thank you.

 

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