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Keeping Up With New Developments in PBC

Zachary Schwartz (DCE): Hello, and welcome to this Clinical Care Options podcast. I'm your host, Zachary Schwartz. In today's episode, we discuss primary biliary cholangitis. We'll hear expert answers to questions from listeners like you. I'm joined by Dr. Christopher Bowlus at UC Davis and Dr. Sonal Kumar at Weill Cornell Medical College in New York. 

Along with the slides, and to see the full educational program, please visit the show notes for this episode. Now let's get started. 

Dr. Christopher Bowlus (University of California, Davis): Thanks for that introduction and welcome, everyone. It's a pleasure to be - excuse me, a pleasure to be here and talk about PBC with Dr. Kumar. 

So first thing to focus on here are our two pillars of treatment of PBC. The first is to prevent the progression of the liver disease and its complications that can occur in patients with PBC. This is when - that we all focus on as clinicians, that is, progression to cirrhosis and its complications of hepatic decompensation and need for liver transplant or eventually liver-related deaths, but perhaps more important to our patients is actually improving their quality of life, and the main burdens of that include itching or pruritus and fatigue. 

So I'm going to focus on the first goal, which is to prevent PBC disease progression and talk about a couple of concepts that are central to this. The first is that there has been essentially a mountain of evidence showing that in patients treated with urso, the level of alkaline phosphatase and total bilirubin after one year of treatment is linearly related to the risk of having subsequent liver transplantation or death. 

Up until the alkaline phosphatase hits multiples of the upper limit of normal, the risk of developing - of having a liver transplantation or death is essentially the same as what we would see in a patient population without PBC. But as the alkaline phosphatase increases, there is an increasing risk of liver transplant or death. So it's a linear relationship. The higher the alkaline phosphatase, it’s the greater that risk. 

And then if you look at bilirubin, we see a similar sort of relationship. But you'll notice that the - the risk starts increasing even before we hit that upper limit of normal. And so this is an important concept to keep in mind when we think about our patients treated with urso and whether they need to be put on a second-line therapy. 

Now when we discuss treatment of PBC, we often talk about a biochemical response rather than looking at this linear relationship, thinking whether a patient has a response or not to treatment. And this is somewhat important. The threshold that's been used in clinical trials is 1.67 times the upper limit of normal, which is a bit of an arbitrary cut-off, but one that we commonly use. And to think about it in clinical terms, we should just think if the alkaline phosphatase is above 200, that essentially is 1.67 times the upper limit of normal. I think a little easier for people that don't deal with PBC every day can keep in their mind. 

And so these are the patients that have been studied in clinical trials and clearly are at increased risk of disease progression and should be considered for second-line therapy. But increasing evidence suggests that normalization of alkaline phosphatase may be better, particularly in certain populations that we'll discuss. 

Now when do we assess treatment response? We typically have used 12 months. And that's what's in our guidelines and what's been used in clinical trials as well as in those studies I presented earlier. But there's clear evidence that the response to alkaline phosphatase occurs relatively rapidly. And by six months, we pretty much can make an assessment about whether a patient is going to achieve response or not, or what their maximal reduction in alkaline phosphatase is going to be. So there's not necessarily a need to wait for 12 months. 

But of course, we also want to continue to monitor patients over time. So just because they had a response at 12 months doesn't mean they will always have that response. And so there may need to be reassessment about second-line therapy throughout the patient's journey with their disease. 

Now, in addition to the alkaline phosphatase and its response to urso, we need to think about where the patient is in terms of their liver fibrosis. On the other hand, patients with a liver stiffness over 15, even if they had a biochemical response, had a relatively poor outcome, it was better than those that didn't have a biocal - biochemical outcome - or response, rather, but they still had a reduced survival. So we probably want to be more aggressive in treating those people with advanced fibrosis, which makes clinical sense. 

And so just as an overview of how to assess our patients with PBC and their risk of disease progression leading to liver transplantation, cirrhosis, its complications. Well, all patients should be started on first-line therapy. There's a mountain of evidence showing that urso is effective in the majority of our patients with PBC, but not all of them. 

And so if the alkaline phosphatase is over about 200, we really should be thinking about a second-line option. And then if it's above normal but not quite up to that 200, there may be patients that we still should be considering treatment, particularly those with advanced fibrosis, but particularly in those that are younger, as emerging evidence suggests that they are also at greater risk, which makes sense because they're going to deal with this disease for a much longer time and frequently have more aggressive disease. 

And so with that, I'm going to turn it over to Dr. Kumar to talk about some of these new treatment options that are available to us. 

Dr. Sonal Kumar (Weill Cornell Medical College): Thank you, Dr. Bowlus. And, you know, as we've been striving for more personalized care and stricter control of disease for our patients, it's been really nice in PBC to have multiple second-line treatment options for our patients that don't respond. Dr. Bowlus mentioned, especially in those patients who may be younger or have more advanced fibrosis or we really want to get their biochemical response to normal. It's been nice that we - we have multiple - multiple options for these patients. 

So first, there was obeticholic acid, which is an FXR agonist, and it was approved almost a decade ago in May of 2016 as second-line treatment for patients with PBC. But just recently it was voluntarily recalled and so it's no longer available. 

One of the side effects that we did see with obeticholic acid where that patients could get treatment-emergent pruritus. And as we talk about quality of life and how we get to symptom control for our patients, that becomes important. 

And then last year, in June of 2024, we had two PPAR - in June and August of 2024, we had two PPARs - PPAR agonists that were approved. So first was elafibranor, which is a PPAR-alpha and delta agonist. Again, that was approved in June of last year. And we'll go through some of the data that led to that - that approval. But this is the first time we're seeing with second-line treatment really the potential to maybe impact symptoms or improve - improve pruritus. 

And then we have seladelpar that was approved in August of 2024. And this is a pure PPAR-delta agonist. And similarly, it was shown - demonstrated potential to improve pruritus in our patient PBC. 

So this is the data for elafibranor. It was - their phase III trial was the ELATIVE trial, and this was a double-blind, placebo-controlled trial. And patients were included in the trial if they had an inadequate response to UDCA or if they were unable to tolerate UDCA. Though the majority of patients, 95% of patients were on UDCA. 

We actually saw in the obeticholic acid trials, where patients were considered responders if they had a decrease in their alkaline phosphatase to less than 1.67 times the upper limit of normal. They had to have a reduction in their alkaline phosphatase by at least 15%. And the bilirubin had to be normal. So you had to hit all three of those - those points to be considered a responder. And here 51% of patients achieved that - that biochemical response compared to 4% in placebo. 

And now as we talk more about alkaline phosphatase normalization, we're starting to see data on that as well. And so in the ELATIVE trial with elafibranor, 15% of patients achieved normalization of their alkaline phosphatase. 

And then we have the RESPONSE trial for seladelpar. So similarly this was a phase III, double-blind, placebo-controlled trial. Patients again had to have an inadequate response to UDCA or unable to tolerate UDCA. And that - and similar to the ELATIVE trial, 94% of patients were on UDCA. So they had almost 62% of patients in the RESPONSE trial achieved that composite response, compared to 20% with placebo. 

And then when looking at normalization, they had 25% of patients achieved alkaline phosphatase normalization compared to 0% in placebo. And what's really nice is that you get a response really, really quickly. So a lot of the alkaline phosphatase reduction comes within the first month of treatment. So it's really encouraging for patients and it's encouraging for providers to see even a month into therapy dramatic improvement in alkaline phosphatase levels. 

So what about quality of life? Dr. Bowlus in the beginning mentioned the two pillars and goals of treatment for patients and wanted biochemical response. And number two is managing quality of life. 

So PBC is unique when compared to a lot of other liver diseases in that it can be really symptomatic for patients, with pruritus probably being the most - one of the most common symptoms that we see in our patient population. 81% of patients with PBC are affected by pruritus. 

But unfortunately, as healthcare providers, we don't do a great job addressing or even evaluating symptoms, particularly pruritus with our patients. So looking at a couple of different studies, but 40% of people with PBC reported no discussion of symptoms with their health - you know, healthcare provider in the last year. And I think it's really important as providers that we ask our patients about their symptoms. They're the ones who have to, you know, deal with this on a day to day basis. And so although we care about liver-related outcomes but we also care about managing their quality of life. 

And then even when we ask about - about pruritus, we often underestimate the severity. So this is a study that showed that in patients who reported having moderate itch, there was only 71% to 73% concordance with what was documented by the healthcare provider. 

And then pruritus can be difficult to treat. So a third of patients with PBC and clinically significant itch did not receive treatment. So it's really important that we recognize this - recognize this and try to address quality of life and symptoms whenever we can. 

Now the one thing to remember about pruritus is that it really does not correlate with disease control. So there are patients that can have a completely normal alkaline phosphatase and still have really severe pruritus. And, you know, if the alkaline phosphatase - phosphatase goes down, it doesn't mean that their pruritus is going to go down. So it's important to note that, especially with UDCA or first-line treatment, PBC associated pruritus does not typically improve. 

So when you're starting patients on first-line therapy, you don't want to tell them that this will address their symptoms because it will - it will help with their disease. It will improve liver outcomes if their alkaline phosphatase goes down and we can get a biochemical response, but it really does not affect symptoms. And treating pruritus or addressing pruritus is - can - should be completely separate from first-line treatment. 

So - but with the new PPARs, we are starting to see acknowledgement or improve - you know, study of - of symptoms in our patients. So the ELATIVE trial in their secondary endpoints actually and in the RESPONSE trial had change in pruritus as a secondary endpoint. So this is that same ELATIVE trial. And there were multiple tools that were used to assess pruritus in patients. So there's a Worst-Itch NRS score. There's the PBC-40 itch and there's the 5-D itch score. 

There's a trend in improvement in patients who were on elafibranor, but compared to placebo, this was not statistically significant. And there's an improvement in PBC-40 itch score and 5-D itch score, but still encouraging to see a trend towards improvement by using elafibranor. 

And then when looking at seladelpar for second-line treatment in patients with - with pruritus at baseline, there's the ENHANCE trial and the RESPONSE trial. And both of those looked at change in pruritus from baseline to month 12 here and month three in the - in the - in the ENHANCE trial. And in the RESPONSE trial, again, you see this decrease in the blue line at the bottom, showing an improvement in pruritus and patients that were on seladelpar. And here in the - in the RESPONSE trial, it was statistically significant. 

So the key take-home points here, you know, one is biochemical response. Alkaline phosphatase is directly related to clinical outcomes in high-risk patients. So again in patients with advanced fibrosis or evidence of fibrosis and patients that are younger, we really want to strive for normalization of alkaline phosphatase. And then second-line PPAR agonist can help achieve that biochemical response in patients who don't achieve that response with first-line treatment with UDCA. 

And then number two, quality of life. So quality of life again is a - is very important for patients. And we need to do a better job as healthcare providers recognizing this, talking to our patients about this and treating our patients for their symptoms, and pruritus should be managed independent of biochemical response. And so just a reminder that UDCA does not improve pruritus, but second-line treatment with the PPAR agonist have shown in their big trials the potential to - to improve pruritus. So that is another highlight of these new second-line treatments that we have available. 

And I think that is it. So again, first-line treatment with UDCA does not affect symptoms in patients, even though it can affect biochemical response and disease progression, etc.. But treatment of symptoms in PBC really should be independent of UDCA. 

Now, the PPARs second-line treatment can potentially improve symptoms, but not with just UDCA. 

And I think with that, we will open it up to a Q&A. So I'll read off the first question. At what alkaline phosphatase level, there should be a second-line treatment? So maybe I can take that. 

I think the goal really is for personalized care and patient. You know, in an older patient who may have no evidence of fibrosis, I would be comfortable if their alkaline phosphatase is between one and 1.5 or 1.67 times the upper limit of normal. But then, you know, someone who's 50 years old and already has evidence of fibrosis, those are the patients that I'm really going to strive to achieve normalization for their alkaline phosphatase. 

Dr. Bowlus: Yeah. And I would agree with you on that Dr. Kumar. The other piece I would suggest considering is symptoms. If a patient is having pruritus, I'm probably going to start therapy at a lower alkaline phosphatase level. But the alkaline phosphatase over 200, definitely am thinking this patient should be started. 

The other question has to do with the tolerability of these medications. And was GI upset include any of the trial data? And yes, as part of the safety data on these medications, there did appear to be a slight increase in GI upset, nausea with both medications, but is a very low rate overall. And these are drugs that are generally very well tolerated. 

Dr. Kumar: Yeah. And if you look at the trial data, the discontinuation rate for both of these drugs is really low, which I think speaks highly to how well tolerated they are. 

What is the cause of PBC? So PBC is an autoimmune condition, so thought to be a genetic predisposition and usually some environmental trigger that sort of unmasks this response. But it's an immune-mediated response that essentially causes damage to the cholangiocytes or the cells of the bile duct. And you get this toxic bile leakage into the liver and build up. And that's what causes the damage. 

Dr. Bowlus: The question had to do with, when do we anticipate updated AASLD PBC guidelines being published? And I know that's being organized right now. Given how these usually work, I suspect it's going to be a year or more before we see new guidelines published. Currently, I think we just have to use the best data we have available. It's obviously the current AASLD guidelines are a bit outdated and don't reflect the new therapies we have available for us. 

Dr. Kumar: I briefly spoke about the withdrawal of obeticholic acid. Dr. Bowlus, how do you feel about this and what are you doing with your patient? 

Dr. Bowlus: Yeah, so I actually thought I still had a lot more patients on obeticholic acid than it turns out I do. Our pharmacist ran the list and we only came up with about three patients. And so we are in the process of transitioning them over to one of the other agents that we have available. And so we're kind of going through it systematically in that way. 

I don't think it's going to have a huge impact. You know, I do feel for patients that have been on it and done well on it for a number of years that they have to move over to something different. But I think it's going to be a minor inconvenience for most patients. 

Dr. Kumar: Yeah. I actually was pretty surprised how your patients - I had on it too. We did the same thing. And I actually - I just had four patients that were still on obeticholic acid. I think some, when the PPARs were approved, switched for, you know, maybe side effects, pruritus. And they had pruritus with obeticholic acid.

So they had already switched, but I - I thought I had more on it, but I guess not. But I agree with you. I think, you know - you know, there are patients that have - it's almost been approved for 10 years now. So there are a lot of patients that have been on it for - for a long time and they were doing well. It's unfortunate that we have to take them off, but hopefully they'll do well on the PPAR still. 

Dr. Bowlus: And so maybe just quickly in terms of how you - oh, do we have another question here? There we go. So are there any non-prescription remedies or lifestyle changes that can help with patient's symptoms, any medications prescribed or over-the-counter to avoid? 

So great question. So I always start with these sort of just lifestyle modifications. I have a copy and paste or dot phrase that I use for patient instructions for management of itch. Generally that includes avoiding heat, generally worsens itch. Clothing, loose fitting clothing, avoiding of course wool, moisturizing and those sorts of things. We often seen in most patients wind up getting on antihistamines, which really, if this is itch from their PBC, is not effective. So those are my go-tos.

And then again, I've been using these agents or similar agents for itch now much more than some of the other prescribed things. I think in a patient that has real severe pruritus or moderate to severe pruritus, when I give them these handouts for kind of conservative measures, they're already doing it and they just say they don't work for them. So I think these are pretty marginal. 

I - I also want to put out there that measuring itch in clinic is relatively easy to do, just like they did in the trial. So essentially the question asked the patient is, “In the last seven days, how bad was your worst itch on a scale of zero to 10, zero being no itch and 10 being the worst itch imaginable?” If they answer four or greater, that's considered moderate to severe itch. And those are the people where generally you want to probably intervene in some way. 

Dr. Kumar: So next question, fibrate or bezafibrate? We've historically used bezafibrate a lot as second-line, especially for patients with pruritus. And I'm not sure the new PPARs will be as effective thought. 

Yeah. So I mean the data on bezafibrate or, you know, the experience of bezafibrate seems to be pretty - pretty good. And you know, until obeticholic acid was drawn from the market, there was a clinical trial looking at abeza - obeticholic acid with bezafibrate. In the United States, we don't have access to bezafibrate, so I haven't had any experience with it and we weren't part of the trial. I don't know, Dr. Bowlus, if you were part of the trial or not. 

But I've used fenofibrate a little bit. You know, I think, you know, it's definitely a possibility, but now with the new PPARs available, I tend to lean towards that more since they are FDA-approved for that for PBC and we see the improvement in - in itch. I don't know, Dr. Bowlus, do you use the fibrates at all? 

Dr. Bowlus: So I think, like you, I've used fenofibrate prior to the availability of these agents. I've had decent success with fenofibrate. I will say I use it at very low doses because I'm concerned about safety with it. I'm not sure it is as effective on itch, but that's just anecdotally and hearing from others. 

I would say yes. The bigger experience is, of course, with bezafibrate, there's one randomized controlled trial. The hard thing about interpreting that is that the endpoints are different. The patient entry criteria were different. And all these things, you know, we don't have head to head comparisons. But in general, if you look at the reduction in alkaline phosphatase with any of these agents, whether it's a fibrate, whether it's obeticholic acid, you get about a 45% reduction in the alkaline phosphatase from baseline, 45, maybe 50%. And it’s - it doesn't matter where you start. 

So if you start with an alkaline phosphatase of 800, you're going to get about a 45% reduction with all these. Similarly, if you start an alkaline phosphatase of 250, you're going to get a 45% reduction. 

Now again going back to, you know, what I was showing about the linear relationship, the patient that starts out at 800 and gets a 45% reduction will get a greater decrease in their risk of progression than someone that's at 250 and drops down by 45%. 

So I think in terms of effectiveness, we can say that from all the data we have, these therapies are going to be as effective, if not more so than bezafibrate, fenofibrate. And we have better safety data on them. I will say also in the bezafibrate study, there were some hepatotoxicities that required patients to stop the drug. So again, I think that's something to think about. 

Dr. Kumar: And maybe, you know, we talked a lot about pruritus. What about fatigue? Are you addressing fatigue in patients? I personally find it - I mean, pruritus, you mentioned is very easy to assess and I 100% agree. But fatigue is much harder and harder to attribute to PBC as well. What's your - your [inaudible]. 

Dr. Bowlus: Yeah. Fatigue is very complicated because it's such a broad term. And when you talk to patients and you go into depth of what they mean by fatigue, is that the brain fog, is it motivational kind of central fatigue not being able to get moving? Is it fatigue that comes on with activity? So I think it's very hard to really get down to what's causing them. But clearly there's something going on in PBC which we see in other inflammatory chronic diseases. 

The good thing that - you know, kind of interestingly is there is emerging data with these agents that seems to be that they do improve fatigue. Some of the evidence suggests maybe it's because they're sleeping better because they're not itching so much. But there's also, you know, recent data coming out in which the improvement in fatigue does not correlate with the improvement in itch, suggesting that there is something else going on that's improving fatigue with these agents. So I think that's really exciting and interesting because fatigue when you talk to patients is - can be pretty debilitating symptom for them. 

Dr. Kumar: Yeah, I have a - I have a hard time assessing it and really capturing how to monitor it over time. But the one thing that I've noticed with these new agents, like you said, there is emerging data showing that the fatigue gets better. They just say they feel better. So overall, like general well-being on these medications - especially if they - you know, were on obeticholic acid and had some pruritus or had some side effects or even if, you know, they were just on UDCA and had their symptoms not controlled. I’ve - I’ve noticed a few - quite a few of them coming in and saying, I just - you know, I feel pretty good on - on this medication, so maybe it's their fatigue getting better. But yeah, it doesn't seem to correlate all the 100% with - with pruritus. 

Dr. Bowlus: There's a question here about the role of immunosuppression in PBC. Do you want to tackle that one? 

Dr. Kumar: You can take that. 

Dr. Bowlus: Yeah. So the only time that immunosuppression really should be considered in - in PBC if you - is if you have really clear evidence of overlap with autoimmune hepatitis. And this is something I think we all see being overdiagnosed. 

When PBC patients present, they frequently will have elevations of their transaminases. A, antinuclear antibodies are very, very common. And even on biopsy, if you go forward with a biopsy, you will see interface hepatitis in a number of patients with PBC. So that does not mean they have autoimmune hepatitis. 

So typically, if there's a question, I would start with urso and see what kind of response you get. And only if there's not a sufficient response or you have clear biopsy evidence that the predominant feature is autoimmune hepatitis, would I use an immunosuppressant? I can tell you if I have a number of patients who are diagnosed as having overlap on chronic immunosuppression, we've been able to withdraw them and avoid the potential long-term side effects of immunosuppression. 

Dr. Kumar: Yeah, I think the important thing to note is that - I mean, just talking about autoimmune hepatitis is that even in PBC, you can really see a mild elevation in AST and ALT, and that should not necessarily make you that’s - that, yeah, if people do get overlap, but it doesn't 100% mean that they get overlap. 

And I similarly sometimes will biopsy these patients and, you know, see this and I put them on UDCA and their labs completely normalized and never even start immunosuppression. 

Dr. Bowlus: And this is kind of an interesting concept that we have a disease that is so quintessentially autoimmune in nature, yet all our experience with immunosuppressants have not been effective, which we don't clearly understand. I would say, you know, one of the kind of exciting areas of potential future therapies has to do with inducing tolerance that is trying to get at the underlying autoimmune nature of this disease, and in a sense, almost curing it.

And there's been some recent trials using what are called nanoparticles that have the autoantigen coated on them, and those are undergoing further study. Maybe sometime down the future, we'll just give our patients an infusion and reverse their - reset their immune system. 

Dr. Kumar: Yeah.

Dr. Bowlus: And if there's not enough - if there's not too much damage, not need these other therapies. But I suspect that once you have injury to the bile ducts, you're going to need to address the cholestasis, which is what these drugs are doing. 

Dr. Kumar: Yeah. We have another question. Do these recently delta - some PPAR delta meds have any significant side effects? 

So we talked a little bit about this before, but overall, these - you know, in the phase III clinical trials and actually from my own clinical experience both of the new PPARs have been pretty well tolerated. And if you look at the discontinuation rates of - in both of the trials, it was 10% or less across the trials. So very well tolerated. 

You know, there are some drug-drug interactions that you have to be mindful of. So I always, you know, tell providers and for myself, I'm always doing a DDI check, but overall pretty - pretty well tolerated. I haven't seen a ton of side effects and definitely nothing significant that I've seen. 

Dr. Bowlus: I would say the one thing - you know, the - the - a few things that we are - we do see, you know, have to do with sort of a rare muscle CPK elevations, liver test elevations, very rare. And then the funny thing had to do with the fractures that we're seeing in the trials. 

Dr. Kumar: Yeah.

Dr. Bowlus: There were none in the placebo. And in both trials with elafibranor and seladelpar, there were a few dramatic fractures. There's data from at least elafibranor that shows there's no change in bone density or markers of changes in - in bone metabolism, suggesting it's not a direct effect on bones. And one of the hypotheses is that, as we talked about earlier, is that they - it improves fatigue. And so patients become more active and then are more likely than to have trauma. 

I think that's an interesting theory. Whether it's true or not, I think we don't know. And it is something to keep an eye out on. But I was really relieved to see that there's not a direct effect on bone density. So I feel better about that concern. 

Dr. Kumar: And I think one other thing that's - this highlights about PBC in general is that they are at - patients with PBC are at higher risk for having low bone density and osteoporosis. And sometimes, you know, primary care providers or other providers that may be seeing the patient may not be aware of this. So I think it's hepatologist and gastroenterologist, it's really important that we, one, tell the patient. And I've actually really been like strict about ordering the DEXA scan for the patient to make sure that we assess for this. 

And not that I'm managing it, but I'm at least making sure that it's checked and then I refer them back to their primary care to - to see if they need any further management. 

Dr. Bowlus: There's a question here about cholestyramine. Do you want to tackle that one and any other kind of emerging therapies we might have for treatment? 

Dr. Kumar: Yeah. So I've used cholestyramine in patients for - for treatment of symptoms. So cholestyramine doesn't work - for biochemical response, but it can, in theory, help with pruritus. I haven't had much luck with it. And you know, it's - it's difficult to use. Patients hate it. You have to time it with other drugs because it can bind - bind other medications. And so it has to be four hours before or after other medications. 

So I used it. I feel like earlier, I used to use it a lot more or try it a lot more. But now that we're seeing some improvement in pruritus with these new PPARs, like you mentioned, Dr. Bowlus, you know, you're - you're a little - in patients with symptoms, you're - you would start second-line therapy a little bit, even with a little bit lower alkaline phosphatase. 

Similarly, I will - you know, if their alk phos is not normal yet, I will shoot for using a PPAR before starting cholestyramine because I just haven't had great luck with it. I don't know if you've... 

Dr. Bowlus: I agree with you completely. You know, I had patients tell me it's like drinking sand. They'll take it if they have - if they're really itching badly. But it's inconvenient. I've used the colesevelam more because it comes in tablets, it's a little easier, but still not clear it's effective. 

You know, there are recent reports out about what are called intestinal bile acid transport inhibitors or IBAT inhibitors. These are medications that kind of act like cholestyramine by blocking reabsorption of bile acids in the intestines and preventing that enterohepatic circulation. So it reduces the serum bile acids. 

And so the first one - well, they're used actually - approved for use right now in pruritus associated with some of these pediatric conditions like AlagilleSyndrome or Progressive Familial Intrahepatic Cholestasis or PFIC. And the reports of their efficacy in PBC have now been reported. And I think we'll have them available in the near future to manage pruritus in individuals. So much easier to deal with and maybe add more to what we have to offer our patients with PBC. 

Dr. Kumar: Next question. How did - how do you decide when treatment has failed even with second-line treatment? Maybe I can start with that. 

So I think, you know, if you've put patients on first-line treatment, we sort of went over criteria when, according to stage of fibrosis or age or what our goals of treatment should be. And then after you put patients on second-line treatment assessing their treatment response, you know, I think it becomes a little more nuanced. 

The one thing that we know from the data that Dr. Bowlus showed is that the lower the alkaline phosphatase, the better the outcome. And so I think even if you get a response, even if it's not normalization of alkaline phosphatase, in the long run, that is - is beneficial to patients. So I mean a true treatment failure. I haven't really had a patient who doesn't get any response whatsoever from first or second-line therapy, because then I would start questioning the diagnosis. That's when I would consider really doing a liver biopsy to see if there's something else going on. 

We have to remember 30% of the population has MASLD. So there could be underlying, you know, fat in the liver that's actually driving this. And you can see a little elevation in alkaline phosphatase. So maybe it's all that instead, and the PBC is actually still controlled. 

So in patients who have failed - “failed second-line treatment”, that's when I really want to biopsy them and make sure that we have the diagnosis correct. 

Dr. Bowlus: Let me ask you a question about maybe some of these more challenging patients and how you would deal with them now. So I have not done this personally, but I know that there are some data on patients that, you know, they have a high alkaline phosphatase on urso. They get started on a PPAR, bezafibrate or whatever, and then also add on obeticholic acid to really try to get them down. Those that are super high risk. 

We don't have obeticholic acid now, so I guess that question is moot. So we're kind of have to live with what we're at. Would you ever switch between these options we currently have? They're all in the same class, but do you see any potential role of switching around? 

Dr. Kumar: Yeah. I mean, we don't know if the same people who respond to elafibranor are going to be the same that respond to seladelpar and if they're going to have different response - you know, different percent respond. 

So especially in a high-risk patient, where - you know, like you said, now we don't have the option for obeticholic acid. Whereas prior, I would say, you know, triple therapy is not a bad option. I haven't - I didn't do it in anyone, but I would have definitely considered it. I would consider switching and seeing what happened to their alkaline phosphatase. 

Dr. Bowlus: Maybe a more basic question. Let me - let me give you a scenario here. So patient comes in with their initial evaluation. Their alk phos is elevated. They are AMA positive. You get a baseline FibroScan. You put them on urso. You make your decision about second-line therapy or not. How do you monitor them? When do you get a FibroScan again? You know, what - what's your kind of routine in clinical practice? 

Dr. Kumar: Yeah, I usually check - do telemedicine appointment either with myself or my nurse practice - the nurse practitioner who works with me in four weeks. And that is really to assess compliance and assess side effects. We kind of do this with all these new medications that have come out, or even when I'm starting older medications, because, you know, the last thing you want, oh, they took it for a month. They had some nausea, vomiting, whatever it may be. And they stopped the medication. And then you see them in three months or six months, and they've been off of the medication for - for a long period of time. 

So we usually do a follow-up, some sort of follow-up within like around the one month mark. If they're in person - I mean, I don't mandate it, but I do like to check their labs around that time as well, if possible, mainly because, you know, in the data we show that rapid response. So within that first month. So it's really just nice to see that. And you get an idea if they're responding or not pretty early on. 

And I would check a FibroScan right away because I don't - you know, it's too soon to really do anything. And I think if anything, any change in FibroScan or improvement in FibroScan is either just user variability or maybe some, you know, inflammatory picture going down. So I don't really make clinical decisions. And I usually wait till the one year mark to repeat a FibroScan. What about you? Do you - are you similar or do you have a different? 

Dr. Bowlus: Yeah, I’d say, I don't check the FibroScan that frequently. I don't think it changes too rapidly. I - I probably am going more to three years before I would recheck it, unless there's, you know, something else unusual that I'm trying to look for. But I think it’s - it's - because we're not doing biopsies, it's really key to get that assessment, to kind of help us make our kind of decisions about second-line therapy. It's - you know, biochemistry is important, but understanding the stage, the age, comorbidities. 

That's why when we start developing these guidelines, I think for the audience, you know, we struggle with this when we write them because we all like to have this algorithm we can follow, but we really have to take into consideration a lot of different aspects of the individual patient, and it's not always quite clear. 

In fact, I can't tell you how often I have these conversations in clinic with patients where I'm like, “Well, we could start this or not start this and how do you feel?” And a lot of shared decision-making I think goes in on these decisions. 

Dr. Kumar: You made - Oh, well, let me just ask my question, then you can take the next one. You reference liver biopsies. I think that's something that comes up frequently when making decisions. And I - we've sort of talked a little bit about that. Do you have a standard approach of when you're - you're doing liver biopsies in patients? 

Dr. Bowlus: In PBC, I have to say it's pretty rare that I wind up getting a liver biopsy. 90% have an AMA and it's pretty clear. If they don't have an AMA, I always go to checking these PBC specific anti-nuclear antibodies. They're clinically available at most of the major labs. You can get a PBC profile. They're called SP100 and GP210, and that'll pick up another 5% or so. So we're really getting down to the really small numbers. And even there, I think a lot of these are not probably PBC or some other disease. 

And so those are the patients I'm doing a liver biopsy diagnostically to make sure it's PBC. And then the other I think end are those that present like autoimmune hepatitis but they have a positive AMA or some overlap and trying to sort those things out. So with the transaminases are much higher and possibly there's also high titer anti-smooth muscle antibodies. 

So it's pretty rare, I would say, for me to get a liver biopsy in PBC patients. 

Dr. Kumar: Updates on JAK inhibitors in PBC. So I know there was a phase II trial, I think by Lilly that looked at JAK inhibitors in PBC a while ago, but I - I thought that was stopped. I don't know if they moved forward with that. I don’t - I'm not as familiar with the - I don't know if you know the data and - I remember there was one trial, but I don't actually know very. 

Dr. Bowlus: Yeah. Yeah, to my knowledge, nothing on the JAK inhibitors in PBC. I'm not sure they would be necessarily effective in PBC, given that even steroids, prednisone doesn't work. 

Dr. Kumar: Yeah. 

Dr. Bowlus: We've tried lots of different approaches. That's an interesting thought. And - but I'm just not aware of any data on it. 

Dr. Kumar: Yeah. Is there anything new that we should be aware of in the pipeline? Do you want to take that? 

Dr. Bowlus: Yeah, I think we covered most of them. The - the things that - approaches that have been tried in PBC of, of course, the immunosuppression. I think those are been unsuccessful. And I'm not sure there's much appetite to try more immunosuppressants. The ones that have shown effects are the ones we've talked about. They target the cholestasis. So whether that's ursodeoxycholic acid, that sort of changes the bile acid pool and makes it less cytotoxic. 

Obeticholic acid and PPARs essentially turn down bile acid production and improved choleresis or reduce the cholestasis. Those have been effective, and I think there are kind of new thoughts about how to target that in different ways, but essentially the same thing, just improving the cholestasis. I think those are the main things coming down. We mentioned the IBAT inhibitors, the approaches with tolerance being immunologic. 

I think for those of you that are kind of into autoimmune conditions or CAR T therapies that are being looked at in that, PBC is a potential area for that. But those are, I think still - those are the moonshots. 

Dr. Kumar: Yeah. 

Dr. Bowlus: So the question here, given the recent approval and clinical adoption of PPAR agonists like elafibranor, seladelpar for patients with insufficient response to UDCA, how do you foresee the integration of these novel agents changing long-term outcome measures such as fibrosis progression, patient-reported symptom relief, and risk of transplantation in PBC, particularly when considering future combination therapy strategies or adjunctive approaches targeting the gut-liver axis? 

So I think we've already sort of talked about the integration of these with UDCA. I mean, that's the way they're used. They're pretty much second-line therapies. I think the big question we have in the kind of the not-too-distant future is how do we then integrate the IBAT inhibitors and what effects will they have? 

So patient with pruritus, for example. You know, the data you showed, Dr. Kumar, does show improvement in itch with these agents, but it's not, you know, resolved in many patients. So there will be patients that need both a PPAR and an IBAT. And whether that's going to improve outcomes is going to be something I think that's going to be hard to address. 

And then I think in terms of gut-liver axis, I'm not sure if that's a question about microbiome or anything else there, but there - there's always a potential looking at effects of the microbiome on, on liver disease. It's a particular interest, of course, in primary sclerosing cholangitis. 

Dr. Kumar: Yeah. You know, I think the - the key will be also looking at how we're measuring these long-term outcomes. And, you know, we've really shifted away from liver biopsies in these patients. So as we get more real world data, are we - we, as in, us as providers, but also the FDA, you know, what are we going to use for, you know, to measure this non-invasive test efficient, etc., etc., I think time will tell. 

Dr. Bowlus: You know, what we've seen in the past is the percent of patients actually getting second-line therapies that need them is less than optimal. And so implementing these changes is going to be key. And hopefully this adds a little bit to it. And you all feel comfortable using these therapies in your patients that it's indicated for. And we can improve patient outcomes and - and how they're feeling, improve their symptoms. Thank you for joining. 

Zachary Schwartz: Thank you to our faculty and many thanks to you, our listeners, for joining us. To learn more from this program on PBC, click on the link in the show notes. And to get access to all of our new podcasts, subscribe to the CCO podcast channel on your favorite player. Thank you and see you on the next podcast soon.

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