Dr Aparna Goel (Stanford University): So, it's my pleasure to present this to you and to help answer any questions you may have throughout the course of this Q&A. We'll, first, just go over a few things. The first is what our treatment goals are for PBC, and we'll focus on preventing disease progression for PBC, and then the second part of our treatment goal, the second real pillar of it, which is managing quality of life. And obviously spend the majority of time, answering your questions and discussing any cases you may have.

[00:20:01]

PBC Treatment Goals

So I like to think of our management of PBC in 2 discrete buckets. The first is thinking about the liver disease itself and the goals of treating the liver disease being preventing the progression of liver disease to cirrhosis. So delaying the development or preventing the development of cirrhosis. And then the subsequent hepatic decompensation, transplantation, or liver-related mortality that may occur once cirrhosis develops.

The second big bucket that I think about is managing quality of life. So there's a lot of associated outside the liver, extra hepatic symptoms that come with PBC and the most notable being pruritus or itch and fatigue. So we'll discuss both of these, briefly today.

[00:20:45]

Goal 1: Preventing PBC Disease Progression

We'll start with the first goal, which is preventing PBC disease progression. So as you may know, when you have diagnosed somebody with PBC, the first thing that we do in terms of managing the disease is starting first-line therapy. And this is therapy that's been established for many decades now. It's been shown to reduce portal hypertension, improve liver-related mortality as well.

So first-line treatment is ursodeoxycholic acid, or UDCA. There's a few important things to know. When you're starting ursodiol, is that it needs to be weight-based dosing. That's 13 to 15 mg/kg/day. It can be in divided doses if patients have issues with tolerability, or it can be used all at the same time. But the total daily dose is what matters.

Now, once you've started first-line therapy, how do you assess if a patient's had response and a good enough response to first-line therapy? That has historically been done by looking at the alkaline phosphatase level as a surrogate biochemical response by looking at the alkaline phosphatase level 1 year after you've started ursodiol. So if after 1 year of starting ursodiol, you have noticed that the alkaline phosphatase level has come down to a certain threshold, then you can determine whether or not the patient has had the response that you are hoping to achieve. That threshold what we're trying to aim for is a little bit under consideration these days.

So, in the past, there's actually probably over a dozen criteria that are used to define that biochemical response after a year. And that in the clinical trials recently, we've used what's called a POISE criteria. Dropping down the alkaline phosphatase to about 1.67 times upper limit and normal. But we're starting to think that more ambitious goals are probably better to use for a select group of patients. So patients that may have advanced fibrosis. And that's defined as a FibroScan or transient elastography measurements greater than 10 kilo pascals, or those that might you - you might want to achieve a normal alkaline phosphatase for that group of patients and a normal bilirubin or less than 0.6 times upper limit of normal bilirubin for those patients.

So those that might have more advanced disease, those that are younger, less than 62 years of age, we think that trying to aim for normal alk phos, bilirubin less than 0.6 times upper limb to normal at that 1-year mark is your goal. And if you can't do that, that's when we think about second-line therapy for PBC.

[00:23:11]

Defining Complete Response; ALP Levels in People With PBC Treated With or Without UDCA

So, this sort of goes into what the benefits are. The liver transplantation or death hazard ratios of bringing down your alkaline phosphatase levels. You can see here that there's a clear inflection point when we analyze patients that had PBC in North America and Europe, that there's a clear inflection point just at any threshold value that's above upper limit of normal. So at 1.67 times there's a clear stratification of liver transplantation or death, but at normal we kind of see that those values are all - all relatively the same. So aiming towards normal is what we're hoping to do for at least the patients that are advanced risk of progression of liver disease.

The 1.67 times upper limit of normal is in the labels for the 2 lead new approved therapies and for obeticholic acid. And that's because it's been accepted by the FDA as a surrogate endpoint to achieve accelerated approval for some of these second-line therapies.

[00:24:07]

How Low Is Low Enough? ALP Adequate Response vs Normalization

So in - in another retrospective study looking at the global PBC study group of 1,000 patients, that had an adequate PBC response, and in this group it was defined as an alkaline phosphatase less than 1.5 times upper limit of normal, we compared patients that had normal values of alk phos and below to those that had 1 to 1.5 times upper limit of normal. And what you could see up here is that there's a clear survival difference between these 2 groups. And - and that survival difference becomes particularly clear when you have patients that have advanced fibrosis. So greater than 10 kilo pascals up here.

So we're really trying to push the limits a little bit, trying to personalize what our goals are for our patients with PBC, depending on stratifying their risk, what their fibrosis measurements are at the time of diagnosis, and then really determining if they would benefit from more normal values of alkaline phosphatase.

[00:25:02]

Newer Agents for Second-line Treatment for PBC

So what are the newer agents for second-line treatment of PBC? So as you know from before probably, obeticholic acid was approved back in May of 2016. The mechanism of action for obeticholic acid is FXR agonism. These are all approved as combination therapy with ursodeoxycholic acid or in as monotherapy for those patients that are unable to tolerate ursodiol.

Now, the 2 newly approved therapies from last summer are elafibranor, which is a PPAR-alpha/delta agonist. This was approved in June of 2024. And seladelpar, which is a PPAR-delta agonist. And this was approved in August. It's important to know that in these studies there were no patients that were decompensated that were enrolled in these trials, and all of these medications are not recommended or are contraindicated in patients that have Child’s or B-cirrhosis currently.

[00:25:58]

ELATIVE: Biochemical response and ALP Normalizations With Elafibranor for People With PBC

So when we look, let's - let's review the data really quickly for those 2 new therapies from last summer. So the ELATIVE trial was the study that assessed the efficacy of elafibranor in patients that were inadequate responders to ursodeoxycholic acid or were intolerant to ursodeoxycholic therapy. This was a double-blind, placebo-controlled, randomized, phase III trial and was published in The New England Journal, prior to its approval.

So as you can see here, compared to placebo, there was a 47% difference in the patients that achieved the primary endpoint, which was a reduction in alkaline phosphatase level. So that threshold value of 1.67 times upper limit of normal, compared to placebo. So 47% treatment effect of elafibranor compared to placebo. And that was after 1 year of therapy.

About 15% of patients were able to achieve a normal alkaline phosphatase level after 1 year of therapy compared to 0% that were in the placebo group. So we can see that there was a significant improvement compared to placebo.

[00:27:00]

RESPONSE: Biochemical Response and ALP Normalization With Seladelpar for People With PBC

Now we'll look at the seladelpar data. So this was the RESPONSE trial, again, very similar population that was enrolled in this study. And you can see that the treatment effect here of seladelpar compared to placebo is about 42%. And 25% of patients were able to achieve a normal alkaline phosphatase after 1 year of therapy.

[00:27:20]

Goal 2: Manage Quality of Life

So we'll switch now to our second pillar. So remember, the second big goal of PBC management is managing the quality of life of our patients.

[00:27:27]

PBC Treatment Goals

And I’ll talk briefly about how the biggest symptoms that affect our patients are pruritus and fatigue. And important to just remember that with ursodiol, we knew that the symptoms of PBC do not improve with treatment.

[00:27:40]

Pruritus in PBC

So you can have patients with a normal alkaline phosphatase level, but yet they still might have significant pruritus.

[00:27:46]

In PBC, Pruritus Is:

So in PBC, we understand that pruritus is quite prevalent, affecting 81% of patients. It's under evaluated with only about 40% of patients, reporting a discussion with their healthcare proxy or with their healthcare provider. It is underappreciated in terms of how well it is managed, and it's undertreated in about 33% of patients. So we see that there's a lot of room for improvement up here.

[00:28:14]

Does Biochemical Response Correlate With Pruritus Improvement?

And we do know, similar to what I've mentioned, we do know already from historical studies with ursodiol that even when you are able to achieve a normal alkaline phosphatase, we don't see an improvement in pruritus in our PBC patients. So it really does require a separate evaluation, a separate discussion, and some additional time, with our patients to understand how to best manage those symptoms.

[00:28:36]

Since First-line PBC Treatments Do Not Improve Pruritus, What About Second-line Treatments?

So how did the second-line therapies affect pruritus?

[00:28:38]

Newer Agents for Second-line Treatment of PBC

Well, first, we know that obeticholic acid when in there—in the POISE clinical trial, we did see that there was treatment-emergent pruritus and there was a discontinuation rate from our patients because their pruritus got worse. The 2 newer therapies that were approved last summer demonstrate potential to improve pruritus. And I'll go through the data briefly for both of them.

[00:28:59]

ELATIVE Pruritus Outcomes: Elafibranor for Second-line Treatment of People With PBC

So in the ELATIVE clinical trial, pruritus was assessed in 3 different tools the PBC-40, 5D itch, and the Worst Itch-NRS score. And in 2 of those tools, patients that had a more significant pruritus did notice an improvement in their pruritus over 52 weeks. But in the Worst Itch-NRS score, there wasn't a significant difference between the placebo group.

[00:29:23]

ENHANCE and RESPONSE Pruritus Outcomes: Seladelpar for Second-line Treatment of People With PBC

In the seladelpar study, similarly, in patients that had moderate to severe pruritus, they did notice an improvement based on Worst Itch-NRS. They noticed an improvement in their provider from baseline to Month 3. And if you follow that out, to Month 12, there was an improvement in pruritus. The patients that had moderate to severe pruritus at the start of the therapy were able to, you know, they had an improvement in their pruritus down to mild categories or mild levels of severity, throughout the course of the study.

And interestingly, throughout the course of the study as well, in the first 12 months, anybody that didn't have pruritus did not develop pruritus throughout the course of the study. So potential improvements of itch that we see.

[00:30:03]

Posttest 1

So we'll do a post-test question up here. Which second-line PBC treatment was or were associated with treatment-emergent pruritus? Is it:

A. Obeticholic acid only;

B. Elafibranor only;

C. Seladelpar only; or

D. Elafibranor and seladelpar only.

Zachary Schwartz: I think the polls are coming in. Yes, they are. We're just going to keep it open a little bit. Make sure we get a good vote. Good representation. Okay, I think we can close the polls here and show the results. We're seeing that about 52% of people are saying it's obeticholic acid, but 26% are saying it's the PPARs

Dr Goel: So remember that treatment-emergent pruritus, the development of pruritus with the initiation of a therapy was seen with obeticholic acid. The other 2 medications, seladelpar and elafibranor have demonstrated the potential to improve pruritus. So not developing it, but actually improving it with therapy. So, it's important to just remember how—if you have a patient that has itch and PBC, how you might think about which second-line therapy, you prefer to use. Because you'll have—it's a discussion now with patients since there are choices.

[00:31:46]

Posttest 1: Rationale

All right, so just remember PPAR's a potential improvement of pruritus.

[00:31:52]

Fatigue in PBC

So we'll switch, now to fatigue and PBC.

[00:31:55]

In PBC, Fatigue Is:

So again, very prevalent. 78% of patients—up to 78% of patients with PBC will experience fatigue. Patients with PBC and pruritus report a sleep disturbance about 74% do. We think that that might be due to some sleep latency diff differences that they have. And remember that this is not improved by ursodiol. It was possibly worsened with obeticholic acid, and we don't know if that's entirely related to the link with pruritus.

[00:32:25]

ELATIVE Fatigue/Sleep Outcomes: Elafibranor for PBC

So in the ELATIVE trial that was looking at elafibranor and PBC, how did this medication affect fatigue? So fatigue, again, was measured by several qualitative instruments. There was the PROMIS Fatigue Short Form, PBC-40 and the Epworth Sleepiness Scale. And in those that had moderate to severe fatigue about anywhere from 30% to 50% had an improvement in their fatigue at week 104, and at a week 130. So really showing that there could be a clinically meaningful improvement in fatigue, with initiation of this medication.

[00:33:01]

RESPONSE Sleep Outcomes: Seladelpar for PBC

And these were all exploratory secondary outcomes that were evaluated in these studies. And what about in - with seladelpar? So again, similar population of patients that were enrolled, patients that had itch at baseline. So those that had severe itch at baseline, and that was determined based on these rating scales. We noticed that there was a correlation if their pruritus improved, that the sleep disturbances improved and the fatigue also improved as well.

So as you can imagine, a lot of our patients that have itch and PBC have nocturnal pruritus. And if you improve that, naturally you'll see an improvement in sleep quality and potentially that can affect the fatigue and improve the fatigue as well. So potential improvements in fatigue and in sleep with these PPAR therapies.

[00:33:50]

Key Take-home Points

So key take home points here, then we'll move to the questions. In terms of treating the disease itself, a biochemical response, should really take into account the disease severity in a patient. So those that have more advanced disease, the alkaline phosphatase normalization should be the goal.

About 60% of patient - 40% to 60% of patients don't respond to first-line therapy. So you will need to think about adding second-line therapy for those patients, and the addition of second line therapy can help achieve that biochemical response.

And then secondly, the other treatment bucket, looking at quality of life, we know that pruritus, fatigue and sleep are very important symptoms that our patients with PBC suffer from, and it needs to be managed independently of the biochemical response. You know, fortunately, these newer therapies may have sort of a dual benefit of biochemical response and improving these symptoms. And sort of personalizing the care that our patients need, by looking at their symptoms and if they need second line therapy to select the right second-line therapy would be important to do in the future.

[00:34:59]

Question and Answers

All right. We'll move over to our questions and answers. So I'll start with maybe the questions that are in the chat box right now, and I'll go through some that were submitted earlier.

So the first question is, I specialize in medical oncology, and I'm curious regarding how likely and risk of cholangiocarcinoma is.

That's interesting. So with PBC, we do not see an increased risk of cholangiocarcinoma. With primary sclerosis cholangitis with PSC, which is a disease that affects the larger or medium sized bile ducts, that carries a much higher lifetime risk of cholangiocarcinoma about 10% to 15% lifetime risk. With PBC, that risk is - the risk of cancer is really what it is for anybody that has cirrhosis. There's a risk of both hepatocellular carcinoma and cholangiocarcinoma, but it's not higher just because of the intra - the small, small, microscopic intrahepatic bile ducts are effective.

The next question was focused on, so do you ever use initial combination therapy for patients who have risk factors for progression or poor response to UDCA? So, that's a great question. So initial, when we're in - when a patient is initially diagnosed with PBC, it isn't recommended yet to start dual therapy, for most patients. I think that that's still something that is being explored. Whether or not combination therapy at the onset for some patients might be beneficial. But really the guidelines still are right now to start with ursodeoxycholic acid measure biochemical response either at 6 months for those at higher risk or 12 months for those that may not be. And then assess whether or not they need second-line therapy.

Now, obviously if you're checking their labs and you see that the alkaline phosphatase is climbing, despite being on ursodiol after 3 to 6 months, you probably want to start second-line therapy earlier.

Zachary Schwartz: Thank you for that answer. I wanted to jump in, hopefully not making things too picky, but would the patient's risk factors influence that at all, or you would still always start with what the guidelines say?

Dr Goel: Yeah, I don't think that we quite know right now how we would use—how we would use combination therapy at the onset. Remember, these FDA approved labels really do say for those that don't have a response or intolerant to ursodiol, but starting combination therapy upfront truly hasn't been studied with these PPARs. There's, you know - yeah, there's - there's other PPARs that are approved in other parts of the country and the world, where some - there's some data to suggest that maybe there is a benefit for some patients, but we don't quite know what was seladelpar and elafibranor yet.

Zachary Schwartz: Very interesting. Thank you.

Dr Goel: All right, so other questions that are coming in. What factors do you consider when choosing between second-line agents, especially between seladelpar and elafibranor? That's a great question. So, they're very similar in terms of their mechanism of action. The big differences in the mechanism is elafibranor has the dual alpha/delta agonism. Seladelpar has a selective delta agonism. The - you saw the efficacy rates pretty similar. You know, 40% to 47% treatment effect.

The biggest things that you have to take into consideration is side effect profile and monitoring. So the side effect profile for elafibranor and seladelpar was actually quite similar. Mainly GI related side effects. With elafibranor, you do have to be mindful if a patient's on a concomitant statin. So a lot of our patients with PBC do have hyperlipidemia and may be on statin therapy.

There were - there were instances of rhabdomyolysis, 1 associated with acute kidney injury in the clinical trials in patients that were taking both elafibranor and a statin. So if you're taking both of the drugs together, just additional monitoring of the CK level, to make sure that they don't develop rhabdo. They don't have muscle injury while they're also on a statin is important.

The other thing to remember is that elafibranor is contraindicated in pregnancy and in breastfeeding right now. So we don't—in anybody that might be childbearing age, that might be a consideration when you're using elafibranor. Those are the big factors to consider.

All right, so the next question that I see is, can you please discuss probiotics that might be helpful with gut issues for those with PBC? Has Augmentin ever been implicated in the development of PBC?

I don't think that there's much that we know in terms of how PBC is affected by antimicrobial therapy. Augmentin hasn't been implicated in the development of PBC. Augmentin has been implicated as potentially, inducing a immune-related liver injury that can sometimes trigger the development of an autoimmune hepatitis. and that has been shown in many, many cases in the past, but nothing that's specific to PBC that comes to mind.

And remember with autoimmune hepatitis, there are probably about 10% of patients with autoimmune hepatitis that have biliary features. That doesn't necessarily mean they have overlap with PBC, but that there is some bile duct involvement.

All right. The next question here is at what point should one be concerned about a patient's elevated numbers, even if they are stable? What does deep response mean? How do these new therapies really benefit the PBC treatment space?

So the - any elevation is abnormal. So if you have an abnormal alkaline phosphatase, even if it's been stably elevated for a long period of time, deserves an evaluation. There are several - you know, there's several studies that really indicate patients with PBC have a super delayed time to their diagnosis because providers will say it's been a mild elevation in alk phos for a long period of time. Probably fat, probably alcohol, but there's never really an investigation.

So if you have an abnormal alkaline phosphatase, if there's an abnormal GGT, if there's - they're consistently abnormal after, you know, with, for over 6 months, it deserves an evaluation. The first thing to check is the anti-mitochondrial antibody. That's a pathognomonic antibody for PBC. It is positive in 95% of our patients. It's an easy test to do.

So if you see any degree of elevation that's consistent over 6 months, get that anti-mitochondrial antibody. If it's negative, it's worth checking the ANA, anti-nuclear antibodies. And if that's positive, there's 2 other PBC specific antibodies that can be checked. That's the anti-gp210 or the anti-Sp100. These are both commercially available at Quesnel[?]. So when the 5% to 10% of patients that are negative for AMA, if they have an ANA that's positive, about 50% of them will have those 2 other PBC specific antibodies. So you haven't fully ruled out PBC unless you've gotten those additional tests.

Now, if the antibodies are all negative, then it is worth doing a biopsy to see if there's evidence of bile duct injury, and then that's the only other way you can make your diagnosis.

Now, the other part of that question was what does a deep response mean. So that deep response is bringing the alkaline phosphatase down to normal. So that's what is sort of being quoted as a deep response and really achieving deep biochemical remission.

So we have great therapies that are approved, to help bring the alkaline phosphatase down to 1.67 times upper limit of normal. But really trying to get the patients to below upper limit of normal is considered a deep response. So normal levels is what's considered a deep response.

And then the last part of that question was how do these new therapies really benefit the PBC treatment space?

There hasn't been a lot of new therapies for quite a long time, and I think that there's significant impact that these therapies will actually have. So, you know, we- up until this past year, we had ursodeoxycholic acid, and we had obeticholic acid that was approved in 2016. Obeticholic acid had some notable side effects that led to treatment discontinuation in many patients and, you know, predominantly pruritus. These newer therapies, we see potential benefits for some of these extra hepatic symptoms that our PBC patients are suffering from.

And I think that, you know, kind of being able to treat both of these, both of the indications that would require treatment in our PBC patients is really beneficial. Now, the long-term treatment benefit of these medications is yet to be determined, right? So these were approved by the FDA based on a surrogate endpoint of biochemical response criteria. So your alkaline phosphatase getting down to below the threshold, and that being the surrogate endpoint showing that if we can get your alkaline phosphatase lower, that will lead to improved mortality, improved rates of transplantation in the future. And that's all based on ursodiol data.

So do these drugs do that? We don't know. And only time will tell, and more long-term studies will tell if they're truly able to, you know, have a difference in liver-related mortality. We believe they will because we see that, that biochemical response usually mirrors, the improvement in liver-related health as well.

Zachary Schwartz: You know, while you're answering that question, I saw a new question come in from someone named Charles. it's down in red the - near the end of the list.

Dr Goel: Yes.

Zachary Schwartz: He asked, do you check alk phos 3 months and if it has not fallen below 1.67 times the upper limit of normal BUN on a second-line agent, do you add on?

Dr Goel: Yeah. so I do follow-up labs usually at 3 months once I'm starting ursodiol. I will check labs 3 months, and then at 6 months. I don't usually start a - so - so there's - my practice pattern's a little bit different depending on the patient. If I have a low risk patient that does not have transient elastography FibroScan measurements indicative of advanced fibrosis. So if their, you know, FibroScan shows kilopascals less than 10, I will give the ursodiol a year to work. So I will not start second-line therapy usually, until closer to a year later. If they're younger, maybe I'll do it a little bit earlier, but usually a year later.

The data from global PBC study cohort suggests that if you're going to consider starting therapy earlier, the - the threshold to use is actually at 6 months if your alkaline phosphatase is over 1.9 times. So if you needed another number to keep in mind - that's the other one to keep in mind.

So if at 6 months your alk phos is over 1.9 times upper limit of normal, you can consider starting second-line therapy, especially for those that have advanced fibrosis. The reason being is that if you follow those patients that are over 1.9 times upper limit of normal, if you follow them out to a 1 year, only 11% of them will meet that alkaline phosphatase threshold of less than 1.67 times at 1 year. So 89% of them will still be above that threshold at 1 year. So you may overtreat 11% of your patients by - by starting second-line therapy at 6 months. But 89% of patients you'll be treating effectively by starting second-line therapy at 6 months if your alk phos is 1.9 times upper limit of normal.

Zachary Schwartz: You ever look as early as 3 months? I think that's what Charles had mentioned. I'm curious.

Dr Goel: No, 3 months is early. I think that you should—it takes some time for that plateau - for us to see what that plateau effect is of the ursodiol. So 3 months is a bit early. Six months I think is a reasonable time to consider.

Okay. Can this therapy for first-line biochemical second-line quality of life or combination be applied in sarcoidosis disease, if any carcinoma components? Okay, so I'm not sure I understand the second part of that, but I don't know the data behind PPAR agonism in sarcoidosis. So I'm not certain. Sarcoidosis can have effects in the liver with granulomatous disease in the liver. It can cause a sclerosing cholangitis type of a picture as well.

We do use ursodiol for patients that have the sclerosing cholangitis type of a picture. I have the - if their sarcoidosis manifests as a sclerosing cholangitis, but ursodiol, if they just have the sort of intrahepatic granulomas, those periportal granulomas that we see on the biopsies, we don't - we don't tech - we don't typically start ursodiol for the treatment of sarcoidosis in those patients.

So I'm not sure entirely about what the other effect would be of second-line therapies and sarcoidosis that - I think that's - that's unknown right now.

Okay. So the other question that I see on here is bile acid lowering with PPARs, and is there - is there a correlation with outcome in endpoints? That's a great question. So the bile acids, themselves are not necessarily reported as part of the clinical trials that are published right now. We did see seladelpar separately published, or there was a separate study looking at seladelpar and IL-31 levels and how it has an effect in lowering IL-31 levels, which we know are associated with pruritus, so other dermatologic conditions that cause pruritus. So we think that there might be some mechanism of action there with lowering IL-31. The exact effect on lowering bile acids is - is unclear right now.

And then I see another question on here of patients on antiviral treatment, what additional precautions are there? We'll have to double check the drug-drug interaction, so I don't want to misspeak up here. But I don't believe that there's any indications to lower the dosage or that there's a contraindication with coadministering with say, VIREAD or hepatitis C therapy. We would have to just double check though with the drug-drug interactions. But nothing that comes to mind.

Okay. And I think that's most of the ones that are in the Q&A chat. And I can go to some of the other questions that were submitted earlier prior to the webinar. So one of the questions that was submitted earlier was related to which drug provides the best overall outcome in reference to reversing early F2 or F3 fibrosis?

That's - that's also a very good question and unfortunately one that we don't have an answer to. So as you probably know, the reversal of fibrosis takes a long time to occur. Just fibrosis regression is a very slow process.

Our data right now for elafibranor and seladelpar are - are limited to, you know, 1 year of all patient data and then some patients that have been on the drug now for 3 years where we have some patient data coming in. What we can see is some stability in FibroScan measurements, stability in ELF measurements with some of the therapies, but we don't see necessarily if there's a signal yet for improvement in fibrosis so soon, or within a year or within 3 years.

But I think as more and more patients reach that sort of long-term outcome evaluation at 3 years, 5 years, 7 years, we'll really be able to get some more long-term data for that.

And then the other one that came in was clinical laboratory features of a AIH, but in the biopsy there was a fluorobiliary[?] lesion in a 39-year-old female. So that's a great. I would be curious to hear if that patient had any other serologic features of PBC. So if their serum IgM was elevated, if their antimitochondrial antibody was elevated, how high their alkaline phosphatase and GGT was.

As I said earlier, you know, his - we have sort of categorized overlap syndrome affecting about 10% of patients that have autoimmune hepatitis. Meaning 10% of patients with autoimmune hepatitis may have both autoimmune hepatitis and PBC. That's probably an overestimation, but we see that that there might be biliary features in patients that have autoimmune hepatitis that does respond to ursodeoxycholic acid.

So if there are other markers, other serologic markers that would be consistent with PBC in this patient, it would be absolutely reasonable to think about starting first-line therapy for PBC. We haven't in the studies for elafibranor and seladelpar, there were no patients that had overlap syndrome that were included. So the effect of these PPARs on patients that have both autoimmune hepatitis and PBC, we don't know yet. So more to come. I think as - as we start to use these drugs and practice, we'll see if our patients that have, you know, autoimmune hepatitis with biliary features, autoimmune hepatitis with PBC have an equally robust response in terms of their alkaline phosphatase reduction.

And then I see up here also, can supplements be used in combination with ursodiol? It really depends on what supplements you're talking about, and some supplements can be unsafe for the liver.

So I highly recommend making sure that you've gone through the list of supplements and checking on LiverTox or other databases to really ensure that they are safe to use for the liver. The one supplements that we do recommend taking with any - and anyone that has PBC is actually vitamin D because we do know that vitamin D levels tend to be low. That there's an effect in vitamin D absorption as it's a fat-soluble vitamin that needs to be absorbed. So, you know, checking vitamin D levels is important and ensuring that patients have an assessment of their bone density is also quite important.

And actually that leads me to—there was another question related to fracture risk in our patients that are started on PPARs. And I think that's an important one to just mention.

So in general, we know our PBC patients, you know, it's a disease that affects women that might be in their 40s to 60s. So in general, we're talking about a population that might have some bone health disease that might have osteopenia or higher risk of osteoporosis to begin with. But with having PBC, we do see a higher incidence of that, and that is related to the vitamin D and - and bone turnover.

So in elafibranor study and in seladelpar study, there was an increase in fracture wrist compared to the placebo arm in both of those trials. So elafibranor had a 6% rate of fractures, and seladelpar had a 4% rate of fractures in the placebo arm. And for both of these studies it was 0%. So the understanding of what these PPARs are doing to the bones, I think we have to be careful about.

The big message that I got from seeing those numbers was ensuring that our patients have up to date bone density scans and if they have osteopenia or osteoporosis, if they're getting appropriate treatment.

There is—mechanistically, we do know that PPARs have an effect on bone mass and bone metabolism. PPAR—you know, there's—there's P - the different isoforms of PPARs have sort of different effects on the bone metabolism. So we do think that there is likely some impact that the PPARs can have on bone turnover and bone health. So just really important to monitor for that as well.

Okay. And then, what should you monitor after starting PPARs when to check labs, including a CK?

So if we are going to start new therapy, I start second-line therapy, I will normally check liver tests in a CK level. If I'm starting elafibranor or seladelpar, I'll normally check liver tests in a CK level 1 month after starting therapy, and then again at 3 months and as long as things are looking like they're improving and 3 months after that, so then at 6 months.

And then you might be able to get on a different cadence of the schedule. But I do think it's very important to be monitoring the CK levels, especially if a patient is on a concomitant statin. And then the cost of new drugs and insurance approval obstacles.

So obviously that's a very practical question and a logistic consideration for prescribing second-line therapies. I will say that with the - with the package insert, as long as your patients meet the alkaline phosphatase thresholds, after a year of therapy, maybe 6 months of therapy for those at advanced risk, insurance has been pretty reasonable at approving these. I have had some insurance companies ask me to use obeticholic acid first before using the PPARs. And that might be appropriate to do. I think just take into consideration if your patient has baseline pruritus that isn't well treated. That their pruritus could potentially get worse if you, start obeticholic acid.

So you really have to make sure you've managed the pruritus first before you start the obeticholic acid. But something that, you know that the - there are mechanisms in place with both elafibranor and seladelpar to receive the medication as you're waiting for insurance authorization approval. And you can do that, you know, I think for up to a month or 2 months with - with each of these drugs. And - and, you know, there's - there's navigation pathways through both - for both of these medications to try to get them to your patients.

Zachary Schwartz: That's great, Dr Goel.

Dr Goel: Did we get through? Yeah, did we get through?

Zachary Schwartz: Yeah, so I think we got through almost all of the questions. We've only got about 4 minutes left. I want to give you the opportunity in case there's other burning questions that you want to make sure you - you cover.

In the meantime, we are asking our audience some questions in the background here to - so that our audience can tell us if you plan to make changes based on what you've learned today. And I think after this poll closes, we'll be asking you to write in what changes you might be making based on this.

So with that opportunity to scan what few questions remain open. Dr Goel, are there any - any more you think we have time to address?

Dr Goel: You know, I think that the only other question that was brought up that I didn't - that I didn't answer yet was, can occasional use of alcohol be detrimental to the liver? And the answer is yes. I think we all know any alcohol can potentially harm the liver. So the guidance from the NIAAA, the guidance from the WHO is the less, the better. There are specific guidelines in terms of no more than 2 drinks for men, no more than 1 drink a day for a woman, in terms of reducing the harm of drinking.

But yes, the answer is any alcohol can harm the liver. And our patients that have PBC, I recommend that you really should limit and try to abstain from alcohol together as there is already 1 disease process going on. And adding another one can compound the effect in the - in the fibrosis progression in those patients. So really limiting any other concomitant, disease can really make a difference. There are a few other questions that are coming in, so-

[00:58:31]

Poll 3

Zachary Schwartz: Yes, feel free. We have got time.

Dr Goel: Yeah. So how do you tease out pruritus from other causes? That is a very, very important question. So, cholestatic pruritus, pruritus because of a biliary disease tends to have a typical pattern. So we tend to see the itch primarily affect the palms and the soles. We tend to see it have some sort of a circadian rhythm. So it tends to be much worse at night than during the daytime. It is important - you know, it is not usually associated with a rash, although sometimes the excoriation marks and the lichenification is so severe that it - it almost looks like a rash for some of our patients. But that's usually the pattern that we see it follow.

If your patients have hives and urticaria and eczema patches, and that's what's associated with the itch, it might not be the cholestatic pruritus, but if those have really been evaluated and - and that's not the case, really think about it being because of the cholestatic disease.

I have actually started to check bile acid levels in my patients that have pruritus where I might not be certain if one is leading to the other, if there might be something else that's going on that's causing the itch. I work closely with our dermatology colleagues as well if I feel like there could be a different process that's going on. But it is important to make sure that - that you're confident it's from the PBC as well.

Remember, if they have PBC, there's an 80% chance that they're going to be suffering from itch. So that is the most likely etiology. But in the event that there's something else that's going on, it, it's worth collaborating with a dermatologist.