Raising the Bar: Innovations in PBC Care

 

[01:11:07]

 

PBC Treatment Is Lifelong

 

So my job was really to discuss risk in PBC and treatment targets. So we all know that PBC is a chronic cholestatic liver disease. And in patients diagnosed with PBC, treatment is lifelong. So here you see data published by the Global PBC Study Group that looks at the impact and outcome benefit of ursodeoxycholic acid in transplant-free survival in patients with PBC.

 

And in the Kaplan-Meier curve on the left, you can see that patients who are treated with ursodeoxycholic acid have a statistically and clinically significant benefit in transplant-free survival with treatment, and that benefit is actually independent of treatment response.

 

So the Kaplan-Meier curve on the right shows you that even in patients who we define as having an incomplete response to Urso, whatever response criteria you think about, those patients still derive transplant-free survival and overall outcome benefits from treatment with Urso. So the take-home and learning point from this is that if a patient is diagnosed with PBC, they should be started on Urso. And that treatment, so long as it's tolerated, should be continued for life.

 

[01:12:24]

 

How and When to Assess Risk?

 

So how and when should we assess risk? Risk, we've historically thought about as it relates to treatment response. And one of the things that people think about are response criteria. There are several response criteria that have been published. It gets complicated when you try to remember the details, but conceptually they are the same. The lower your ALP is on treatment with ursodeoxycholic acid, the more normal your bilirubin is, that's associated with an improved survival or an improved outcome.

 

So there's Rochester criteria, the Barcelona criteria, Paris I, Paris II, Toronto, Rotterdam and POISE. The details, as I said, are not that important. I highlighted the Toronto criteria not because that's where I live, but because the response criteria of an ALP of less than 1.67 times the upper limit of normal is what you'll recognize as the primary endpoint that's been used in the - in the clinical studies that have evaluated second-line therapy.

 

So again, the more normal your ALP is, the better. And this regulatory response criteria of 1.67 times the upper limit of normal is what you'll see as in the clinical trials.

 

[01:13:35]

 

Global PBC Group: UDCA Outcomes by ALP and Total Bilirubin

 

So this data looks at the - again, Global PBC Study Group data and response with ALP and bilirubin. So this was a meta-analysis of 15 North American and European patients included, almost 5,000 patients, and showed that a normal bilirubin independent of ALP was associated with outcome benefit.

 

So important points are that surrogate endpoints in PBC have been validated and are really important at predicting outcomes. So bilirubin and ALP are important predictors of outcome. You can see that the curves in blue represent those patients with a normal bilirubin, in orange with an abnormal bilirubin, and those with a normal bilirubin independent of their ALP do better in terms of transplant-free survival.

 

[01:14:20]

 

Other Risk Factors in PBC

 

And biochemical response is no doubt important. But that's not the only thing that you should be thinking about when you're assessing patients risk in - in those with PBC. Their blood tests are relevant. But other factors that you should remember are what is their age at diagnosis. Because Urso slows disease, Urso doesn't necessarily stop disease. So patients who are young at diagnosis have to live with their disease for a long period of time, and they still have risk over time of developing outcomes.

 

So biochemical response, age at diagnosis, the precise cutoff is not entirely clear, but I tend to think about an age of less than 50 at diagnosis. And then histologic changes or biochemical risk stratifiers or other risk stratifiers like liver stiffness.

 

So fibrosis stage is also an independent predictor of outcome in patients with PBC and should be considered alongside age and biochemical response when you're assessing someone's risk.

 

[01:15:20]

 

Biochemical Treatment Response and Fibrosis Stage as Predictors of Transplant-Free Survival

 

And this goes to show that that biochemical response and fibrosis stage are independent predictors of transplant-free survival. So patients with advanced fibrosis, be that F3 or F4 on biopsy or elevated liver stiffness measures, those patients, even with normal liver tests, have a higher rate of outcomes, or mildly elevated liver tests have a mild - an increased risk of outcomes. So assessing someone's fibrosis stage, however you decide to do that rarely with histology, but with non-invasive measures, either biochemical risk stratifiers or liver stiffness is a really important thing to do when you're assessing a patient with PBC’s risk.

 

[01:15:59]

 

Liver Stiffness Measure: Thresholds of Risk

 

And this is just to show the data about liver stiffness and thresholds of risk. And again, we try to divide these into sort of discrete cutoffs, mostly to remember sort of that there are levels of risk associated with FibroScan level. But we also know that there is a continuous risk based on elevated liver stiffness. So this just shows - categorizes patients with PBC into low, medium and high-risk cohorts based on liver stiffness at certain thresholds.

 

So low risk cohort being a liver stiffness of less than eight kilopascals, a high-risk cohort being a liver - having a liver stiffness of greater than or equal to 15 kilopascals, and a moderate risk in between. And again, this is from a large series within the Global PBC Study Group.

 

[01:16:47]

 

Dynamics of LSM and Clinical Outcomes in PBC

 

And that's assessing liver stiffness or fibrosis stage at baseline. But the dynamics of liver stiffness are also relevant. So this is data that shows that changes in liver stiffness over time in the figure on the left does - is associated with outcomes or a rise in liver stiffness over time, or an improvement in liver stiffness over time is associated with a worse or improved outcome, respectively.

 

And more recently, a data - there's data again from Global PBC that shows that the recent liver stiffness is - is actually a really strong predictor of outcomes. So you don't have to worry about, you know, this patient was initially seen 10 years ago in an outside clinic. I don't have what their first FibroScan looks like. A FibroScan, cross-sectionally, even at the time you're seeing them is irrelevant and a strong predictor of risk.

 

[01:17:36]

 

Improved Prognosis With Bilirubin <1x ULN

 

And we'll move back to biochemistries again. The - the conceptual point is that biochemistries, a bilirubin and an ALP are really strong predictors of outcome in patients with PBC. And maybe our thresholds that we've been thinking about can even be improved upon. So a normal bilirubin is great, but a subnormal bilirubin is even better. So this is data that shows that a bilirubin level of less than or equal to 0.6 times the upper limit of normal is improve - is associated with an improvement in survival and a decreased risk of liver transplant, above and beyond patients that have a bilirubin between 0.6 and 1 times the upper limit of normal.

 

[01:18:18]

 

How Low Is Low Enough? ALP Adequate Response vs Normalization

 

So now that we have - I mean, in the era of just using Urso, we kind of risk stratified patients based on biochemical response or fibrosis, but we didn't have other options to really target what we now call sort of deep response, really normal bilirubins and really normal alkaline phosphatase. But how low is low enough?

 

And again, this is data that shows that, you know, while we had these response criteria that show 1.67 times the upper limit of normal, or 1.5 times the upper limit of normal, is associated with benefit. What about those patients that sit in between, right?

 

And this will show you that patients that have an ALP that's normal have outcome benefit compared to patients that you let live in this 1 to 1.67 times the upper limit of normal. So maybe those targets aren't enough, right? Maybe they are regulatory targets as they are, but ideal targets perhaps really should be normalization of liver tests.

 

And that's especially true for patients with advanced fibrosis. So remember, we talked about age, fibrosis stage and biochemical response. And in those patients with an elevated liver stiffness. So the - the figure on the right, here defined as a liver stiffness of more than or equal to 10 kilopascals, those patients derived the most benefit with normalization of liver tests.

 

[01:19:39]

 

Complication-Free Survival at 10 Yr

 

And this translates into real numbers, right? Absolute survival gain in months, right. So this is meaningful in what patients want you to be able to know and tell them, right?

 

So if you look at the entire cohort that was studied in this - in this - in this paper, which was more than 1,000 patients, this is looking at complication-free survival at 10 years. The first row is absolute. Here you can see - oops, sorry. The first row is absolute survival gain. So in the entire cohort, you can see that there's an absolute survival gain of about 7.5 months in patients that you push to normalization of ALP.

 

Whereas if you look at the cohort of patients that is less than 62 years old or has a FibroScan - and has a FibroScan of more than 10 kilopascals, again, a small number, but still an absolute survival gain of 52 months, right. That's meaningful.

 

And so I think we - this paper uses these thresholds of less than 62 and greater than 10. But conceptually, a young patient with advanced fibrosis is the one that you should think about for really pushing towards normalization of liver tests.

 

[01:20:50]

 

Case 1: Whom to Treat

 

Okay, so that's all I wanted to talk about in terms of a didactic assessment of patient risk. And we'll move on to talk about cases which I've intentionally made I think a little bit challenging. So the first one is a case of who to treat.

 

So this is a 68-year-old woman with PBC who's referred for further evaluation. Her medical history is significant for celiac disease. She's compliant with the gluten-free diet, but otherwise she is completely well, highly functional, working full time. Her current medications include ursodeoxycholic acid alone at 1,000 milligrams a day, which is appropriately dosed for her weight, so that's at 15 milligrams per kilogram.

 

Her history of disease is such that she was diagnosed with PBC 6 years ago. She has no itch. She has mild sicca, so dry eyes and mouth. She has no symptoms of advanced liver disease at all or decompensation. She is adherent to therapy, and she is referred to you for ongoing elevation in liver tests, despite appropriately dosed and - Urso and adherence.

 

[01:21:55]

 

Case 1: Labs and Imaging at >12 Mo

 

So these are her labs and imaging after 1 full year of ursodeoxycholic acid. So investigations wise, she's AMA-positive. She's also gp210-positive, but otherwise serologically negative. Her transaminases, you can see here. So she has a mild anicteric hepatitis. Her AST is 42, ALT 55, ALP 195 with an upper limit of normal of 120. Her GGT is elevated, but markers of liver function are normal, with a bilirubin of 1.2, INR of 1, and platelets of 150.

 

Her ultrasound shows mild surface nodularity with a spleen of 11 centimeters, no nodules and a normal biliary tree. And her liver stiffness is 9.9 kilopascals.

 

[01:22:41]

 

Case 1 Panel Discussion: Assuming Access to Treatment

 

So for the panel. Assuming - let's - let's put access to treatment aside, because that's going to vary across place you live and reimbursement, all those things. So put access to treatment aside. So for this patient, again she's 68. She has a mildly elevated ALP that may not meet thresholds of 1.67 times the upper limit of normal. And she has a liver stiffness that's not quite 10, right? 9.9 Kilopascals. So would you recommend adding second-line therapy for this patient?

 

Dr. Goel: I can give my initial comments. So how to look at this patient.

 

Dr. Gulamhusein: Sure.

 

Dr. Goel: So I think a few things. One is this person is on ursodeoxycholic therapy. And I think ensuring, one, that the weight has not changed so that you are adequately weight dosing it. I believe you did say they were already on 15 mgs per kg per day, and that they're compliant with it. And if you can ensure both of those, and if the ursodeoxycholic acid has been optimized, then you're looking at someone that is 60s with sort of borderline advanced fibrosis and potentially at risk.

 

And I - you know, before I would say, 5 years ago I would leave this person alone. I'd say you've met the threshold of 1.67 times the upper limit of normal. That's good enough. Let it be. You'll be fine. But I think now we have something better that we can potentially provide. So I would have a discussion about trying to push the threshold lower, especially if there's not any significant other comorbidities that would markedly shorten this person's lifespan. So I think I would consider second-line therapy.

 

Dr. Gulamhusein: Chris, what do you think?

 

Dr. Bowlus: Yeah. So if you go back to the slide before with the liver test, so maybe the audience can tell me, can you figure out what 1.67 to 120 is quickly?

 

Dr. Gulamhusein: It's not quite - it's like…

 

Dr. Bowlus: Only hepatologists would come up with a threshold of 1.67 times the upper limit of normal, which is about 200. That's kind of what I use in my head.

 

Dr. Gulamhusein: Yeah, exactly.

 

Dr. Bowlus: So that's - that's my threshold. So anybody out there that's kind of wondering what - just look at 200. But it's not an absolute either. And so you do have to take into consideration other factors. And I think the ones that Aparna mentioned are important. I would also say that you didn't notice the bilirubin which you showed is, you know, maybe it's within the normal range, but a 1.2 total bilirubin is not normal.

 

Dr. Gulamhusein: Right.

 

Dr. Bowlus: So there are some concerns here in this patient. I think we all see that. And so, yes, I think adding a second-line therapy in this patient is pretty straightforward. And I think definitely we'd want to do that. Even though, you know, she's not under - she's not the younger age group and things like that. But she's clearly advanced. And - and honestly, you know, she's 68 I think you said?

 

Dr. Gulamhusein: Yeah.

 

Dr. Bowlus: So chances are she's going to live - live at least 20 more years.

 

Dr. Gulamhusein: Right.

 

Dr. Bowlus: I mean, so in 20 years if you don't do something, she's going to decompensate.

 

Dr. Gulamhusein: Right. So I - I agree. I think - I think conceptually what this brings out is that you think about these factors of age, fibrosis stage and what their blood tests look like. And while we've made these binary categories or these discrete categories, they don't necessarily have to live like that in the real world. Right? You think about ALP as a continuous variable. A FibroScan threshold of 10 doesn't mean 10 and 9.9 isn't high enough.

 

So I agree. I would start second-line therapy in this patient after having a discussion about risks and benefits, and in conjunction with what the patient wants. And evaluating comorbidities, I think is really important.

 

So let's turn it around and say, what if the patient's ALP was 1.7? And so for Chris, that's 1.4 times the upper limit of normal or 1.3 times the upper limit of normal. And her liver stiffness is seven. Would you recommend adding second-line therapy in that patient? Aparna what do you think?

 

Dr. Goel: This - this - again, not necessarily meeting the - the prior thresholds that we're using. But if age aside, I think that you could - you could still make an argument that normal is important. So pushing to ALP normalization and trying to get it down is important. I think what would really push me in this - of all the other laboratory values were the same. What would really push me to add second-line therapy is actually the bilirubin.

 

So bilirubin being 1.2, even if your alk phos is like this, I - I - I do think I would really try to press to bring the bilirubin down.

 

Dr. Gulamhusein: Okay.

 

Dr. Goel: So I - I would add second-line therapy still.

 

Dr. Bowlus: Yeah, and I think - I - I agree completely. I think this is one of those ones where you have that discussion with the patient. And again, assuming the bilirubin is that high, I'm going to be looking for Gilbert's or something else is causing it because typically if they're not fibrotic, if they're not nodular, I'm assuming also their platelet counts are normal.

 

Dr. Gulamhusein: Yeah. Platelets are 150. There is a little bit of nodularity on their imaging.

 

Dr. Bowlus: But still those things I'm still concerned, even if their liver stiff - if the only thing change is liver stiffness and maybe a little bit lower alk phos. I'd still - I think - I think having - I think we have to take the whole picture of the patient.

 

Dr. Gulamhusein: Right.

 

Dr. Bowlus: We can't just rely on an LSM. We know how variable those are. So if you have those other warning signs that tells you something, and I think you probably would push and want this patient to be on a second-line therapy and get it to normal.

 

Dr. Gulamhusein: Yeah. I mean, I - I think I agree too. I think a conversation with the patient is really important. And, you know, some patients may say, I'm not sure I want therapy at this stage, but then it's a chronic disease, right? You have the luxury of sort of monitoring over time and saying, you know, if you don't want therapy today, then our thresholds for initiating therapy down the line may change or if things change. So I agree. I would probably have a low threshold for this patient if they were agreeable and we may change over time.

 

Dr. Goel: I think one more quick comment is, one of the most very common coexistent diagnoses in our people living with PBC is osteoporosis, so bone disease. So I - I don't remember if there was a GGT value that was...

 

Dr. Gulamhusein: It was high.

 

Dr. Goel: Elevated. But just ensuring that the alkaline phosphatase is truly coming from the bone, especially when it's at that threshold, as - I'm sorry, ensuring that it's coming from the liver and not the bone, especially when that threshold is like 170, 160 or so. So confirming that it is truly hepatic source. And that's - that's the etiology of the ALP elevation.

 

Dr. Gulamhusein: And weight-based dosing as you mentioned, and ensuring weights haven't changed, I think that's helpful. Okay. I was almost on time.

 

With that, I will transition to introduce Dr. Bowlus.

 

[01:28:58]

 

Innovations in PBC: Role of Second-line Agents in Reaching Treatment Goals

 

Dr. Bowlus: Great. All right. Thank you. Thank you, Aliya. And I'm not sure we've gotten any questions yet, but I think everyone's almost done with their lunch and wiped their hands down. So I'm not going to put all the potato chips on the screen share, it'd be great.

 

So let's - so we've talked about what the - the targets might be. Let's talk about what the evidence is for these second-line agents that we now have available.

 

[01:29:27]

 

Patient Video

 

To start off with though, we're going to have a video from a patient.

 

Brenda Remo: My name is Brenda Remo. I live in Phoenix, Arizona, and I was diagnosed with PBC in April of 2021. Currently, I'm seeing a hepatologist just like when I was first diagnosed and I was not responding to the, you know, Urso and Ocaliva. There was nothing else.

 

And so it was - it was a lot on your mind. You know, it's - it's a lot mentally too, when you have this progressive disease and you're not responding to the only medicines that are out there, I mean, it's a lot. So I just appreciate the spotlight that is now being put on PBC. When I was first diagnosed, there wasn't much. And now there is quite a bit more research going into it, so I appreciate that.

 

[01:30:22]

 

Second-line Treatment of PBC

 

Dr. Bowlus: Well, that's great. I think that's a - a concern that we frequently hear from our patients is not knowing what the future holds for them. And there's been a lot of change over the last 10 years in terms of what we have to offer. And so what are our second-line treatments that we have available?

 

So they're classified here in - into basically 4 different groups. So we have the fibrates, which actually are our PPAR agonists themselves. And then the - the approved therapies include obeticholic acid, which I think you all know is no longer available here in the US or Europe, though it is available in other countries. So still a potential option for some - some people perhaps in the audience here. And then we have the 2 new agents, elafibranor, which is a PPAR-alpha/delta agonist, and seladelpar, a delta-specific agonist that were approved just a little over a year ago.

 

In terms of off-label use, of course, bezafibrate has been used extensively outside the United States. Fenofibrate is available in the US, and there are some limited data on it. But just so everyone's aware, there is a label warning on its use in PBC for what that's worse - worth.

 

There are other PPAR treatments in clinical trials. A phase III trial just recently completed on saroglitazar, so there may be more players in the market in not too distant future.

 

And there's some interesting results coming out with some other therapies. And I'd highlight the CNP-104. This is a nanoparticle that is coated with the - the mitochondrial protein that induces the PBC, the anti-mitochondrial antibody. It's the actual epitope.

 

And the idea here is that you're going to induce tolerance to that. So it's trying to get at the underlying immunopathogenesis of PBC. And there are some promising early stage results on that, some of which are being presented at this meeting.

 

[01:32:22]

 

POISE: Biochemical Response and ALP Normalization With OCA for People With PBC

 

But what do we have today? So today, what we have is really based on 4 phase III trials that I'm going to review for you. And the first one that set this all up was the POISE trial. And this is really, I think, the - the landmark study that set the design really for all future trials.

 

And so this was a double-blind, placebo-controlled trial of patients with either an inadequate response to Urso or who were unable to tolerate Urso. And those unable to tolerate Urso, it's usually about 5% to 7%. So the majority of these are patients that had an inadequate biochemical response, which, as we heard earlier, was defined as having that alk phos greater than 1.67 or about 200 at baseline.

 

And the response criteria was to get that alkaline phosphatase below that 1.67, but it also had to be at least a 15% reduction, right. So you couldn't start just above it and then just get below. It had to be at least that. And then you had to have a normal bilirubin. Now most of these patients entered the trial with normal bilirubin. So that was really not an important part of the response criteria - criteria.

 

And then as you can see here, then in the double-blind phase, patients were randomized either to receive obeticholic acid at 5 milligrams with the option to titrate at month 6 up to 10 milligrams, depending on the response and their tolerability, or treated with 10 milligrams throughout or placebo in the orange. And by the end of 1 year, about 40%, 45% of patients achieved that biochemical response, compared to less than 10% in the placebo group. And then there's an open label extension, and you see the placebo group catching up.

 

And then you look at the alkaline phosphatase changes, you can see this relatively rapid reduction in the alkaline phosphatase in the treated groups compared to placebo, and it - it remains durable. And that's been seen throughout.

 

[01:34:22]

 

OCA Transplant-Free Survival: POISE vs Real-world External Controls

 

So this was - these were the results of the OCA POISE trial that led to its approval. Unfortunately, the approval process is what's called accelerated approval, which I'm sure many of you are aware of. So it gives the opportunity to market the drug and make it available to our patients commercially. But it requires a confirmatory trial to show that it actually improves patient outcomes. It reduces clinical events.

 

And so the COBALT trial was set up to do just that in patients with more advanced PBC to randomize them to either placebo or obeticholic acid, and then look to see if it could be demonstrated that obeticholic acid actually prevented hepatic decompensation, liver transplantations, or death.

 

However, as you can imagine, it's hard to enroll in a trial like that when you have the medication available commercially, as well as the fact that patients in the trial could be functionally unblinded by just looking at their alkaline phosphatase and seeing that it's not going down and assuming they're on placebo and then disenrolling from the trial. And that's what happened. And so the COBALT trial was terminated due to lack of feasibility.

 

Now, to try to demonstrate that there was actually an effect of obeticholic acid on survival, patients that were treated in the POISE trial and kept on open-label treatment for up to 6 years were compared to 2 different external real-world controls who had been treated only with Urso.

 

And in both comparisons, patients treated in the POISE trial with obeticholic acid had an improved transplant-free survival, and in one group, survival free of hepatic decompensation compared to the historical controls, suggesting that there was some real benefit, though there's always the possibility of confounders not being accounted for in these analyses.

 

[01:36:19]

 

Fibrate and PPAR Agonist Targets

 

So the other issue we have with obeticholic acid, of course, is that it induces pruritus, and there's some concern about its use in patients with advanced liver disease. So in the end, though, that's not available for us today in this country. But as I said, it appears to be available for others. And I think many of us still have patients on obeticholic acid who have done quite well with it for a number of years.

 

So now enter the - the PPARs. And there are 3 different isoforms of the receptor: alpha, delta, and gamma. And they have different effects which is interesting because as we'll talk about in a minute, all these PPARs seem to have some effect on cholestasis regardless of their target specificity.

 

So the PPAR-alpha like fenofibrate, it targets mainly hepatocytes, delta hepatocytes, cholangiocytes, Kupffer cells and stellate cells and then the gamma Kupffer cells. And the - the mechanism of action is thought to be primarily a reduction in the synthesis of bile acids, along with reductions in uptake and increase in detoxification. There is also some increase in production of phospholipids to make the bile more cytoprotective, and then also some improvements in inflammation through down regulation of cytokines.

 

As you can see here, the different PPAR agonists have different specificity, with bezafibrate being pan-PPAR agonist, elafibranor activating alpha and delta, and then seladelpar just delta.

 

[01:37:51]

 

Bezafibrate for People With PBC

 

So the phase III study of bezafibrate was in France. And this study design, it's important to recognize is a little different than the POISE or the other trials we're going to talk about. It included patients that had an alkaline phosphatase greater than 1.5 times the upper limit of normal. So a little bit lower threshold. So they had lower alk phos’ coming in.

 

But then the response criteria was greater. They had to have normalization of alkaline phosphatase bilirubin, AST, albumin and prothrombin time. So you can't really compare the response rates here. But regardless, they showed an increased response rate compared to placebo over 24 months.

 

[01:38:34]

 

ELATIVE: Biochemical Response and ALP Normalization With Elafibranor for People With PBC

 

And then more recently, we've had the 2 non-fibrate PPAR agonist, elafibranor and seladelpar report their results. For elafibranor, it's the ELATIVE trial. And as we can see here using the POISE criteria again, 51% of the patients had a biochemical response compared to 4% in the placebo control arm.

 

And then if you look at alkaline phosphatase normalization, 15% of the patients actually achieved normalization compared to none in the placebo group.

 

[01:39:08]

 

ELATIVE: Elafibranor Safety

 

In general, elafibranor is well tolerated. There are some minor GI effects that are seen in a minority of patients and generally does quite - quite well.

 

[01:39:21]

 

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

 

And then in the RESPONSE study of seladelpar, we see that 61% of the patients achieved a biochemical response compared to 20% in the placebo, and 25% achieved alkaline phosphatase normalization. And over here on the right, we can see, the - the change - the difference in the response rates.

 

And you can see that the decrease in alkaline phosphatase and all these drugs occurs very early within 4 weeks we generally see the response.

 

[01:39:49]

 

RESPONSE: Seladelpar Safety

 

And again, similar safety with seladelpar. Mild GI side effects but otherwise well tolerated and safe.

 

[01:40:00]

 

Summaries of Separate Studies—Not Head-to-Head

 

Now there are no studies comparing these head-to-head, so it's really impossible to say one is superior to another. And I think the important thing that we can look at and see is that if we look at the therapeutic response, that is the difference between the treated group and the placebo group, they're pretty similar. And really, I think for us in clinical practice is how far can you expect your alkaline phosphatase to improve? How far will it go down?

 

And we can expect with these drugs, regardless of where we start, we'll get about a 40% reduction in our alkaline phosphatase. So if a patient comes in and their alkaline phosphatase is 500, I would not expect them to necessarily get normal. But even going from 500 to 250 is a big benefit for them.

 

So while we want to get to normal, what we want to get for all our patients at the lowest alkaline phosphatase we can.

 

[01:40:52]

 

Case 2: When to Treat

 

And so with that, let's move on to our case number 2. This is a 54-year-old woman with PSC[?] who's referred - or referred for evaluation for PBC, of course. She's got celiac disease. She's on the same dose of Urso as our other cases, but she was just diagnosed 6 months ago. She's got some mild itch using a numeric rating scale of 2 that we'll hear a little bit more about in the third talk, some dryness symptoms, but no evidence of advanced liver disease. She's adherent to therapy and she's got the following liver tests.

 

[01:41:28]

 

Case 2: Labs and Imaging

 

So her alkaline phosphatase initially started at 500. Six months into treatment with Urso, it's down to 360. Her GGT is similarly dropped. Her bilirubin is unchanged at 1.2. Her platelets are low at 150. She had an ultrasound that shows surface nodularity, same sort of spleen size and liver stiffness at 7.2.

 

[01:41:53]

 

Case 2: Panel Discussion

 

So let's start with the panel discussion.

 

Dr. Gulamhusein: Should I start? Okay. Yeah. I mean - can - can we go back to the numbers again in terms of blood tests?

 

[01:42:05]

 

Case 2: Labs and Imaging 

 

I mean, I think this patient, again, if you're thinking of biochemical response, you kind of have reason to start second-line therapy. When do you start, I think is an important question. I think, do we have to wait for 12 months? I don't think we do. My approach has generally been to talk about patients who I don't think are going to meet normalization or close to normalization pretty quickly upfront.

 

You see with the second-line therapies that responses happen very quickly. As you said, at 4 weeks numbers will improve. And then they generally improve a little bit more but are sustained at this low level, right? And so in the patients that don't that - that with Urso have elevated liver tests ongoing, I talk about the need for second-line therapy pretty quickly up front, and they may not want to start on the first time I talk about it, but I will definitely open that line of discussion at 6 months and start when they're ready thereafter.

 

Dr. Goel: I think part of the decision about deciding when to start is - second-line therapy 6 months versus 12 months is actually the trajectory of the alk phos decline. So if this is 500 and, you know, it took a - you see a plateau for the last 3 months, I don't think you're going to get much more waiting 6 months. It's going to hover around there. So it makes sense to have a discussion about starting second-line therapy earlier. There's the data from Global PBC about using that alk phos threshold of greater than 1.9 times upper limit of normal at 6 months.

 

And, you know, if you use that at 6 months, you're probably going to accurately treat 89% of your patients by starting second-line therapy earlier as opposed to waiting a year. So you can potentially use a 6-month cutoff earlier.

 

The - one of the questions that came up from the audience is especially from the trial entries that you discussed, how do you determine ursodiol intolerance? And is that just based on patient experience?

 

Dr. Bowlus: Yeah. So - so that was basically exactly it. It was based on patient tolerance, what they reported I should say. So there's no specific test for it. I mean, I think we've all experienced it. Certain patients come in and they describe the nausea or other side effects. Sometimes hair loss, which I'm not completely convinced is Urso related. But those tend to be the 2 main ones that lead to intolerance.

 

Dr. Goel: Aliya, what would you start for second-line therapy?

 

Dr. Gulamhusein: What would I start? I mean, I think it's a discussion with patients. We have a spectrum of agents available and it differs by center, right? So I think in this era, probably a PPAR is your first option for a second-line therapy. And then you sort of discuss pros and cons of whether you pick elafibranor or seladelpar.

 

I think in general, as - as Chris said, you expect about a 40% decline in blood tests and - and the differences biochemically between the agents, I don't think in the real world will be that different. As we'll talk about, I think symptoms are really important. Pruritus is a really impactful point for patients. And so if you're going to get added benefit with using seladelpar in itch versus elafibranor at 80 milligrams, then maybe that's a factor that you think about.

 

But maybe I'll ask you guys. What about at 3 months? Would you think about starting therapy at 3 months even? Or what's the difference between 3 months versus 6 months?

 

Dr. Bowlus: So the earliest - I just a month ago started a patient after only 4 months.

 

Dr. Gulamhusein: Really?

 

Dr. Bowlus: She - she'd come in, and it was clear she wasn't going to have an adequate response. There was no reason to wait. She was also symptomatic.

 

Dr. Gulamhusein: Right.

 

Dr. Bowlus: And we were able to get it approved, which is also the important thing.

 

Dr. Gulamhusein: Right.

 

Dr. Bowlus: But yeah, I don't think we necessarily have to wait 6 to 12 months. You could wait to see if they plateau. There's no - there's no rush to - to treat it sooner. I mean, this is a chronic disease, as you mentioned. But when you have the patient in the office, how many patients do we lose at times and lose that opportunity? So to me, intervening early is more about making sure we get them on the therapy and not kicking the can down the road and then not getting taken care of. So it's more of a practical issue than - than anything else.

 

Dr. Goel: A related question is if you don't see a response to one of the PPARs, and this is from the audience, have you switched to another PPAR and have you been able to demonstrate a response to a different one?

 

Dr. Gulamhusein: Silence.

 

Dr. Goel: So I think maybe - maybe thinking about patients that you might have had on fenofibrate that you might be switching over could...

 

Dr. Bowlus: That’s again - so - so personally, my own experience is I have had a few patients that are on fenofibrate and discuss switching them over. Most of them are happy. So I've not done that or they've chosen not to do that, I would say, and they've all responded well to the fenofibrate at the time, so.

 

Dr. Gulamhusein: I agree. But these are like real-world questions that are going to emerge, right? And so Global PBC is amazing in what they've been able to capture across the globe. And even the Fi-OCA study, right, has shown that there is dynamics in what patients are treated with over time. And I think we'll learn more about what - patients that are switched between PPARs and patients that come off FXR agonists and move to PPARs over time.

 

So personally, I have not switched anyone unless they're having intolerance, or there's a reason they're doing poorly or there's something that - there's a reason to switch. But I think that that's going to be a really important real-world question.

 

Dr. Bowlus: We do have a poster here on switching from OCA to - to - to PPARs. So - and it does seem that you might get a little bit better improvement in the alk phos there, but there's no downside to it.

 

Dr. Gulamhusein: Right.

 

Dr. Bowlus: So if your patients are on OCA and they need to switch, there's probably no downside to it.

 

Dr. Gulamhusein: Yeah, the so-called like treatment-experienced patient, right?

 

Dr. Bowlus: Yeah. Exactly, exactly. Okay. Well, I think we'll end it there, unless there are other questions from the audience coming in. No? All right. We'll move on to our third topic.

 

[01:48:14]

 

Raising the Bar in Symptom Management

 

Dr. Goel: All right. So I'm so lucky to be able to speak about pruritus and fatigue with full bellies and postprandial slumps and everyone. So we'll try to keep this as interesting as we can. So my goal is to talk about how we can do a better job addressing symptom management in our patients with PBC.

 

[01:48:34]

 

In PBC, Pruritus Is:

 

So just a reminder, the 2 big symptoms that we think about are pruritus and fatigue. We'll focus on pruritus first. Pruritus cholestatic itch is incredibly highly prevalent in people living with PBC. It affects up to 81% of people.

 

Up to 40% of our patients say that they have had no discussion regarding their itch with their healthcare providers, so we're under-evaluating it in practice. A lot of the times there's a disconnect between the severity that's reported by our providers and by patients. So it's often underappreciated. And the - the concordance rate is only 70%. And up to 33% of people living with itch say that they have never received treatment for it. So we can do better. That all goes to say we can do a better job treating itch in our patients with PBC.

 

[01:49:20]

 

Patient Video

 

We'll switch to a video that describes a person living with PBC and itch and how it impacts their life.

 

Brenda Remo: See, it's - it's really weird with how different it is for everyone. Most - most everybody has the itching or some form of the itching. I'm grateful I don't have it on the bottom of my feet. That's what a lot of people have, is extreme itching on the bottom of their feet. They - I do not have that. But otherwise everybody is - the complaint is the itching. Yeah.

 

So the itching with PBC, it's not like a normal itching. It's not - It's a - it's an itch that you can't scratch. It's - it's internal. I kind of tell my husband I associate it kind of like when you touch fiberglass, how you can't ever - you can't get that feeling away. That's kind of how the itch with PBC is.

 

It's - it's just this feeling that no matter what you do and you scratch and you scratch it, you can't touch it. It's like it's internal and it's just this constant itch. And you - you can scratch till you're raw. And to hear providers just say they don't know what to do. It's - it's discouraging. Because the itching is a lot. It keeps you up at night. It - it makes you completely self-conscious. I swear, I'm in stores itching, and people probably think I'm - you know, I have bugs or something.

 

[01:50:57]

 

Nonpharmacologic Treatments for PBC Pruritus

 

Dr. Goel: So quite a big impact in terms of quality of life. And this - this phrase of this itch you can't scratch is something that you might hear from your patients not infrequently. So when - when someone with PBC describes mild itch symptoms, we’ll often talk about using nonpharmacologic therapy first. And there's a host here that you can think about topical moisturizers, discouraging hot showers, so using cooler showers, hypoallergenic laundry detergents and soaps, avoiding irritating factors. And then cognitive behavioral therapy has shown to be beneficial as well.

 

[01:51:29]

 

Management of Cholestatic Pruritus

 

A reminder that while ursodeoxycholic acid is first-line treatment for PBC for disease modification itself, it does not impact pruritus. So the pruritus needs to be addressed separately and needs to be treated independently of PBC.

 

[01:51:46]

 

Mechanism of Pruritus in PBC

 

The mechanisms in which pruritus happen in people living with PBC is quite complex. We know that bile acids and pruritogens are implicated in the process, and that there's sensory receptors on the peripheral nervous system that are likely activated on the skin. So that's the MRGPRX4 protein that's on peripheral nervous system there.

 

And then we also know that lysophosphatidic acid, or LPA, is likely an important activating factor for some of these ion channels that induce itch on our skin. Autotaxin A is the one factor that has been strongly linked to cholestatic pruritus, and ATX or autotaxin is one of the rate-limiting factors for the production of lysophosphatidic acid, so LPA.

 

So there are some correlations that do exist. We know that we can modulate some of these things with our therapy. And there's - there's various treatments that we have tried that we have experimented with and used in our patients with PBC. And - and hopefully some of the second-line therapy will address the - the pruritus and some of these patients as well.

 

[01:52:49]

 

Management of Cholestatic Pruritus

 

So the list of medications that have been used in PBC pruritus is long. The only approved medication for cholestatic pruritus is cholestyramine, which is a bile acid binding resin. It is poorly tolerated by many of our patients and often causes constipation, fatigue, bloating, and - and, you know, retention is probably less than 15% for cholestyramine. A pruritogen reducer like rifampin is commonly used and can be quite effective.

 

The modulation of central itch and pain pathways with naltrexone or sertraline or butorphanol can be quite effective as well. IBATs or ileal bile acid transport inhibitors have been studied for PBC and itch and for other cholestatic itch, and have shown that in people living with moderate to severe itch, it could be quite beneficial and more to come with some of those ongoing studies.

 

We've discussed, and we'll discuss a little bit more the data on some of the PPARs and their impact on itch. And then there's sort of salvage therapies that we think about as well, with phototherapy and plasmapheresis. And very rarely thinking about liver transplant when the pruritus is quite severe.

 

[01:53:53]

 

Pruritus Outcomes: Bezafibrate for People With PBC

 

So let's talk a little bit about the PPARs and what have been used. And we'll talk first about bezafibrate. So Dr. Bowlus had reviewed the data for bezafibrate in terms of efficacy for alkaline phosphatase improvement.

 

When you look at people that are enrolled in the trial that had higher itch and you evaluate their itch intensity scores, you can see that the group of patients that were treated with bezafibrate and ursodeoxycholic acid had an improvement in their itch scores on a visual analog scale. That's a visual analog scale, that's the graph in - in blue up here at 24 weeks. So compared to placebo, there was an improvement in itch.

 

And then separately the fibrates in itch trial, so the FITCH trial evaluated bezafibrate in - in - in several different cholestatic conditions, PBC, PSC and secondary sclerosing cholangitis and enrolled patients that had moderate to severe pruritus. And you can tell that in the group with PBC that there was a significant reduction at 50% - over 55% of patients had over a 50% reduction in their VAS score compared to the placebo group. So there was a notable improvement in itch with bezafibrate.

 

[01:55:02]

 

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

 

What about in the ELATIVE trial with elafibranor? So we - we again discussed already the results that elafibranor has in terms of statistically significant improvement in alkaline phosphatase levels and alk phos normalization. How did it do with itch?

 

Well, the itch was evaluated in several different methods in - in these trials. So there's the worst itch NRS score. Then the separately, all of our patients that were enrolled in this trial completed the PBC 40 - PBC 40 survey. And they also completed a 5D itch score.

 

So when you look at what is validated with cholestatic pruritus with the worst itch NRS score, there was actually not a statistically significant difference in the control of itch between the elafibranor and placebo groups. But when you look at some of the other scores that were used to analyze itch with PBC 40 and with the 5D itch score, you can see that there was an improvement in the elafibranor group compared to what the placebo group saw.

 

So while it didn't meet statistical significance with the worst itch NRS, I think more to come to - to see if there are longer term improvements or other improvements with itch with elafibranor.

 

[01:56:09]

 

Summary of Phase III Studies

 

So just to summarize, with elafibranor, we saw significant improvement in biochemical response in alkaline phosphatase levels. And we saw that there was a numerical improvement that wasn't statistically significant in itch. There is the additional results from the open-label study of ELATIVE with findings up to 3 years or greater than 3 years, actually, that are going to be presented at the liver meeting here.

 

[01:56:31]

 

          Posttest 1

 

So a post-test question now. Your colleague asks about the second-line PBC therapy, elafibranor. You advise them that in the ELATIVE study, compared with placebo, participants who received elafibranor had significant improvement in:

 

1. Biochemical response only;
2. Biochemical response and itch;
3. Biochemical response and ALP normalization; or
4. Biochemical response, ALP normalization and itch.

 

So I'll give you a moment to answer that on your iPads.

 

[01:57:21]

 

          Posttest 1: Results

 

Okay. So the first bar is the pre. So the red bar is what you all said before we talked. And the gray bar is the now answer. So the correct answer here is the third choice, biochemical response in ALP normalization. And it looks like we got more right this time, which is wonderful.

 

[01:57:40]

 

          Posttest 1: Rationale

 

All right, so just a reminder, we just reviewed this, numerical improvement in itch that wasn't statistically significant.

 

[01:57:48]

 

RESPONSE Pruritus Outcome: Seladelpar for Second-line Treatment of People With PBC

 

So how about with seladelpar? So in the RESPONSE trial, if you look at the patients with PBC that had moderate to severe pruritus defined as an NRS score greater than 4 that were enrolled in the trial, we do see that at the end of the trial, there was a significant difference in those treated with seladelpar compared to the placebo arm up here. So there was a significant improvement in itch as defined by the - the - the worst itch NRS score.

 

There's also been data presented on how seladelpar changes levels of interleukin-31, which we know has been implicated with cholestatic pruritus. And you can see that there is a reduction in - in IL-31 levels compared to baseline at month 3 and those that are treated in seladelpar. And there was no reduction or no improvement in IL-31 levels.

 

So the role - the postulation is that perhaps seladelpar modulates IL-31 and the production of IL-31, which can potentially reduce cholestatic pruritus.

 

[01:58:51]

 

Summary of Phase III Studies

 

So just a summary of seladelpar from the - the - the presentation so far. Significant improvement was noted in biochemical response and ALP, and a significant improvement was noted in itch. There are some abstracts here to further learn more about seladelpar, including long-term pruritus results from both the RESPONSE and the open-label ASSURE studies.

 

Liver stiffness data measurements from the open-label ASSURE study will also be presented. And then real-world data indicating biochemical response and safety will be presented at this meeting.

 

[01:59:25]

 

          Posttest 2

 

So a post-test question now. So your colleague again asks you about the second-line PBC therapy, seladelpar. You advise them that in the RESPONSE study compared to placebo, participants who received seladelpar had significant improvement in:

 

1. Biochemical response only;
2. Biochemical response and itch;
3. Biochemical response and ALP normalization; or
4. Biochemical response, ALP normalization and itch.

 

Take a moment and answer that on your iPads as well.

 

[02:00:09]

 

          Posttest 2: Results

 

All right. Wonderful. So almost everybody answered correctly.

 

[02:00:18]

 

          Posttest 2: Rationale

 

The last answer is correct here, biochemical response ALP normalization and itch.

 

[02:00:23]

 

Investigational Agents for PBC Pruritus

 

All right. Investigational agents for PBC providers. So what happens if you have used a second-line therapy like seladelpar and someone that is experiencing itch that needs additional control of their PBC, yet they continue to suffer from itch? What else can we potentially provide them?

 

[02:00:39]

 

VANTAGE: Investigational Volixibat Change in Pruritus Through Wk 28

 

The IBAT inhibitors have been - are being studied for the treatment of pruritus in PBC. So the VANTAGE trial was an investigational volixibat trial studying pruritus changes through week 28. This was a phase II study. And you can see the volixibat was studied in 2 doses up here, both 20 milligrams and 80 milligrams doses up here. And at week 28, you can see that there's a significant difference in itch scores and the adult itch row - itch row scores in the seladelpar - I'm sorry in the volixibat treated group compared to the placebo treated group.

 

So it gives a signal that potentially another mechanism for which we could control cholestatic pruritus in PBC is with a depletion of the bile acids.

 

[02:01:21]

 

GLISTEN: Investigational Linerixibat Change in Pruritus Through Wk 24

 

And then similarly, the GLISTEN trial was a phase III study of linerixibat in people with PBC that had moderate to severe pruritus, and they were treated with linerixibat for 24 weeks. And in this study, you can see up here that the curves separate really nicely quite early on actually. And at week 24, you see that there is a significant improvement in itch in those that were treated with linerixibat compared to the placebo arm.

 

The study is interesting that there was a crossover after, and you can see that when patients were taken off the linerixibat, you can see that there was, again, an increase in their itch. And then separately, the placebo group that was crossed over to linerixibat had an improvement in their itch score.

 

So it really does help lead credence to, you know, potentially treating severe cholestatic pruritus with IBAT inhibitors.

 

[02:02:09]

 

Fatigue

 

We'll switch gears now to talk about fatigue.

 

[02:02:11]

 

In PBC, Fatigue Is:

 

So fatigue in PBC, again, quite prevalent affecting up to 78% of people living with PBC. We know that dependent or independent of sleep causes the - I'm sorry, independent of pruritus. It can cause significant sleep disturbances. Or the pruritus we know causes sleep disturbances. Fatigue can be separate from that.

 

The fatigue is also worsened with obeticholic acid, and we know that it is not improved with ursodeoxycholic acid.

 

[02:02:40]

 

Patient Video

 

So we'll take a look at a patient video that discusses the impact of fatigue on their lives.

 

Brenda Remo: Brain fog. It - it's completely changed my life and completely changed who I was. I used to be a very independent person. I used to be the person that was up at 7:00 in the morning going to the grocery store, and then I'd be home unpacking and cooking breakfast while everybody's still sleeping.

 

Now, sometimes I go into the shower and I'm too tired after that, or I - I - I can't go grocery shopping at all anymore. My husband has to push the cart because just the cart - pushing the cart, the energy that that takes is stupid. It shouldn't be like that. You have to plan everything. I plan my life. If there's something going on, on a Saturday, I know I have to rest and prepare for it. I know that that the next day, I'm not going to be moving off my couch because I'm going to be exhausted. And that's just what you have to do.

 

That's what we're forced to do. Just to live our lives is really just be in tune with our bodies and, you know, take the good days with the bad days and just roll with it until something can be found to help us.

 

[02:04:04]

 

Mechanisms of Fatigue in Pruritus

 

Dr. Goel: So you can tell a really, really big impact on quality of life. And when we discuss the impact of fatigue with our patients, it's really hard, I think, in a 15, 20-minute visit to quite understand how big of an impact it can have on their quality of life and what you can do to sort of address it with them. But it is something that, you know, we should be asking about. Unfortunately, how we can treat it, it remains - I think there's a lot of study that we can do and a lot of improvement there.

 

So how and why does fatigue happen in cholestatic liver disease and especially in PBC? The short answer is we're not really sure. There's a lot of different theories and a lot of different confounding variables that likely are contributing to the significant fatigue and the brain fog that our patients are experiencing. We know that this is an inflammatory process. So likely inflammation is - is - is triggering the fatigue as well. The cholestasis likely contributes.

 

There's concomitant psychologic factors and mental health comorbidities that go along and sort of go hand-in-hand with having bad quality of life, including depression, anxiety, impaired cognition, and the worry about the future. We see that many of our patients end up socially isolating because of their quality of life, the impact that pruritus has on their skin or their clothing that they're wearing, or the impact that fatigue has on their desire to go out and have dinner with a friend, so the social isolation likely contributes - contributes to it as well.

 

We also know that there's - there's neuropathic factors at play. The central nervous system is involved in some way. The peripheral muscular system we know is likely involved in that. There's differences with impaired relaxation of both motor neurons and sensory neurons, and it can play a role. So it's quite - there's multiple mechanisms at play. And how to address them I think is - is a really big challenge.

 

[02:05:53]

 

Nonpharmacologic Treatments for PBC Fatigue

 

So what can we do? We obviously educate and validate their symptoms and understand that this is part of their disease. And I think that a lot of the times they just need to hear that. They need to hear that it's not in their heads that the people around them might not see it because they might look completely healthy, but they need to have their symptoms validated and to - and kind of recognize that this is likely related to their PBC, as long as they've excluded other causes as well.

 

We do encourage regular physical activity. Obviously, timing that physical activity to patterns during their day or during their week when they tend to have less fatigue. We talk about pacing strategies and task management. So, you know, don't schedule things when you know in the middle of the day or at the end of the day, you're going to be quite fatigued or quite tired, or after a weekend when you're running after your kids. Try to make that Monday or Tuesday really light for you. So really talking about that task management.

 

Many of our - many of our patients with PBC do have mental health providers, therapists or psychiatrists that help with psychologic interventions, including both CBT and - and ACT. And we talk about mind body therapies as well.

 

[02:07:04]

 

Unsuccessful Pharmacologic Therapies for PBC Fatigue

 

There's been a slew of medications that have been unsuccessfully tried in PBC fatigue. So modafinil was studied for 12 weeks. It was safe, but it didn't result in any sort of beneficial effects on fatigue compared to placebo. Rituximab was also studied and - and to see the improvement in fatigue over a 12-month study period, and again did not show effectiveness at treating PBC-related fatigue.

 

SSRIs, including fluoxetine, did not show an improvement in the fatigue specifically, and there was some concern about drug-related adverse events. And then separately, a host of antioxidants have demonstrated safety but no other real benefit in terms of fatigue.

 

[02:07:45]

 

ELATIVE: Elafibranor for PBC

 

Let's talk a little bit about how these medications that are approved for second-line therapy for PBC control, how they have - if they have an influence on fatigue now. So again, in the ELATIVE study, there was a subgroup analysis of participants that had moderate to severe fatigue at baseline. That was defined again in 2 different ways. It was defined either using the PROMIS Fatigue Short Form or the PBC 40 Fatigue Domain.

 

And when you look at the participants that were enrolled in the elafibranor arm that had moderate to severe fatigue compared to the placebo arm, they showed benefit. The - the patients treated with elafibranor had an improvement in their fatigue using the PROMIS score compared to placebo.

 

Similarly, when you look at the PBC 40 Fatigue Domain, the participants that were treated with elafibranor had a 39.6% improvement in fatigue, compared to 26% in the placebo arm. So potentially lending some really good signals that the fatigue may be modulated with elafibranor, and something to take into consideration when we're selecting second-line therapy for our patients.

 

[02:08:59]

 

ELATIVE: Is Fatigue Related to Pruritus Alone?

 

I think the natural next question is, “Well, did the fatigue get better because you controlled the itch better?” So the pruritus gets better potentially with your second-line therapy. And is that why the fatigue is getting better? You're not itching at nighttime. You're able to get better quality of sleep and you're not tired in the morning.

 

So this was looked at with all - with all the possible permutations you can imagine using the fatigue domains and using the itch domains, and looking at the entire cohort of the study, and also looking at just the folks treated with elafibranor. And what they - what - what the study investigators found is that there was actually no correlation.

 

So in every permutation that you looked at, there was a very weak correlation between the fatigue and the pruritus. So the impact that elafibranor had on fatigue is independent of the pruritus impact.

 

[02:09:45]

 

Seladepar for PBC

 

What about with seladelpar? Well, in the open-label phase II study, you're looking at patient-reported outcomes, and this included patients that were treated with both seladelpar 5 and then 10 milligrams, and then also 10 milligrams group. The blue represents the patients that had an improvement in the fatigue, and the red represents worsening of fatigue.

 

You can see that there were more patients that potentially had an improvement in fatigue, but I think more to learn about the fatigue impact with seladelpar still.

 

[02:10:15]

 

Investigational Setanaxib: PBC Fatigue

 

There are invest - investigational agents as well. So Dr. Bowlus had mentioned the NOX 1/4 inhibitor, setanaxib. Setanaxib at a dose of 400 milligrams given twice a day did show that there were reductions in - in fatigue looking at the PBC 40 Fatigue Domain. So I think this lends - you know, these studies or these results, the last few with the - with the second-line therapies with the NOX 1/4 inhibitors, do give us some hope that some of these therapies may also not only modulate the disease activity, but may also influence some of these extrahepatic symptoms that our patients suffer from with PBC.

 

[02:10:53]

 

Summary of PBC Symptom Management

 

So just to summarize, a summary of PBC symptom management. Remember that symptoms, pruritus and fatigue need to be treated independently of the PBC itself. Biochemical response itself does not correlate with an improvement in pruritus and fatigue. We see that especially in the IBAT trials, that people had a good biochemical response, but still did suffer from moderate to severe itch. And don't dismiss the symptoms that people bring in because they've normalized it.

 

So if they say, “I'm okay, it's not that bad, I can deal with it.” Really, really do question what - their symptoms, how their symptoms are affecting their quality of life, and what you can possibly give them to make them feel better.

 

Reminder that UDCA does not improve symptoms. Obeticholic acid may worsen symptoms, and PPAR agonists may improve symptoms as well.

 

[02:11:46]

 

          Posttest 3

 

So a post-test question now. In clinical trials, which drug or class showed promise for improvement of PBC pruritus?

 

1. Ursodeoxycholic acid;
2. FXR agonists;
3. PPAR agonists; or
4. All of the above.

 

[02:12:19]

 

          Posttest 3: Results

 

All right. So great. I think that there was an improvement in the score, as I saw from 79 to 90.

 

[02:12:26]

 

          Posttest 3: Rationale

 

So the answer is the PPAR agonists have shown that there could be benefit in pruritus from PBC. So the seladelpar study did show that.

 

[02:12:36]

 

Case 3: Management of Pruritus

 

Well, briefly with the last few minutes that we have, I'm sure that there's questions that we can answer from the audience as well. We'll briefly review a case now to help us understand how to manage pruritus in - in the real-world setting.

 

So this is a 71-year-old woman who has PBC, who's referred to you for pruritus. Her medical history includes celiac disease, and she's compliant with a gluten-free diet. And she also has ITP.

 

Her history of present illness, she was diagnosed with PBC at the age of 56. So she's been living with this disease now for 15 years. She has severe pruritus with an NRS score of 10. And you've given her all these treatments listed over here. So she's on cholestyr - cholestyramine, rifampin, sertraline and gabapentin. And despite all this therapy, she has ongoing pruritus with an NRS score between 5 to 6. And she remains on ursodeoxycholic therapy.

 

[02:13:25]

 

Case 3: Labs and Imaging

 

Her laboratory values indicate that she has an alkaline phosphatase level that's elevated but less than 200, and her GGT values elevated. Her bilirubin is 0.9. Her ultrasound shows mild nodularity in a normal biliary tree, and her liver stiffness is 6.9 kilopascals.

 

[02:13:44]

 

Case 3 Panel Discussion

 

So we'll move to our panel discussion now. So for - for this patient, what would you do next?

 

Dr. Gulamhusein: Me? Okay. So it seems like pruritus is a really hot topic. So this is exciting to talk about I think. I mean, her liver tests aren't completely normal, right? Her - she's 71. Her liver stiffness is low. But I think this is the kind of person that, despite what regulatory endpoints are, that you would want to push to symptom benefit - push to treatment for symptom benefit and normalization of liver tests. So for this patient I would probably pick seladelpar upfront.

 

Dr. Goel: Chris, what would you do?

 

Dr. Bowlus: Yeah, I think the same. I think that, you know, given the results of the trials, the balance kind of tips towards seladelpar in this case in terms of trying to address the pruritus. I think, you know, one of the concerns is she's going to get better with the pruritus to some degree. But even with these PPAR agonists, if she's got moderate to severe pruritus, we aren't going to expect it to get completely resolved.

 

And most of these patients will get a tremendous improvement and they'll express that. But I think - I think going forward, the question is she's going to have continued pruritus, if we have an IBAT or do we use off-label IBAT in - in - in these settings, right?

 

[02:15:09]

 

Q&A

 

Dr. Gulamhusein: Right. I mean, this is walking into a lot of really excellent questions that come up. So why don't we go through some of them?

 

One that I thought was interesting. It says there's - there seems to be one PPAR that talks about fatigue more and one PPAR that talks about pruritus more. Why is that? What do we make of that data? And how do we use that when we're informing decisions in the real world?

 

Dr. Goel: Yeah. I think - I think we have a lot to learn still with - as these drugs are used for longer periods of time and as we get more real-world data. The way that the analysis has been sort of provided with these phase IIII results is these were secondary endpoints and exploratory endpoints.

 

So what is being reported is what was interesting in the studies is - is kind of the way that I see it, right? So there was an improvement on some of these itch scores, but not - the main one that they were looking at, we didn't necessarily see an improvement in fatigue overall, but like here's a bar graph that shows that there was some improvement in fatigue with seladelpar.

 

So I think that the statistical significance, you know, is I think remains to be determined as we get a larger number of patients treated with these and as we start to use them more, and as these patients are followed in the open-label extensions. But in practice, I am taking what the available data into consideration. So in somebody that does have significant fatigue, I am tending to use seladelpar more. And in someone that is experiencing fatigue more, I am talking to them about elafibranor more.

 

Dr. Gulamhusein: Yeah, it's hard, right? Like the PBC is an uncommon, rare disease, right? It's not - the numbers in the studies are not huge. And then when you start to sort of siphon them off into subgroups, it becomes hard to take a ton away from it. But I agree with that approach. That's kind of what I'm doing as well.

 

Another really good question that I'm not sure we're going to be able to answer. But what about patients with normal liver tests? Treatment response to Urso with normal liver tests. Should we use PPARs in those patients for pruritus?

 

Dr. Bowlus: We - we had this discussion.

 

Dr. Gulamhusein: Yes.

 

Dr. Bowlus: And - and I'm a bit of a skeptic. I think itch is - you know, symptoms are hard because they are - they are symptoms. So it’s - and itch in particular is a very common symptom. And so just because someone with PBC has itch doesn't mean that their itch is coming from PBC. And I think that a patient that has normal alkaline phosphatase and - and we talked about this before, normal serum bile acids, I would be looking for other causes of itch, honestly.

 

If we had - if we could measure IL-31, that would be great, because then I would feel more confident that it's not cholestasis that's causing her - the itch. But I would be investigating other causes.

 

Dr. Gulamhusein: Yeah. I mean, I think I agree, too. But I also acknowledge that, you know what, in - in about at least 50% of patients respond well to Urso. Right? We have - I mean, the proportion that have incomplete responses to Urso, just the numbers in the literature vary, but somewhere maybe 30% to 50% depending on the criteria you use. But there are patients with PBC that we know that have normal liver tests with itch. Right?

 

I think we don't have the data that PPAR - I agree. You have to rule out other causes of pruritus for sure. But today, we don't have the data for pruritus in normal liver tests with a PPAR, right? Those patients just weren't included in these studies.

 

Aparna, what do you think about IBATs?

 

Dr. Goel: Yeah. I was - so I think my approach would be very similar, rule everything else out. But ruling everything else out means I'm also checking the serum bile acids. So if the serum bile acids are elevated, then I would consider an IBAT inhibitor in someone like…

 

Dr. Gulamhusein: Provocative.

 

Dr. Goel: Yeah, someone like this person. Because - and if - if they are really elevated, then you have to think about, you know, ruling out other intrahepatic cholestasis diseases as well. But depending on the degree of elevation. But this is somebody that - then I would consider either off label use or - or maybe soon something that would be available, an IBAT inhibitor for - for ongoing pruritus despite disease control that is cholestatic pruritus.

 

Dr. Gulamhusein: Okay. Another question about IBATs in cirrhotics. Is that - how many in the subgroups of volixibat and linerixibat had cirrhosis? I can't - I can't even remember up front. But - but a minority, right?

 

Dr. Goel: Yeah, I wouldn't know.

 

Dr. Gulamhusein: Yeah, a minority. I mean, I think in all of - all of the studies that a proportion of them did have elevated liver stiffness, but not a significant number for sure.

 

Dr. Bowlus: And importantly, they were not decompensated cirrhotics. So your patients that are really advanced. We just don't know.

 

Dr. Gulamhusein: Okay. Symptoms. Is there a correlation between peri and post-menopause fatigue in PBC - or sorry, is there a correlation between peri and post-menopause-associated fatigue and PBC-associated fatigue in women? Hard.

 

Dr. Goel: Yeah, that's a really, really good question. I recently was at this other patient forum where I listened to a gynecologist talk about fatigue-associated with autoimmune hepatitis and talking about assessing for perimenopause. The - my - there's no guidelines to - to help us in this area at all. But the - I think it is important that it be considered in anyone that is over the age of 40 that is experiencing fatigue - a woman over the age of 40 that is experiencing fatigue, there should be an evaluation for whether or not there might be perimenopausal symptoms, and having a discussion about - and if - if those symptoms are potentially contributing to fatigue as well. They can be addressed. And a discussion about hormone replacement therapy to see if there is an improvement in fatigue is something that should be on the table. That’s sort of my takeaway from - from this discussion.

 

Dr. Bowlus: And I'm not sure the point of the question. I think just like any of our patients that have fatigue, we want to rule out other causes, right? Anemia, thyroid, etc.. But the cause of fatigue in PBC is not because it's women that are perimenopausal or - or menopausal. I mean, it's - it's not that. It is, you know, a biologic response to the disease that we see in other inflammatory diseases.

 

And if you listen to their symptoms, it's very similar to long COVID, which is a real thing, right? I mean, you have a clearly defined event, and after the event is resolved, you still have ongoing fatigue. And you see it in rheumatoid arthritis and everything else. So it's - it’s a real thing.

 

Dr. Gulamhusein: Yeah. And I mean, there could be additional reasons for fatigue beyond the PBC. But I think you're right. PBC is - the - the fatigue brain fog sort of battery depleted symptom that people talk about is independent of those things.

 

Okay. So I think that was most of the questions about symptoms. I mean, there's questions about the - the confidence in the fatigue data versus the pruritus data. And it's hard, right? There's many patient-reported outcome scores that have been used across these studies. And I think you have to sort of take away what the key secondary endpoints were. And for itch, that was mostly the NRS, right?

 

What do you guys feel about the confidence in symptom benefit from a pruritus standpoint versus a fatigue standpoint?

 

Dr. Bowlus: So regarding the - the pruritus, I think it's a good point, right? So the - the NRS, the numeric rating scale, what it is, is that you ask the patient, what was your worst itch in the last seven days on a scale of zero being no itch and 10 being the worst itch imaginable? And then if you're 4 or greater, you're considered moderate to severe. And those are the people that are being analyzed.

 

Dr. Goel: Right.

 

Dr. Bowlus: The other things like the 5D itch and PBC 40, or ask you more about what the impact of itch is, and a little more descriptive of what the itch is, right? Because that - the severity of it doesn't really capture all of the parts of itch.

 

So the NRS is just nice because it's a single value and you can do nice statistics on it, but it doesn't really capture everything. So I think, you know, in clinical practice, the important thing is to talk to your patient. And you know, I do ask the NRS now because I want to gauge how severe it is. But it's interesting when you talk about medication, and a lot of times that tells you how severe it is for them, because if they don't want to start a treatment, I guess it's not as bad, is it as opposed to they actually do want to take a - take a new medication for it.

 

Dr. Goel: I - I agree. I don't - I don't think that there is a one way to ask patients, but I think it needs to be addressed. Our level of confidence is - is as good as an N of 30, 40 people that had moderate to severe pruritus, I think, in - in - in these trials. So it's - it's not a lot of patients that we have data for yet. I think that we really do - we will learn more over the next year or 2, 3 years to understand what the - what the larger impact is.

 

I think anecdotally, you know, we have seen patients that are on seladelpar or on a PPAR that have an improvement in itch. So I do think that you - you know, that the data is not necessarily unbelievable. You do see patients improve on the PPARs.

 

Dr. Gulamhusein: And I mean we have a lot of data with bezafibrate.

 

Dr. Goel: Yeah.

 

Dr. Gulamhusein: Right? So I think - I think the itch data is real. I think what - what is really important is that we objectively document, right, and follow patients over time. So the NRS is handy to use in the clinic. It doesn't take a ton of time and you can really see patients improve or not for yourself. A PBC 40 will never be used in my clinic. It's not practical, right? It's just it takes too much time and it's not practical. But - but maybe shows some impact in patient function that's different to what NRS captures.

 

Dr. Goel: I think one of the other ways we've assessed impact of the PPARs on itch is seeing what other medications they've been able to come off of. So there are some patients we start on second-line therapy, and kind of like this last case we had, they are off of all of the other antipruritic agents within 3 months. So they're not - within - within a month. They're not taking cholestyramine anymore. They're off their sertraline, gabapentin. They've been able to actually stop everything because their pruritus is controlled. So just another way to sort of gauge if the itch has gotten better.

 

Dr. Bowlus: I think - I think what you were saying is - is really nice that, as a class, I think we can say pretty confidently that PPAR agonists are improve - improve itch.

 

Dr. Gulamhusein: Right.

 

Dr. Bowlus: And I think we can - whether one is better than the other, this, that and the other, we can argue and discuss. But in general, they improve itch. I think what's really going to be interesting going forward is what is their impact on fatigue. And is that - is that something we're going to see? And as we learn more, describe that. Because right now that's the thing that - to me in clinic that's the most challenging. The itch is - is challenging. But we have some things to offer.

 

The fatigue is the one where you say, “Well, just, you know, arrange your schedule, do this, do that.” But it's just really unsatisfying to really help our patients. So if there's really an effect there, I think that will be a real improvement in our care.

 

Dr. Gulamhusein: That was planted. So the next really good question is, how do you measure fatigue in your practice?

 

Dr. Goel: That's a hard one. I don't use any scales. It's - it’s so impracticable, impractical to ask patients to fill out scales to measure fatigue. What I will ask them is, have you been - have you - did you cancel plans with friends or did you take time off of work? Those are the 2 questions I tend to ask because of the fatigue. Because you were so tired, you couldn't go to work. You were so tired you had to cancel plans that you had.

 

Dr. Gulamhusein: Yeah. You know, it's really hard. I mean, I'm intentional about ruling out secondary causes, right? Celiac disease, anemia, hypothyroidism, sleep apnea. I really do that intentionally. We talk a lot about mindfulness and things like that to intervene. But I almost even sometimes use 1 to 10 scores in terms of severity and impact, you know, just to have something objective that's quick and practical.

 

But you're right to - to the - to the person who posed the question, it's really - it's - there's - there's nothing at the bedside that's really easy to use, at least that I've found.

 

Dr. Bowlus: You know, to me, in the fatigue side, it's more about having them describe it because I - I don't have anything to offer them necessarily than listen - other than listening and just letting them describe it and express what - how it impacts their life, I think is somewhat therapeutic. So.

 

Dr. Gulamhusein: So asking and validating.

 

Dr. Bowlus: Just asking and make sure...

 

Dr. Goel: And there are a lot more psychologists that are starting to get involved with CBT and ACT. So, you know, the acceptance training. And I - and I do think it has been beneficial for some of our patients that truly struggle with fatigue because we don't have anything to offer them. So just trying to understand how to accept the disease, the diagnosis, the symptoms, and - and still have a quality of life that they - that they appreciate.

 

Dr. Gulamhusein: So there's a few questions about disease control maybe that will target a little bit different to symptoms. The first is - maybe I'll take this that I wasn't clear. You tell us normal as normal. Yet we seem to be unsure as to whether a patient with an ALP of 1.4 times the upper limit of normal should be on second-line therapy.

 

And I think this goes back to concepts, right? There's regulatory endpoints. I like to think about things as regulatory endpoints of this ALP of 1.67 times the upper limit of normal and ideal endpoints. For me, I think a normal liver test is what we should strive for. Whether you're going to be able to access therapy for those patients in between is different and will differ by country and by region, right?

 

So simple way to answer that is that, yes, I think normal liver tests are probably better for everybody. But you have to think about the context of the patient, whether normalizing their liver tests is going to improve their outcome in the long-term based on comorbidities. But in general, I would say if you want to be simplistic about the answer, yes, normal liver test is probably best.

 

Triple therapy. There's a question about Urso plus PPARs plus obeticholic acid as an option in the real-world.

 

Dr. Bowlus: It's the only one.

 

Dr. Goel: Viewpoint in the US.

 

Dr. Gulamhusein: I will happily answer that. So we use that a lot. I mean, in Canada we still have access to obeticholic acid. So we had published a series of patient - about 50 patients who showed that you do get normalization in a patient’s improvement/normalization in patients on triple therapy with a PPAR plus obeticholic acid, despite the order you use of those second and third-line therapies.

 

So, I mean, it's limited to patients who are truly high risk, right? Those young patients who have ongoing elevations in liver tests, particularly over 200, despite your initial second-line option that we have used triple therapy in for.

 

So I think if you have access and the patient is at high-risk, that it's not an unreasonable choice as long as you are comfortable and see a fair number of these patients. Right?

 

Okay. Will we ever have RCTs comparing beza versus ela versus sela?

 

Dr. Goel: No.

 

Dr. Bowlus: No.

 

Dr. Gulamhusein: So what about - I mean, what about cost? Right? Bezafibrate is available in many countries at a much more affordable price point. How do you feel about use of an off-label option in such a context?

 

Dr. Bowlus: So I'll say that - I can't speak to beza because I think it's a little more complicated with beza, because you do have a randomized controlled trial. You know, you have more data there. For us in the US with fenofibrate, we really don't have much data. We were using it sort of because of the lack of other options. But now that we have options of drugs that have been demonstrated to be safe and effective, we use that.

 

Dr. Gulamhusein: Right.

 

Dr. Bowlus: I will say that I am a bit concerned about the doses used of bezafibrate for safety reasons. And - and when I've used fenofibrate in the past, I start at the baby dose like 48 milligrams because I don't know if it's a class effect or what, but it's - you know, the hepatotoxicity of these drugs seems to be more - it seems to be more sensitive in cholestatic diseases. We saw that with seladelpar in the early stages of its development.

 

I think with bezafibrate - if you look at the BEZURSO study, the number of adverse events they had was relatively high compared to the number of patients. So we do have to be careful when we apply doses of these drugs that weren't necessarily designed for the diseases we're treating.

 

Dr. Goel: There's been some smaller studies using fenofibrate in the US, and there - there have been decent discontinuation rates because of these adverse events, so my practice is - is similar now. If someone has been on fenofibrate for a long period of time and has good control, I will tell them that there's approved therapies now. But most of them want to stay on fenofibrate and don't want to change anything.

 

But for others that don't have disease control, I'm not going to start - someone that needs new second-line therapy, I will not choose fenofibrate over 2 potentially equally, if not more effective therapies that are now FDA approved. So I'll be using either elafibranor or seladelpar.

 

Dr. Gulamhusein: Maybe we'll do one more question then we'll end. But just to say I - I also agree. I worry a little bit about toxicity too. And I'll say we have access to bezafibrate and I rarely ever start someone on full dose. I always start every other day 400 milligrams of bezafibrate, and if they're fine on that, they stay on that. And if they are not, and we slowly up titrate and monitor.

 

So the last one is, do you think the mechanisms of PPARs have differential impacts on, say, disease activity and/or symptoms?

 

Dr. Bowlus: I think that's a great question. We just don't really understand. You know, everyone talks about these differential effects of these isoforms of PPARs, but they all seem to have - at least in terms of improvement in alkaline phosphatase, they all are anti-cholestatic.

 

Dr. Gulamhusein: Right.

 

Dr. Bowlus: So it's possible there are some differences that we're not able to measure. But so far it's hard to say there's a real differentiator there at this time. I mean, I think clinically.

 

Dr. Goel: Tying into the question earlier about switching the PPARs, I think that might shed some light into if you add a little bit of alpha activity, then maybe there's a change there. But I don't think we know the answer yet.

 

Dr. Gulamhusein: Real-world dynamic use I think will change - will help understand some of these things. But my approach right now is just to say, you know what? Regardless of what PPAR you use biochemically, at least, you're probably going to end up with the same result.

 

Dr. Bowlus: Yeah. Well, I think we need to wrap up. So, well that's right. Just have it. Okay. I'll stand up. Harder and harder. So we have just a few seconds left. So - so thank you all for joining us. I hope you found it educational.

 

Really important, I think, to be sure that in the patients that need second-line therapies, you really think about implementing it. We know from past experience that getting patients treated that need second-line therapy is not being fully implemented. And so that's really important. So thank you again for your attention and have a wonderful rest of the meeting.