Introduction 

Welcome to this program titled Keeping Up with New Developments in PBC.  My name is Sonal Kumar.  I'm a hepatologist at Weill Cornell Medicine in New York City.  For this specific medical minute, I'll really be focusing on updates on PBC from AASLD 2024 that just passed, but be sure to check out the other medical minutes in this series, along with ClinicalThought commentaries and podcasts on the Clinical Care Options website. 

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          Poll 1

So before we begin, let's just start off with a poll question.  Number one, how many people with PBC are under your care? 

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          Pretest 1

And we're going to have a few pretest questions.  So the first one, your colleague asks about elafibranor for PBC.  You advise them that in the ELATIVE study, among participants who received elafibranor, GLOBE and UK-PBC prognostic scores for risk of liver transplantation or death are improved as early as…

[00:01:33]

          Pretest 2

And then pretest question number two.  Your colleague asks about long-term use of seladelpar for PBC.  You advise them that in the ASSURE study, compared to the placebo arm at month 30, those in the seladelpar arm had:

[00:01:52]

          ELATIVE: Elafibranor for PBC

Okay, so let's move on to talking about the abstracts that I thought were important from AASLD 2024. 

Now, it's been a really exciting year for the field of primary biliary cholangitis, because in the US, we've had two new therapies that have been approved by the FDA for patients with PBC who have inadequate control with first-line therapy with UDCA. 

And when new medications are approved, as providers, the major questions we ask ourselves are really about safety and efficacy.  Are these meds going to change the disease course for my patients?  Are the effects long-term?  Are there any risks with – with taking these medications, especially when they are potentially needed for many years or indefinitely? 

And so the abstracts that I'll be talking about today will really give us more insight into some of those questions, and beyond what we saw with the primary studies that led to the approval of these new medications. 

So let's start off by talking about the ELATIVE trial.  So this was the study that looked at elafibranor for patients with PBC.  It was a multinational, double-blind, placebo-controlled, randomized phase III trial.  Patients were eligible for enrollment into the trial if they had PBC and an inadequate response or intolerance to UDCA.  They also had to have an alk phos level that was at least 1.67 times the upper limit of normal.  A total bilirubin that was 2 or below times the upper limit of normal. 

There were 161 patients.  They were stratified by alk phos levels greater than or less than three times the upper limit of normal or elevated bilirubin.  And they were also – they also looked at pruritus scores.  And so stratified by numerical rating scale score of 4 or above. 

Patients were randomized to elafibranor 80 milligrams once a day or placebo, and then they were treated up to week 104.  And there was an open label extension, where patients that were in the placebo arm were offered to cross over into an open label trial.  And those patients are followed up to week 156. 

The primary endpoint are – is a composite biochemical response.  And that comprised of three components.  So their alk phos level had to be less than 1.67 times the upper limit of normal.  There had to be an alk phos decrease of at least 15%, and the total bilirubin had to be within normal limits.  So in order to achieve that primary endpoint, patients had to hit all three of those components. 

Secondary endpoints included alk phos normalization.  And then there were additional analyses.  And so we'll look at some of these things as well.  The GLOBE and UK-PBC scores which are validated prognostic scores that estimate the risk of liver transplant or death after one year of UDCA therapy.  And these are more comprehensive scores than just looking at alkaline phosphatase level – levels. 

They're based on alk phos still, but it's a more comprehensive score.  So you take into account total bilirubin AST, ALT, albumin, platelets, plus or minus age.  And it gives us more insight into transplant-free survival. 

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ELATIVE: Baseline Characteristics

So these are the baseline characteristics of patients in the ELATIVE trial.  In the – in the – I'm going to start over at that slide.  So these are the baseline characteristics for patients in the ELATIVE trial.  The mean time since diagnosis was about seven to eight years.  There were about a third of patients to 38% of patients who had evidence of more advanced fibrosis, so their liver stiffness score was greater than 10 kilopascals, or if they had a liver biopsy, there was evidence of advanced fibrosis or cirrhosis on histology. 

I'd like to point out that the mean alkaline phosphatase level for the both groups was over 300, which is about 320 in both of the groups, and a significant percentage of patients had high alk phos levels at baseline.  So almost 40% had alk phos levels that were greater than three times the upper limit of normal. 

You can see the bilirubin, majority had a normal bilirubin.  Liver enzymes, some were mildly elevated.  Mean albumin was normal.  And mean platelets were within normal limits as well. 

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ELATIVE: GLOBE and UK-PBC Prognostic Scores at Wk 52

So here we see what happened to the GLOBE and UK-PBC prognostic scores at the end of the trial.  So patients were enrolled in the trial - in the double blind trial up to week 104.  But the primary endpoint was at week 52.  And you can see here there was an improvement in the GLOBE and UK-PBC scores that were observed with elafibranor by week four.  And it was sustained through week 52. 

So this is taking the initial data on alk phos and alk phos normalization, bilirubin, and just expanding it a little more to composite scores that have been validated to correlate with transplant-free survival.  So you can see here that on the left, we have the GLOBE score.  And the patients in the placebo arm had a slight rise in their GLOBE score throughout the course of the trial.  Whereas on – in patients with – that were on elafibranor, there was a decrease in the GLOBE score. 

And we saw a similar effect – impact on – of elafibranor on the UK-PBC score.  So it happens early.  By week four, we notice a decrease in the – in the – these composite scores and then it was sustained throughout the entire trial. 

So it just gives us more information – more comprehensive information on how the impact – or on the impact of elafibranor may be on transplant-free survival in our patients. 

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ELATIVE: Estimated Transplant-free Survival Rates Based on GLOBE Scores at Wk 52

And when they estimated transplant free survival rates based on these composite scores.  So the – the trial itself ended at week 52 for the double-blind, placebo-controlled trial component of the trial.  But they did estimates to – as to what the – if this was extended out to ten and 15 years, what would transplant-free survival rates look at – look like? 

And by week 52, because of the change that we saw at week 52, there were higher estimated transplant-free survival rates estimated with elafibranor complete – compared to placebo.  This is here based on the GLOBE score.  And similarly we saw this with the UK-PBC scores. 

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ELATIVE: Estimated Transplant-free Survival Rates Based on UK-PBC Scores at Wk 52

So if you look at the change in biochemistry.  So these are the components of the GLOBE and PBC – UK-PBC scores.  You can see that there was an improvement in – in multiple parameters.  But this was driven a lot by alkaline phosphatase levels. 

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          Posttest 1

So we have a posttest question based on this abstract.  So your colleague asks about elafibranor for PBC.  You advise them that in the ELATIVE study, among participants who received elafibranor, GLOBE and UK-PBC prognostic scores for the risk of liver transplantation or death improved as early as... 

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          Posttest 1: Rationale

The answer is A.  week four.  And this was sustained through week 52.  So in the ELATIVE trial, which was a phase III trial of elafibranor versus placebo in people with PBC, among participants who received elafibranor.  So the patients that were in the treatment arm, their GLOBE and UK-PBC prognostic scores for risk of liver transplantation or death improved early and it was sustained throughout week 52. 

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ELATIVE OLE: Biochemical Response and ALP Normalization at Wk 156

So this is another extension of the ELATIVE trial.  So this is the open-label extension.  I'm going to start over on that slide. 

So this is the open-label extension data of the ELATIVE trial.  So the patients were included for the primary part of the trial was up until week 52.  And then at week 52, patients were offered to continue if they were in the active treatment arm or to cross over if they were in the placebo arm. 

And here you can see that the biochemical response, again, that composite response in alk phos decrease of at least 15% and alk phos level of 1.67 times upper limit of normal or lower, and a normal bilirubin, that is the defined biochemical response.  And you can see the effect was really sustained throughout the 156-week open-label extension. 

And then if you look just at alk phos normalization, which has become a really important marker of disease activity in – in patients with PBC.  And it's really – we've shifted our goals to – in terms of treatment goals to try and get alkaline phosphatase levels down to normal as quickly as possible and as close to normal as possible, especially in patients who are at higher risk. 

And you can see here the alk phos normalization by week 52 was at 16% in the treatment arm.  And then the open label extension starts.  And you can see the alk phos level normalization being sustained.  So this really answers the question of a sustained response in – in – with elafibranor in patients at least up until 100 – week 156. 

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ELATIVE OLE: Change in ALP at Wk 156

So here you can see with the open-label extension what happens to alk phos levels.  So this is just looking at alk phos changes from baseline.  So here, again, in the dark green arm, you can see that the elafibranor arm, alk phos changed from baseline dramatically pretty early on whereas placebo stayed relatively constant. 

And then this alk phos change was sustained.  If not, there – trend to even further lowering in that treatment arm.  And those patients that went to placebo – went from placebo to crossing over into the elafibranor arm, had a similar response with a very quick drop in their alkaline phosphatase levels.  And it - it was sustained throughout the open-label extension. 

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ELATIVE OLE: Change to Total Bilirubin at Wk 156

Here you can see the change in bilirubin levels.  Again, slight decrease in bilirubin levels in the treatment arm at the double-blind, placebo-controlled part.  And then those patients that crossed over, here at week 104 or 52 for the crossover arm, there is an increase in – in – hold on.  I'm going to have you come back on for a second because there's an error in this slide. 

Jacqueline Meredith: Yeah, what error do you see? 

Dr.  Kumar: So here it says alk phos change from baseline, but it should be bilirubin. 

Jacqueline Meredith: Okay.  Yeah.  Let me – and I can cross-reference the graph to make sure.  But yeah, I'll make that change. 

Dr.  Kumar: Okay.  Yeah.  So I'm just – I'll just start off over on that side.  So I can keep going, right?  We don't need to change it right now. 

Jacqueline Meredith: You can keep going. 

Dr.  Kumar: Okay.  So then here looking at the open-label extension arm with regards to bilirubin level, you can see here, on the left, the bilirubin level was slightly increased in the placebo arm during the double blind, placebo controlled section of the – of the trial.  Whereas in the treatment arm there was a slight decrease in bilirubin. 

In the patients who had continuous elafibranor that reduction – that bilirubin level was sustained throughout week 156.  And those patients that crossed over from placebo into elafibranor in the open-label extension had also a decrease in their bilirubin. 

At week 52, for the crossover arm, there is a – is an increase in – in bilirubin.  But you can see that the range is very big.  And just to note that there are very – there not that many patients in this arm.  So this will be important to just follow through – through 156 weeks. 

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          ELATIVE OLE: Improvement in Itch in Participants With Moderate-to-Severe Pruritus at Wk 156

So one of the things about PBC that's also important is – is symptom burden.  And we know that pruritus is an important symptom in patients with PBC.  And it can really be life altering and it can be very disruptive to patients.  So this is looking at the change in different itch scores. 

So in the – in the primary trial, the ELATIVE trial looked at PBC worst-itch NRS score, the 5-D itch score and the PBC-40 itch domain.  And here this is – this was also assessed through the open-label extension.  And here you can see the trend down in the all three different measures of – of pruritus of itch in our – in the patients.  And then similarly in patients that crossed over, there was a decrease in their scores as well. 

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RESPONSE: Seladelpar for PBC

So let's move on and talk about the other drug that was approved recently for PBC.  So this is seladelpar.  So seladelpar was approved based on the RESPONSE trial.  So the RESPONSE trials is a double-blind, placebo-controlled, randomized phase III trial, that was followed by open-label – an open-label study as well, similar to elafibranor.  So their open label study is the ASSURE study. 

They had similar criteria for entry into – into the RESPONSE trial, people with PBC and an inadequate response or intolerance to UDCA.  Alk phos level had to be at least 1.67 times the upper limit of normal.  AST/ALT had to be less than or equal to 3 times the upper limit of normal.  Bilirubin, 2 – less than or equal to 2 times the upper limit of normal. 

There were 193 patients.  They were randomized to seladelpar 10 milligrams versus placebo, and they were stratified by alk phos levels greater than or equal to 350 or less than 350.  And then also stratified by their NRS score greater than or equal to four or less than one. 

So their – their primary trial was for one year.  So 12 months.  And then again the open-label ASSURE study.  Their primary outcome was a biochemical response.  And it was the same composite score.  So alk phos level less than 1.67 times the upper limit of normal, a decrease of at least 15%, and normalization of bilirubin. 

Your secondary endpoints included alk phos normalization and change in pruritus NRS scores.  And their current – the current subgroup analysis that we'll be talking about today are the change in biochemistries among patients with cirrhosis.  So higher risk patients.  We want to make sure not only is it safe in this patient – these patient population – this patient population, but we also want to make sure that it works as well because these are the patients that probably need second-line treatment more than anyone. 

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RESPONSE: Participants With Cirrhosis

So these are the participants with cirrhosis.  So the way they determined whether a patient had cirrhosis, they had to meet at least two criteria for cirrhosis.  And you can see the criteria on the graph on the – on the bottom.  None were based on laboratory findings alone.  And you can see the percentage of patients in the seladelpar and placebo arms, that – of how they met the criteria for cirrhosis per protocol.  14% in the seladelpar arm had cirrhosis and in the placebo arm as well. 

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          RESPONSE: Change in ALP at Mo 12

So here we can see the change in alkaline phosphatase at month 12 in patients with cirrhosis.  And what it shows is that there were significantly higher alk phos reductions with seladelpar versus placebo regardless of the presence of cirrhosis.  So cirrhosis or degree of fibrosis really doesn't seem to have an impact on efficacy in patients who are prescribed seladelpar. 

So here you can see on the left, the alk phos levels in patients with cirrhosis slightly increased throughout the course of – the one year course of the trial.  Whereas in the – in patients with cirrhosis, the alk phos decreased by 121.4 units per liter. 

In patients with – without cirrhosis, we saw very slight decrease in – in the placebo arm of 18 units per liter in alkaline phosphatase levels, whereas in the seladelpar arm it was a decrease of 134.8 units.  So very similar degree of impact with seladelpar, regardless of the patients having cirrhosis or not. 

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RESPONSE: Change in Total Bilirubin at Mo 12

Here you can see bilirubin levels.  Total bilirubin was stable among participants with or without cirrhosis.  Here you can see in patients with cirrhosis what happens to the bilirubin and here in patients without cirrhosis. 

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ASSURE: Seladelpar for PBC

Now their long-term efficacy – sorry, I'm going to start over.  So as I mentioned earlier, ASSURE was the long-term, open-label extension study for seladelpar in patients with PBC.  And this was actually a pooled analysis from the ongoing open-label phase III ASSURE – I'm going to start over again. 

So as I mentioned, the ASSURE study is the long-term, open-label extension study for seladelpar in patients with PBC.  Patients who were invited to participate in the study were those who were in the RESPONSE study.  So those can – those patients could continue on into the ASSURE study. 

But they also offered enrollment into their long-term, open-label extension study to patients who had participated in the past in some of these legacy studies.  So they – the patients that were offered from the legacy studies, they had to have an AST/ALT that was less than or equal to 3 times the upper limit of normal.  Bilirubin less than or equal to 2 times the upper limit of normal.  Meld score less than 12, and no evidence of advanced PBC. 

So similar inclusion criteria to what we saw in the RESPONSE study.  So if they would have met criteria to be included in the RESPONSE study, they were also offered enrollment into ASSURE.  But they did have a gap because these legacy studies had closed.  They did have a gap before they were enrolled into the study, whereas the patients in the RESPONSE study were just continued on. 

Primary endpoint was a composite biochemical response, same as the RESPONSE study.  And then other endpoints that they looked at included alk phos normalization and liver biochemistries. 

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ASSURE: Baseline Characteristics

So here are the baseline characteristics of patients in the ASSURE study.  So again this is the legacy patients and the RESPONSE patients.  Mean age was 58.  Majority were female.  Here you can see the distribution of race and ethnicity with white being the most predominant.  Mean BMI was 27.  Those – 16% had cirrhosis at baseline with majority of being Child-Pugh class A. 

The mean alkaline phosphatase level here was 287.  Mean bilirubin was 0.8.  And the mean NRS score was 6.3 in patients who had a score of at least 4. 

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ASSURE: Composite Biochemical Response and ALP Normalization at Mo 30

Here you can look at the composite biochemical response.  So this is over 30 months of the study.  And you can see that the percentage of patients that achieved the biochemical response, that composite response was sustained throughout the open-label extension.  And then same thing with the alk phos normalization.  So through month 30, you can see a significant amount – number of patients had achieved alk phos normalization. 

And this becomes really important as we – as I – again, I mentioned that we are really striving to achieve alk phos normalization in our patients or at least getting the alk phos as low as possible. 

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ASSURE: Change in ALP and Total Bilirubin at Mo 30

So here we can look at the change in alkaline phosphatase and total bilirubin at month – at month 30.  So alk phos improvement after one month.  Here again we see a very quick response, which is really nice to see.  We can get patients alk phos levels down quickly as possible.  And then this is sustained throughout the 30-month ASSURE trial.  And then same with bilirubin.  We see a slight decrease in bilirubin.  And this is also sustained. 

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ASSURE: Change in Pruritus NRS at Mo 6

And I think it's really important with both of these studies that we see these long-term effects so that patients are reassured that this is not a temporary response.  And we, as providers, are – are reassured that this is not a temporary response. 

Okay.  So they looked at change in pruritus in the NRS score at month six.  So this – in patients with baseline and moderate to severe pruritus, you can see here the change in NRS score.  It went down to – I'm going to start over. 

So here is the change in pruritus by NRS score at month six.  So among participants with a baseline moderate to severe pruritus, the mean NRS change was 3.3 decrease.  You can see – you can see here it's a pretty early response.  But even at month – month six, there is still a trend towards more improvement. 

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          Posttest 2

This is the post question – posttest question number two.  Your colleague asks about long-term use of seladelpar for PBC.  You advise them that in the ASSURE study, compared to the placebo arm at 130, those in the seladelpar arm had:

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          Posttest 2: Rationale

The answer is A.  Sustained biochemical response in alk phos normalization.  So in the ASSURE trial, which was a trial for seladelpar versus placebo in patients – in people with PBC, at month 30, those in the seladelpar arm had sustained biochemical response and sustained alk phos normalization. 

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          Key Take-home Points

So I think – you know, I tried to highlight the – the important take home points throughout the – the different studies as we talked about them.  But just to bring it full circle, you know, there are new medications that are approved for PBC.  And these – it's a very excited – exciting time, as providers and as patients to help get patients disease under control and symptoms under control. 

But we want to make sure that these medications are appropriate.  They're safe and they have long-term effects in our patients.  So I think the biggest highlight is that we have now longer term data beyond the one year trials for both elafibranor and seladelpar that show that the effects that we see in the 52-week weak arm or the one-year arm of the trials are sustained throughout longer term – longer term studies. 

And we didn't really talk about as much about safety.  But at least in the higher risk patients, it – the patients with cirrhosis, seladelpar is very well – well, it is well tolerated.  But also just as efficacious in – in patient as – in patients without cirrhosis.  And then from a – point from elafibranor, the composite scores of the GLOBE – GLOBE score and the UK-PBC score show that even beyond just looking at lab parameters, we can hopefully impact patients transplant free survival. 

And that is it.  Thank you so much for joining. 

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          Go Online for More CCO Coverage of PBC!

You can go online for more Clinical Care Options coverage of PBC.  There are medical minute modules, ClinicalThought commentaries and podcasts on key updates and downloadable slide sets to share with your colleagues. 

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          Poll 2

So poll question number two.  Do you plan to make any changes in your clinical practice based on what you learned in today's program? 

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          Poll 3

Poll question number three.  Please take a moment to text in one key change that you plan to make in your clinical practice based on this education? 

Thank you. 

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