Good day, and thank you for standing by. Welcome to the Pliant Therapeutics INTEGRIS-PSC Phase 2a Trial Results Conference Call. At this time, all participants are on a listen-only mode .
After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised.
To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I'd now like to hand the conference over to our speaker today, Christopher Keenan, Vice President of Investor Relations. Please go ahead.
Thank you, Shannon. Good morning, everyone.
Thank you for joining us for Pliant's presentation of top-line data from the INTEGRIS-PSC trial, our Phase 2a clinical trial evaluating bexotegrast, previously known as PLN-74809, in patients with primary sclerosing cholangitis. The press release that we will be referencing today is available under the Investors and Media section of our corporate website. A replay of this event and the slides accompanying this webcast will be available in the same section of our website following the conclusion of this call. During today's call, we will be making forward-looking statements, including those related to the therapeutic potential of bexotegrast and our plans for its future development. Because forward-looking statements relate to the future, they are subject to inherent risks and uncertainties that are difficult to predict and many of which are outside of our control.
Important risks and uncertainties are set forth in our most recent public filings with the SEC, which are available at sec.gov. Pliant undertakes no obligation to update any forward-looking statements, whether as a result of new information, future developments, or otherwise. Joining me with prepared remarks are members of our management team, Dr. Bernard Coulie, President and Chief Executive Officer, Dr. Éric Lefebvre, Chief Medical Officer. Pliant team members will be joined by Dr. Gideon Hirschfield, the Lily and Terry Horner Chair in Autoimmune Liver Disease Research at the University of Toronto and an investigator in the INTEGRIS-PSC trial. Dr. Keith Cummings, Pliant’s Chief Financial Officer, Dr. Richard Pancewicz , Pliant Senior Director of Clinical Development, and Dr. Christopher Barnes, Pliant’s Head of Biostatistics, will join us for the question-and-answer session. With that, I will turn the call over to Bernard.
Thank you, Chris. Good morning, everybody, and thank you for joining us. It's a pleasure for my colleagues and me to share with you today the compelling data that we announced this morning from our INTEGRIS-PSC Phase 2a clinical trial of our lead asset, bexotegrast. Just to remind you, bexotegrast is an oral small molecule, dual selective inhibitor of alpha v beta 6 and alpha v beta 1 integrins, that is currently in development for patients with idiopathic pulmonary fibrosis and patients with primary sclerosing cholangitis. The results that we are sharing with you today from INTEGRIS-PSC have surpassed what we expected to see in a trial of this size and duration. As many of there is no medication proven to be effective in the treatment of PSC, a chronic, debilitating, and often fatal disease.
To date, bexotegrast has been dosed to over 600 human subjects, including healthy volunteers and patients with IPF or PSC, with no safety concerns. Turning now to this morning's news. Eric will begin with an overview of the INTEGRIS-PSC trial and then review the trial's findings, including the achievement of the primary and secondary endpoints. He will then discuss the encouraging findings from the exploratory endpoints of the trial. Next, we will hear from Gideon on his thoughts on these results before I conclude with next steps and closing thoughts. Today's data is a major step forward for the program and further validation of the bexotegrast franchise. With these data, bexotegrast has shown meaningful antifibrotic effects across multiple tissue types and organs, as well as in two diseases. This provides further evidence that localized tissue-specific inhibition of TGF-beta blocks the common pro-fibrotic pathway seen in multiple fibrotic diseases.
We are very encouraged with today's results as they build on validating the antifibrotic activity of bexotegrast and present a potential opportunity for a new treatment for what is a devastating disease for which there have been no effective therapeutic options. I will now turn the call over to Éric. Éric?
Hello. Thank you, Bernard. Excuse me, I had to unmute myself. Do you hear me okay?
Yes.
Perfect.
Thanks, Eric.
Let's start by reviewing the INTEGRIS-PSC study design and how it differs from previous PSC trials. To our awareness, this is the first randomized clinical PSC trial enriched with patients having suspected liver fibrosis. This enrichment strategy was selected to identify patients with active fibrogenesis and therefore increase the likelihood of detecting antifibrotic effects over a 12-week treatment period. To be eligible, patients needed to be at risk for moderate to severe fibrosis based on ELF score and/or liver stiffness thresholds or historical biopsy, if available. Essentially, patients with mild or no fibrosis were excluded from this study, while those with cirrhosis were ineligible, leaving with patients that were at risk for moderate to severe fibrosis. The primary and secondary endpoints were safety, tolerability, and PK. Exploratory endpoints included change in circulating liver fibrosis markers such as ELF and PRO-C3, liver biochemistry, and MRI imaging.
Today's presentation focuses on the first week 12 interim analysis of the study, where bexotegrast daily doses of 40, 80, or 160 milligrams were compared to placebo over a 12-week treatment period. Slide 5. Now, I'll start with the key findings of this study. Bexotegrast was well tolerated over 12 weeks of treatment in these patients with PSC. The adverse event rates that we saw were comparable to placebo, with all drug-related treatment-emergent adverse events being mild or moderate in severity. There were low rates of discontinuations due to adverse events and no treatment-related serious adverse events. Patients with IBD experienced no clinically relevant changes in their IBD symptoms, and bexotegrast total and unbound plasma concentrations increased with dose. Bexotegrast demonstrated antifibrotic activity in a PSC population with suspected moderate to severe liver fibrosis.
All doses reduced ELF scores relative to placebo, with a statistically significant difference for 160 milligram. Interestingly, the 160 milligrams also achieved statistical significance at week 12 across all components of the ELF score listed here. All doses reduced collagen synthesis marker PRO-C3 relative to placebo, with a statistical significance at the 160 milligram dose. Additional findings from our study, MRI imaging analysis suggested improved hepatocyte function and bile flow relative to placebo at week 12. Liver biochemistry markers, including alkaline phosphatase, were improved relative to placebo at week 12, and we saw dose-dependent reduction in itch with statistical significance at the 160 milligram dose relative to placebo at week 12. Slide 6, participant disposition. So we screened 179 patients for this study and enrolled 85 study participants.
We had a 3-to-1 randomization ratio, and had 64 patients that were treated with bexotegrast compared to 21 treated with placebo. So we'll be describing the safety population in this analysis. We see that we have very few patients that discontinued treatment and that the large proportion of our patients were receiving concomitant UDCA. Slide 7. Speaking of baseline demographics. So we saw no notable differences in baseline demographics across the treatment groups. At baseline, the mean age for all participants was 45 years old, 75% were male, 65% had IBD, and 65% received concomitant treatment with UDCA. In participants with IBD, the disease was stable, as evidenced by the low Partial Mayo scores, and patient-reported itch severity was mild, as assessed by the Itch Numerical Rating Scale. Slide 8.
No notable differences were observed in baseline disease activity markers, except for higher alkaline phosphatase levels in the 40-milligram group. Mean ELF scores and liver stiffness by FibroScan were 9.4 and 9.0 kPa, respectively, indicating a population at risk for suspected moderate to severe fibrosis. Slide 9, for the safety summary. Bexotegrast was safe and well-tolerated over 12 weeks of treatment, with low discontinuations due to treatment-emergent adverse events and no drug-related serious adverse events. Most treatment-emergent adverse events were of mild or moderate severity, and Grade 3 or higher treatment-emergent adverse events were not related to bexo and associated with underlying biliary disease, including events of cholecystitis and cholangitis, which are common in this patient population. Slide 10, reviewing the most frequent treatment-emergent adverse events.
The incidence of TEAEs was generally comparable between Bexo and placebo, with the exception of fatigue and nausea. Most events of nausea were transient, mild in severity, and deemed unrelated to study drugs. Fatigue was also mild to moderate in severity. It's a common symptom in PSC and has not been frequently reported in trials of Bexo. Interestingly, TEAEs of cholangitis, a common complication in PSC, were less frequent with Bexo than placebo. Slide 11, reviewing serious adverse events. There were 2 serious adverse events in our study on Bexo. None were related to treatment. The first one was a patient receiving 40 milligrams, who had a Grade 3 events of cholecystitis, abdominal pain, and pancreatitis, and these events all occurred 4 weeks after the last dose of study drug.
And the pancreatitis was deemed to be related to an ERCP procedure and not related to drug, and the second patient received 80 milligrams, had a grade 3 event of cholangitis that was hospitalized but recovered and resolved and was not deemed to be treatment-related. Slide 12. Now looking at treatment adverse, treatment emergent adverse events leading to withdrawal of study drug. So no obvious pattern was seen here. One patient with COVID at the 40 milligram group, a patient at the 80 milligram had a grade 1 hepatic enzyme increase, and then a patient on 160 milligrams that had grade 2 fatigue. So in all these cases, the drug was resolved and the outcome, the patients completely recovered. Now we'll move on to slide 13, which describes the antifibrotic properties of bexotegrast in this study.
We'll first start with the ELF score, and we're looking now at the change from baseline to week 12. What you see is that bexotegrast reduced the ELF score relative to placebo at all doses, with statistical significance at the 160 mg dose. The dashed line you see on the figure represents a change of 0.19, and that is a threshold that has been derived from a simtuzumab study, where a change of that magnitude or above that magnitude at 12 weeks was able to predict clinical progression within 2 years. Importantly, when we look at the relative change from placebo, the 160 mg group showed an 80% reduction. Now we'll move to slide 14, which has the three components of the ELF score, the TIMP-1, P3NP, and HA.
Again, we see very strong effects for the bexotegrast group, with the 160 milligram showing statistically significant differences across all three components compared to placebo. We'll move to slide 17, which describes PRO-C3, collagen synthesis marker. In this study, we saw a continued increase in PRO-C3 in patients treated with placebo, reflective of active fibrogenesis, what we had seek to find in terms of patients for our study. And this increase was attenuated by bexotegrast treatment, with statistically significant differences at week 12 for both the 160 milligram and the 40 milligram dose.
We'll move to slide 18, which has the itch numerical rating scale, and looking again here at the change from baseline to week 12, and we see that bexotegrast showed dose-dependent reductions in itch relative to placebo, with statistical significance at the 160 milligram dose. So in summary, on slide 19, bexotegrast demonstrated a favorable safety and tolerability profile in the PSC patient population with suspected moderate to severe liver fibrosis. Bexotegrast showed anti-fibrotic activity based on ELF and PRO-C3, with statistically significant differences relative to placebo observed at week 12 for the 160 milligram dose. Liver biochemistry and imaging parameters were improved relative to placebo at week 12, and dose-dependent changes in itch numerical rating scale at week 12, with statistical significance at the 160 milligram dose.
Finally, the 320 milligram 12-week data are expected in Q1 of 2024, with a 24-week, 320 milligram data in mid-2024.
Éric, would you mind covering also alkaline phosphatase and MRI in more detail? Because those slides, I think you skipped.
I think so. Apologies for that. So in our,
Slide 16 first.
Yes, I'm sorry for that. It skipped. So slide 15 will review the change in baseline to week 12 in terms of alkaline phosphatase. You see that there was a dose-dependent trend in reduction of alkaline phosphatase in patients that had elevated values at baseline. That was in contrast to placebo. And on slide 17, this is the MRI imaging we used in our study that used a gadoxetate contrast agent. And what we see here on the left-hand side is the increased enhancement of MRI in patients treated with bexo and a decreased enhancement in patients on placebo, suggesting improved hepatocyte function.
On the right hand of the slide, it's the time to arrival to the common bile duct of the contrast agent, and all doses reduce the time to arrival to the common bile duct compared to placebo, in contrast to placebo, where we saw an increase in the amount of time needed for that, suggesting improved bile flow. And with that, I'll pass it over to Dr. Gideon Hirschfield, who will talk about his interpretation of the study results.
Good morning, everyone, and thank you, Bernard, and thank you, Eric. As a clinician, I'm really thrilled to be here. It's a great way for me to start a clinical day at work. I spend much of my time looking after patients with PSC and really appreciate significantly the unmet need for these patients. I therefore want to thank the trial participants and the sponsor of this trial. I listened carefully to the data just released. For me, I want to highlight how I look at these Phase IIa results. I believe when I comment, my thoughts match how others will also likely think, and we all look forward, of course, to further analysis by Pliant. So first and foremost, I think the unmet need is huge in this disease.
Secondly, I'm really thrilled to see the patient willingness to take part in clinical trials and to see that the sponsor can recruit a representative population of patients with great unmet need. Thirdly, I think it's really important to understand the innovations that we're going through in development of clinical trials in PSC, and this study itself has some innovations. It's the first trial, I believe, to really look at enhanced inclusion criteria, enhancing for the presence of fibrosis. And I think this is highly relevant when we then think about interpreting the data, because we have to apply the trial inclusion and relate that to the mechanism of this particular drug, which, as we know, is an oral integrin inhibitor, which we hope will be inhibiting TGF-beta and will be antifibrotic.
Then naturally, as a clinician and a patient advocate, I'm looking at safety first, and I'm thrilled that, we see absolutely very reassuring data on safety in the time frame studied. And that safety is relevant both from a liver perspective and from an IBD perspective, as of course, everyone will know that patients living with PSC also have got concomitant inflammatory bowel disease. Then, of course, I'm also interested to look at efficacy, recognizing this is a phase 2a study. And what I do is I look to see consistency across different signals from different measures of the mechanistic intent for this drug.
So I'm pleased to see the data for ELF, PRO-C3, and MRI are all providing insights that oral integrin inhibition has the clear potential to move the stubborn needle of fibrosis in PSC. I think we know that surrogate endpoints are difficult in PSC, but we're all clear that ELF is a prognostic marker in patients living with PSC. And there's emerging data on how to use the ELF score in both clinical practice and clinical trial design. Finally, of course, I also take a helicopter view and recognize that this drug is in development for other conditions which are fibrotic, and therefore, when I see the efficacy data presented today, I'm pleased to see that it has parallels to the data presented for other fibrotic disease.
So overall, I really am very pleased that Pliant has released this data today, and I'm happy to address any questions relevant to myself at the end of this webcast. I'll hand back to Bernard for further comments.
Thanks, Gideon, for sharing your thoughts. As you heard today, the team and I are extremely pleased with these data as they mark another step forward in Pliant's development of bexotegrast as an innovative approach to addressing the unmet needs of the PSC patient. Finally, I want to leave you with a couple of conclusions and next steps for the program. So I think it's safe to say that bexotegrast has the potential to become a broadly applicable antifibrotic. There is now growing evidence that localized TGF-beta inhibition has the potential as a backbone antifibrotic, with tissue-specific TGF-beta inhibition, avoiding the systemic toxicities while maintaining the antifibrotic effect, as we have seen now in our phase II studies, both in IPF and PSC. We continue to see a favorable safety and tolerability profile with bexotegrast.
As mentioned before, it's well tolerated in over 600 participants across multiple different patient populations. Finally, it shows the potential to treat fibrotic diseases across multiple organ systems. We have seen that effect has been observed across multiple exploratory endpoints and biomarkers, both in IPF and now again in PSC, including ELF, including MRI imaging, and also including HA. Bexotegrast is well-positioned to expand into multiple indications across pulmonary and liver fibrosis. We would like to thank our INTEGRIS-PSC investigators and their study teams for their dedication and support of the successful execution of this trial. Special thanks to the INTEGRIS-PSC clinical trial participants, their families, and support networks for helping us advance this promising program. With that, let's open the call to questions, Chris.
Shannon, you can now open the call.
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is now open.
Hi, this is Joanne for Brian. Congrats on the strong data, and thank you for taking our question. Certainly a robust set of data showing safety and antifibrotic efficacy of bexo. Can you talk a little more about how much correlation you're seeing around the target engagement or degree of TGF-beta suppression or exposure levels that they can further support bexo's safety profile in IPF?
Eric?
So, Brian, just your question is related to IPF or PSC?
In PSC and IPF as well, and how much correlation you're seeing at those molecular levels?
Yes. So we have shown it's a little bit easier to show target engagement in the lung than in the liver. And as we've conducted a PET study showing that we get near saturation of alpha V beta 6 in lungs with IPF patients with our compound. We've also shown the ability for the drug to reduce TGF-beta activation in the lungs of healthy volunteers. So this is because of the way we can sample the lung is much different than what we could do with the liver. We are, in terms of target engagement, we have done preclinical work and precision cut slices work in animal models, also tissue explants from patients with PSC and PBC, and continue to see these antifibrotic properties being manifested in those models.
We have not been able to have a clear way to assess target engagement in the liver, but we know that the drug concentration, because it's metabolized by the liver, is about 3- to 5-fold higher in that organ compared to the lung.
Got it. That was super helpful. Thank you, and, congrats on the data again.
Thank you. Our next question comes from the line of Yasmeen Rahimi with Piper Sandler. Your line is now open.
Hi, this is Emma on for Yas. Thanks for taking our questions. First ones are for Dr. Hirschfield. How do you think the consistency of data predicts one-point improvement of fibrosis in future studies? And with that, how do you think the 320 mg dose group at week 24 will perform?
Well, that's a great question. Clearly, we'll have to wait and see the data next year for 320 milligrams. And also, I think, what you're asking is: how do serum markers of fibrosis translate to liver histology? So that data, to my knowledge, is not clear. I think that the effects that we're seeing are consistent with an antifibrotic effect. I think that's consistent with what would derive ultimately patient benefit. I think the current trial design for Phase 3 clinical trials in PSC is wedded to liver histology, but I think the academic community is questioning whether this is the best approach to developing drugs in PSC.
So, I'm not sure that for forever and a day, liver histology will be the endpoint in phase 3 clinical trials in PSC, but I don't know whether the academic community can change that, but certainly that is the intent of the academic community. So, to directly answer, I don't think we can correlate, but what we can say is that it looks promising, it looks consistent with drugs before. So for where this drug development is at, this is very positive news.
Thank you very much. And then next is for Pliant. Could you please provide a bit of color on what you're thinking about next steps in PSC, regulatory landscape, et cetera?
I can take this question. This is Eric. So in terms of, as we mentioned, the 320 milligram interim analysis will be important set of data, and we will engage with the regulators once we have that set of data. We plan to do that to start discussing the late-stage development program. And currently, I can just share that we're-our position is that we're likely to move to a late-stage evaluation that includes histology. Obviously, this is the regulatory precedent right now, so we are taking that approach. Maybe just pointing out that some of the differences that have been used in PSC relative to other liver diseases in PSC is the prevention of worsening of fibrosis stage that is used and not the improvement by one fibrosis stage.
That's in contrast to NASH. So when we look at, maybe dovetailing on the previous question, the fact that we can attenuate fibrogenesis with our compound suggests that there is a likelihood that we would be able to prevent progression. Obviously, the late-stage development will need to teach us that, but in essence, this, these data are very compelling in that sense. And the other aspect that we are contemplating in our, our late-stage evaluation would be also to combine with biomarkers that are relevant to the mechanism of action, and these would, for example, be ELF, similar to what we've shown in our study today.
Thank you very much.
Thank you. Our next question comes from the line of Ritu Baral with TD Cowen. Your line is now open.
Good morning, guys. Thanks for taking the question. I wanted to ask about any trends that you might have seen in any sub-analysis based on background UDCA, either on biomarkers or especially the fatigue and pruritus tolerability signals that you saw there start with that.
Thanks, Ritu. So I can take that, and Eric again. We have done subgroup analyses as part of the pre-specified statistical analysis plan, whether patients were receiving URSO or not receiving URSO, and really overall, there was not much difference whether patients were using URSO or not for all of these endpoints. So directionally, everything was as we presented today for the overall group.
Got it. A question for Dr. Hirschfield. The gadoxetate enhancement on slide 17, the MRI. We're not really familiar very much with what that actually means as far as aspects of hepatocyte function. Could you tell us specifically what that data means tells you about how happy the hepatocytes are?
Sure. And I think I can, and Eric can also chime in, but I think it's really interesting and really important, and I'm very grateful for Pliant including a functional MRI readout in the study so that we can see that data on top of the safety and the fibrosis markers. So as I understand it, I mean, this is a test that could be applied more applicably 'cause it's a contrast agent that we use in clinical care. And you can see two things, that with drug exposure, the hepatocyte seems happier and that the time of arrival to the common bile duct is also improved. So this is still a research readout.
This readout is not used in clinical practice, but it's very consistent with a therapeutic agent that is offering the liver and the biliary tree therapeutic improvement. I think Éric can probably comment more about the sub-study, 'cause it was only a sub-study in a smaller number of patients, Éric.
Thanks, Gideon. So Ritu, we did this sub-study to evaluate whether there was a possibility of improving the bile flow with bexotegrast treatment, potentially due to, fewer strictures in the bile ducts. This is something that at least this thought came when we saw the preclinical data. So if you recall, we did we studied bexotegrast in the MDR2 knockout model, which is the most standard primary or secondary cirrhosis model, if you wish. And we also had a DDC diet-induced model. In both of these, we saw that at the high doses tested, we saw decreases in ALP and total bilirubin, which we couldn't really explain by our mechanism, and we thought that there was a possibility that maybe we're seeing the bile duct open up.
That could be, for example, a reason why you see at the time to arrival to the common bile duct being shorter with bexotegrast. And if there's more flow and less backup, you could also imagine that potentially the hepatocyte might be better protected against, the damages that are caused by this cholestasis. So these are , this is purely exploratory, as we talked about, but certainly very intriguing results.
Understood. And final question, actually, probably for the both of you as well. When we've spoken to other doctors in the PSC landscape, they didn't really have any flattering things to say about the biopsy scale, and the qualifiers for moving up and down that scale and reader variability. Éric, could you walk us through, like, the, I guess, architectural features of the different stages within PSC as we think about histopath? And Dr. Hirschfield would love your opinion on the usability of that scale from a regulatory perspective or feasibility perspective, really.
I can start, Ritu. So in essence, I mean, there are different staging systems that are used for PSC, and those differ slightly from what's been used in NASH, but in essence, they all come to the same overall classification, which is no mild, moderate, severe, or severe fibrosis or cirrhosis. I think the challenge for PSC, and surely Gideon has more to share on that, but it's really about the fact that the disease is really in the bile duct, and then it damages the liver sections that are connected to these bile ducts. So the fibrosis in PSC tends to be patchy, and that's how it's described by most thought leaders in the field.
The challenge with that is that that can increase sampling variability, and this is why in Phase III studies or late-stage studies, we would definitely wanna complement the histology results with biomarkers that are relevant to the mechanism of action, because we would expect that to also be, telling a story in terms of the benefits that patients could derive. But I'll pass it on to Gideon for more color.
I think what you've hit on is the fact that, in clinical practice, we don't use liver biopsy routinely, and its use in clinical trials is a historic thing that gives comfort to regulators, 'cause conceptually, it should be a good endpoint. But, we've learned in many liver diseases, but PSC in particular, that it really is not a gold standard at all. And I think it's fair to say that the academic and clinical community is set on generating the evidence to show that biomarkers, be they blood biomarkers, elastography biomarkers or imaging biomarkers, need to be the way forward for getting a drug approved for, particularly for PSC, given its unmet need and given its slow progression.
And to Eric's point, biopsy is variable because of what the nature of the disease is variable, where the biliary injury can vary. And then on top of that, we know that, using classical, essentially pathologist review, with the best will in the world, there's variability between pathology when they read it, and we don't yet have automated AI or, very significant data on collagen proportionate area. So I don't discount the fact that biopsy is prognostic. I don't discount the fact that, in theory, biopsy sounds like a good endpoint for clinical trials.
But I think the data that we're learning from other trials that have been presented, like there was a presentation from Professor Trauner at EASL from a Gilead study, just demonstrates that we need to move beyond biopsy. And I think that's the reason why this particular study is important, not only because of its efforts to enrich the population, but also, its efforts to use other biomarkers such as ALP and PRO-C3 and other data to emerge, no doubt, to assess efficacy.
Very helpful. Thanks, everyone. Dr. Hirschfield.
Thank you. Our next question comes from the line of Jeff Jones with Oppenheimer. Your line is now open.
Thanks, guys, and congratulations on the data. Two questions. I believe in the enrollment criteria, you looked at liver stiffness scores, and I wanted to see if I missed it, if you had seen an effect there. Then the second question was, for those who look at other diseases of liver fibrosis, where ALP is a more relevant biomarker, can you just remind us why it's less relevant in that—this case? Of course, you do also show a dose-dependent effect here and speak to that. Thanks.
Thanks for your question, Jeff. This is Eric. So first, we didn't show the transient elastography data just because the changes were minimal and also within the variability seen with that, that method. And so, no, no big findings there as we expected that, over that short treatment period, we shouldn't expect to see any meaningful change in transient elastography. And the second question, maybe I'll pass that over to Gideon.
So I think that, you're asking about the utility of alkaline phosphatase in clinical trials in PSC. So unlike primary biliary cholangitis, where alkaline phosphatase really is an excellent surrogate of efficacy, certainly in short phase studies in PSC, alkaline phosphatase is challenging. So alkaline phosphatase is prognostic in primary sclerosing cholangitis, but the delta over the short timeframe of relevant clinical trials in PSC is less so. And that's because the nature of the disease, the medium to large bile inflammation, means that we will see fluctuations in alkaline phosphatase. So when I look at this data, I'm really not homing in on alkaline phosphatase as the first signal to look at. I mean, I'm obviously interested.
I look forward to seeing the data presented by Pliant on all the liver biochemistry, but it really is a low priority marker in this setting because of the mechanism of action, which is a drug that is targeting the, fibrogenesis and fibrosis. So it's not an expectation. And on top of that, the variability of alkaline phosphatase has really challenged its primacy in clinical trials for primary sclerosing cholangitis.
Appreciate that. Thank you very much.
Thank you. Our next question comes from the line of Eric Joseph with JP Morgan. Your line is now open.
Hi, good morning. Thanks for taking the questions. We have a few. First, on, I guess what's interesting is the sort of the, what's the seeming signal of progression on a couple of the biomarkers, ALP and, and PRO-C3 change in the placebo group. Was that anticipated? It seems to be a little bit higher than sort of comparator studies, particularly with seladelpar. And then a couple in relation to the, the MRI sub-study. I'm curious as to whether patients participating in that subgroup analysis were biased in any way, based on their tolerability or change in biomarkers. Is there a plan to sort of get a more comprehensive participation in the 320 milligram cohort? And then perhaps for Dr.
Hirschfield, is there a way to think about those data, the gadoxetic acid enhancement as sort of a function of normalization? Is there an understanding, I guess, of what a normal read on bile flow would look like and how these data, these enhancements sort of compare as a function of normal flow? Thank you.
So, Eric, I can take the first question. Eric again. So in terms of the increases in PRO-C3 levels that we saw, so this is the second phase 2 trial where we've seen these effects that have been reported. The previous one was NGM. I think it's important to mention that the trials had different aspects in terms of who was let into the study. We know that, for example, we talked about our screening strategy to enrich for patients with fibrosis. That was not an approach that was taken by NGM, and certainly the PRO-C3 levels seem to be relatively stable. Although we did see an increase in placebo for PRO-C3 in that study as well.
That was maybe of a lesser magnitude in our study, but that could explain also the fact that we've enriched with patients with suspected fibrosis. would explain also why increases in PRO-C3 in our placebo group might be a little bit higher. So in essence, I think these are, these data are certainly novel and this is the first time that we study a at-risk population in PSC patients, which is could explain these differences across the different studies. And then your second question was on was on the MRI imaging. So this was, really keeping in mind that this is a randomized controlled clinical trial. So we have, we have placebo control, so there's no way for patients to know what active, whether they're on active or placebo.
So we don't think that biased the participation of patients in this study. In fact, we were quite surprised by the high number of patients agreeing to do this method because it does, it's more burden on the patients. Obviously, they need to not only go to their study visits but also undergo an MRI. So it's quite a lot of time at the clinic. We'll see what the 320 milligram brings, but certainly we're looking forward to see the results because this part of the study, the substudy, is still active with the 320 milligram. And maybe I'll pass your next question to Gideon. I think it would be-
So there's a lot to learn from the MRI data over time, and I think, it needs to be interpreted as preliminary. But I would just add a few things to what Eric said. Patients with PSC have an MRI every year. This particular contrast agent is already used in clinical practice, so there's already the ability to translate what we see. there's potential for sponsors to do more of this, these kind of functional imaging as opposed to just static images of what the biliary tree looks like in what is a slowly progressive disease.
The second thing is that there is some data out there around a correlation between some of these markers reported here and overall liver function and other risk scores in PSC. So, I don't see that there'd be necessarily any bias there from a patient perspective. But I do see them as really opening up the opportunity to get an additional marker of efficacy that will supplement and support other data around targeting fibrosis in patients.
Thank you. Our next question comes from the line of Michael Kratky with Leerink Partners. Your line is now open.
Hi, everyone. Thanks for taking our questions. So I know it's early, but what learnings from this phase 2 study would you plan to incorporate in a pivotal phase 3? And then for Dr. Hirschfield, across the data that were presented today, what do you see as the most compelling evidence that suggests bexotegrast could have a clinically meaningful benefit for patients on efficacy?
I'll take the first question, Mike. So, thank you. I think that's a very good question, and I can tell you that when we designed the PSC study, this INTEGRIS-PSC study, the idea of enrichment was not necessarily. There was no consensus on whether we should do it or not. But I think the results from this trial would argue that this enrichment strategy should be considered in late-stage development, especially developing a direct-acting antifibrotic like bexotegrast, that you would want to enrich with patients with suspected liver fibrosis. Obviously, when we do, a biopsy-based study in late stage, we would be able to collect the different stages of fibrosis that are, that are the patients that are enrolled have.
But there's definitely this consideration for enrichment that I think in my mind deserves attention. Pass it on to Gideon for the next question.
Thanks, Éric. So I mean, I think the compellingness comes from the mixture of, clearly no safety signals. And then, what I look at is the ELF score compared to placebo and the components of the ELF score, and the consistency in the differences relative to placebo that we see on top of similar data for PRO-C3. And then, the MRI substudy, although exploratory, gives me a completely independent way of looking at bioactivity of this novel molecule. So, that's how I interpret what is phase 2a data, and that's why, I think it's fair to interpret it, positively.
Understood. Thanks very much.
Thank you. Our next question comes from the line of David Lebowitz with Citi. Your line is now open.
Thank you very much for taking my question. When you look across the data at the various doses, and then you look towards the Q1 update at the highest dose, what takeaways do you think we can have regarding, I guess, expectations for that update?
I can take that, Eric again. So for the 320 milligrams, the reason also why we did the same strategy in our INTEGRIS-PSC study as the IPF study, is we wanted to generate some long-term safety, data at the top dose that's planned for the program. So that's, that was the key consideration. And certainly, we would, we would hope to see, the same type of changes that we've seen with the 160 milligram is not higher. But, I think it's fair to also, to qualify that it's not clear what-- for example, when you look at non-invasive biomarkers, how discriminative they can be for dose selection as well.
So for example, even if we saw some similar findings with 320 milligram at 12 weeks than what we showed with 160, I think that would really bode well for for thinking about these two doses to be considered for phase 3 development. And it's really have to do with, how, how accurate are these markers at being able to detect change? So that's, we know that they can detect change, but how discriminate can be, can they be between two doses? That's not well understood.
Thank you. As a reminder, we ask that you please limit yourself to one question at this time. Our next question comes from the line of Tom Shrader with BTIG. Your line is now open.
Congratulations, more beautiful data. Just a quick one on safety. How different is this safety look? How impaired in liver function are these patients, is kind of what I'm getting at. And then quickly, is this trial over, or are we going to see 24-week data for these patients as well? Thank you.
Thanks for the question, Tom. So we did not enroll any cirrhotics in our patient population, so those are excluded. We also had some criteria that addressed or identified any patients with possible hepatic impairment, which patients couldn't participate if that was the case. So we don't have any patients with hepatic impairment in our study. But we have conducted a hepatic impairment study for the program that doesn't show any meaningful concerns in that patient population. The other point to mention is these dose cohorts were by design treated for 12 weeks, and then patients were exiting the study. The 320 milligram dose is the dose that will go out to 24 weeks and up to 48 weeks.
The long-term evaluation will come from the top dose in our program. The reason why we did this is because at the time that we initiated the 320 milligram cohort, we also had the chronic tox to support long-term dosing and decided to take this approach to provide some meaningful risk-benefit information for late-stage development.
Great. Thank you.
Thank you. Our next question comes from the line of Joel Beatty with Baird. Your line is now open.
Hi, thanks for taking the questions. Two questions for Dr. Hirschfield. One is on the, for regulatory endpoints for PSC, is there any consensus in the academic community on a specific non-invasive endpoint that could be used instead of biopsy? And the second question is, are there other liver indications that appear promising for bexotegrast based on the mechanism in today's data?
Well, good questions. I think for the first part, I think the consensus is clear that the academic and clinical community wants to move away from liver biopsy. I think the consensus is that the top two things that we'd like to study more and get the greatest data are ELF and fibroscan or, and other markers of liver fibrosis noninvasively by MRI. And then to learn about other exploratory functional MR imaging. I mean, so that I think is work in progress.
There's, I'd point out a really huge effort from the patient community to take part in that work, and a huge effort from the patient community to work with the academics to generate the prospective data on top of retrospective data for novel biomarkers to allow us to move beyond liver biopsy in phase three programs. I think it's a broader question around which other liver fibrotic diseases that this molecule would be relevant to, and it's not really my sort of area of expertise. But clearly, all biliary fibrosis is relevant. I don't know the plans, and Pliant can comment if they have any other ideas about liver disease generally.
Thank you. Our next question comes from the line of Joseph Stringer with Needham and Company. Your line is now open.
Hi, thanks for taking our questions. One question for the doc, Dr. Hirschfield, more specifically, how representative are these patients in this phase 2 trial, just in terms of baseline characteristics to the PSC patients that you see in practice? And based on the data today, what I know it's early, but what are some of your thoughts in terms of where the drug could be or could fit into the treatment paradigm? And then the follow-up question is around the ELF score. And I suppose my question is around, you showed the graph with the change in ELF score at week 12. I guess my question is, can you talk about the relative significance of the absolute level?
what was the baseline ELF score for the 160 mg, and the relative importance of the 0.1, 0.19 score change as opposed to what the actual ELF score level is at 12 weeks. And compare and contrast those to the importance of those in terms of a risk of disease progression or development of cirrhosis liver events. Maybe just some more color around that ELF score. Thank you.
Well, I'll start off with the clinical question. So I think this is a very relevant population of patients with PSC, and the population is enhanced for the patients who have the highest likelihood of progressing to cirrhosis, liver failure, and death without liver transplantation. Clearly, in clinic, we see the whole spectrum of disease. This disease, can have a long natural history and will obviously span the spectrum of patients with nearly normal liver tests and, and no fibrosis, all the way up to our patients needing to have liver transplants in their 40s, 50s, and often younger.
But when I look at the population, taking into account how Éric described the, the selection, which was mindful and was thoughtful around the mechanism of action, to enhance the ability to detect efficacy, then I'm comfortable that this does look like the patients who are in my radar, and when I'm seeing them in clinic, I'm writing high-risk disease, likelihood of, future events within the next, five to ten years. So it's a very relevant.
Where it then fits in, I think that's a bit early to extrapolate all the way, from a Phase 2a data, 'cause remember that we have no effective treatments for patients with PSC, and the community is very keen to be applying widely to the majority of our patients with PSC, who ultimately are at risk of progressive disease, new therapies that are, anti-inflammatory, anti-fibrotic, and ultimately reduced biliary stricturing. So, I think that, the molecule would find, clearly a role to play within the treatment paradigms if further data can, confirm safety and long-term efficacy. I think I'll hand to Eric to
The details of the ELF is beyond the data that I have.
Yes, in terms of ELF score, basically, we had in terms of the placebo ELF scores that were approximately 9.1, 9.2, and they went up to 9.8, 9.9 at the end of treatment. So, this is something that, again, I think ELF has components that are really highlighting fibrogenesis markers, so TIMP-1, HA, and P3NP. In fact, P3NP, for those who may not be familiar, is very similar to the PRO-C3 assay by Nordic. And so we expect that the fact that we enrich these patients with active fibrogenesis would explain the increase in ELFs that we've seen in our study.
And what further supports that is that all the dose groups for bexotegrast had attenuated that increase, which is quite interesting as a finding.
Thank you. Our next question comes from the line of Ed Arce with H.C. Wainwright. Your line is now open.
All right, thank you for taking my questions and congrats on the data. So I have three questions. First, for management, I know when we've spoken before, a priority, the expectations were for perhaps favorable trends in these biomarkers and not necessarily stat sig results. So I'm just wondering if you could frame for us the difference with the actual results. Secondly, a question for both management and Dr. Hirschfield. Just in general, where do we stand on agreement with the FDA on a pivotal primary endpoint? In particular, it sounds like it may still be histology, but biomarkers are still considered important in the totality of the data. And then lastly, discussing the stat sig improvement in pruritus, how clinically meaningful is this? This is for Dr. Hirschfield.
Especially since the mechanism does appear to improve the bile duct flow, and what is being used now to help with pruritus for patients? Thanks so much.
Thanks for your question, Ed. I'll tackle the first one. So in terms of the stat sig that we observed, this was unexpected in such a small study, right? We had thought that we would see dose-dependent trends in terms of these biomarkers. We didn't think necessarily that. our study was not powered for any of those biomarkers, so we didn't necessarily expect a trend. But certainly, the results go really very much in line with the antifibrotic mechanism of action of bexotegrast, because that's where we see the change in terms of the fibrosis biomarkers, whether that's ELF or PRO-C3, the different components of ELF are there for the 160 milligram dose, which is the highest dose that we reported on today.
Whereas we see trends for ELF reductions and the like. So I think that the fact that we have this mechanism and the fact that we get stat sigs on the mechanisms that the biomarkers that highlight the effects of this mechanism is really, I think, really lines up well, even though maybe it wasn't completely expected. And I'll pass it on to Gideon for the
So I kind of alluded to this before. I mean, I can't comment on behalf of sponsors or regulators, but I think that, there is a clear effort in the PSC community to work collaboratively, and there's been a lot of work with patients, academics, regulators, and sponsors to move the needle on what a registration study needs to look like to get success. And I think, when one goes to forums such as, the PSC forum, and there's been also forums led by the patient groups, there's a clear willingness for everyone to work beyond liver histology. How that translates, to individual sponsors and their plans, I couldn't comment.
But it's certainly one of our highest priorities with patients and academics, is to generate the data to allow that meaningful discussion to move forward. As regards itch, I think it's interesting. I think it's any symptom study is always difficult. I interpret it in the context of, 12-week, phase 2a data.
and it just- it reinforces to me that symptoms are important for patients, and in the development plans for any sponsor developing drugs, measuring symptoms, over a longer duration using, tools that we've become much more comfortable with, such as the, some of these NRS scores, is, is really key and would be something that would be potentially distinguishing for any compound, going forward from a, from a, from a patient perspective. But, I mean, but this is phase 2a data in a small number of patients. So, naturally, my interpretation is through that lens.
Thank you. Our next question comes from the line of Alex Thompson with Stifel. Your line is now open.
Hi, this is Charles here, stepping in for Alex. Congrats again on the data. I think one thing we were curious about was perhaps better understanding that, greater than 0.9 ELF score change. In terms of, like, a range of increase where we could see disease progression halted, that would be good to understand. And then my second question was for, the PRO-C3 biomarker, is there any literature that also suggests a similar score from baseline or a score in general that would prevent any, disease halting of progression? Thank you.
Yes, I can take the first question on the threshold that we talked about, so the 0.19 threshold for ELF, and that was really coming from the simtuzumab phase 2b study that was published a few years ago by Dr. Muir. And this was a study that was the first of its kind in the sense that it had serial biopsies in PSC patients. They had a variety of measurements, and they followed the patients for at least 2 years. And this is a study that identified such a threshold from that study population. So that's important to keep in mind.
This is not, an MCID or anything like that, but it comes from what is referred to as probably the best natural history study in PSC, and certainly Gideon can add a little bit of color on that. But because simtuzumab didn't show any treatment effects, they pretty much used that study to look at different correlations with baseline parameters and how these could predict outcomes. And in this study, they found that, this change, if you exceeded this amount of change at week 12, you could be at increased risk of clinical outcomes and in the 2-year period of the study. And why we chose to talk about it here is because there is no pre-specified threshold for, how much reduction or how much increase is worrisome, how much reduction translate to a clinical benefit.
We don't really know that yet, but we wanted to provide some context in terms of the magnitude of changes that we saw for both active and placebo groups in our study.
Just to add, I think that's a fair interpretation of the literature. And most of the ELF data, has come. There's either been data from the Gilead clinical trials or from the Norwegian cohorts. PRO-C3 has been studied less to the degree of, stratification and delta, but there is, again, some data from the people who've been measuring PRO-C3 Nordic and some of the academic groups, including Norway and the Royal Free, looking at the prognostic ability of PRO-C3. But it's a fair point that there's still some work to do to get to the exact thresholds, plus how to interpret that when you enrich populations for patients with fibrosis at the outset.
Thank you. With the question and answer session complete, let me turn the call over to Christopher Keenan.
On behalf of my leadership team and all my Pliant colleagues, thank you for joining us this morning. This is certainly a great day for Pliant and potentially for patients with PSC. We look forward to sharing updates from across the Pliant portfolio in the near future. Have a good day, everyone.
This concludes today's conference call. Thank you for participating. You may now disconnect.