Pliant Therapeutics, Inc. (PLRX) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by. Welcome to Pliant Therapeutics INTEGRIS-PSC Phase IIa Trial Results 320 milligrams. [Operator Instructions] Please be advised that today's conference is being recorded. I would like now to turn the conference over to Christopher Keenan, Vice President of Investor Relations. Please go ahead.

Thank you, Michelle, and good morning, everyone. Thank you for joining us for Pliant's presentation of top line data from the 320 mg dose group of INTEGRIS-PSC. Our Phase IIa clinical trial evaluating bexotegrast, previously known as PLN-74809 in patients with primary sclerosing cholangitis. The press release that we'll be referencing today is available under the Investors & 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 future development. Because forward-looking statements relate to the future, they are subject to inherent uncertainties and risks 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 today with prepared remarks are members of our management team. Dr. Bernard Coulie, President and Chief Executive Officer; and 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 Pencek, Pliant's 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, let me turn the call over to Bernard.

Thank you, [indiscernible]. Good morning, everybody, and thank you for joining us. It's a pleasure for us to share with you today additional data from the INTEGRIS-PSC Phase IIa clinical trial of our lead asset, bexotegrast. Just to remind you, bexotegrast is an oral small molecule, dual selective inhibitor of avß6 and avß1 integrins that is currently in development for patients with IPF as well as PSC. We are pleased with today's results. They are consistent with the previously reported data from the lower doses from this trial, confirming both a favorable safety profile and encouraging treatment effects. These data are very much in line with what we were hoping for, and we believe that these data support the continuous development of bexotegrast in PSC. Today's data is another significant step forward for the program and further validation of bexotegrast as a PAM anti-fibrotic. With these data, bexotegrast continues to show a good safety profile and anti-fibrotic effects consistent -- consistent with previously announced data in 2 disease indications and patient populations. Turning now to this morning's news. Éric 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 very 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 conclusions. I will now turn the call over to Éric.

Thank you, Bernard. First, I'll start by reminding everyone for about the INTEGRIS study design and its objective. And the study was done in -- evaluated 4 doses of bexotegrast starting from 40, 80, 160, to 320-milligram and was compared to placebo. Treatment was in this analysis with 12 weeks for all patients and placebo patients were embedded in each of the dose cohorts in a 3:1 active to placebo randomization scheme. The primary and secondary endpoints of this study were safety, tolerability and PK. As part of the exploratory endpoints, these were changes in liver fibrosis markers, ELF and PRO-C3. We also evaluated changes in liver imaging, changes in liver biochemistry and reminding everyone that this is a trial that was enriched for participants with suspected liver fibrosis and to meet entry criteria, patients had to have elevated ELF, transient elastography or historical biopsy. Now I'll start by giving you the key findings of this interim analysis, focusing on the 320-milligram dose. Bexotegrast was well tolerated in these participants with PSC. We identified no safety concerns at all dose groups, including the 320-milligram dose. The most common adverse events were observed at lower rates in bexotegrast-treated patients versus placebo, and there were no treatment-related SAEs on bexotegrast. Bexotegrast demonstrated anti-fibrotic activity in this patient population with suspected liver fibrosis by reducing liver fibrosis markers of ELF and PRO-C3 at all doses relative to placebo, and this is over short-term treatment. Contrast MRI findings suggest that improved hepatocyte function and bile flow at all doses relative to placebo and additional findings include a statistically significant itch -- reduction in itch relative to placebo for the 160 and 320-milligram doses. And finally, alkaline phosphatase levels remained stable at all doses to increases that were observed on placebo. Now I'll start with the patient disposition. And we screened 205 patients for this study and randomized a total of 121 patients. You see that we had 91 patients that were randomized to bexotegrast compared to 30 patients on placebo and few patients discontinued treatment overall, ranging from 6.7% to 8.8%. Now moving to baseline demographics and focusing specifically on the 320-milligram group, we saw that some of the main differences here across the groups were perhaps that the patients with -- receiving that dose had maybe slower rates of IBD compared to the rest of our population. But other than that, really no meaningful difference were observed. Also with the exception of perhaps more female patients in that dose group. And now I'll move on to the next slide, which shows the baseline disease activity markers. Again, focusing on the 320-milligram group, we see that alk phos levels tended to be somewhat lower in this dose group. And -- this is also reflected by maybe lower changes in -- or lower trends in elastography, but comparable to the rest of the population here. So overall, really no meaningful differences in the patient population. Moving on now to the overall safety summary. So the drug, again, was well tolerated. We saw no serious treatment-emergent adverse events in the bexotegrast treatment group. There was one Grade 3 or higher adverse event in that group, but it was not related to study drug. And then we had a few patients that had temporary interruptions of study drug, but only 1 patient that discontinued study drug. And that was 1 patient that had a mild increase in alkaline phosphatase and ALT and AST. I'll move on now to the next slide, which shows the most frequent treatment-emergent adverse events. And overall, as I mentioned before, the most commonly observed or reported adverse events tend to be less frequent in bexotegrast-treated patients. And we see here on the slide that perhaps where we saw some difference was nausea, mild nausea was seen in the patients on bexotegrast but if you focus now on the data in the dotted lines, we see that events of pruritus which is itch, and cholangitis, which are infections that tend to occur in these patients in the bile ducts, were -- occurred less frequently on bexotegrast overall than on placebo. And reciprocal findings here are the itch numerical rating scale where we saw a statistically significant difference in itch, so much lower itch on the 160 and 300-milligram (sic) [ 320-milligram ] doses compared to placebo. And this was also statistically significant when we pooled all bexotegrast doses together. Now moving on now to the fibrosis biomarkers and starting with the ELF score. Looking at the change from baseline at week 12 and we see here that all doses of bexotegrast had smaller increases in ELF compared to placebo, and this is also reflected by the pool analysis that you see here. Moving on to the 3 components of ELF shown on this next slide. And we see here again that overall, all the bexotegrast-treated patients had smaller increase across the analytes compared to placebo. I'll point your attention to PIIINP, where larger increases have been seen with the 320-milligram dose group, and this was mainly driven by 1 patient who had a sizable increase at week 12. But interestingly, this increase was not as pronounced when looking at PRO-C3 levels. Now moving on to the PRO-C3 slide. We see that bexotegrast blunted the PRO-C3 elevations in these patients, whereas we continue to see an increase in placebo patients. And then when we look at the overall analysis, we have the statistical significance that is seen for the pooled placebo group compared to bexotegrast -- sorry, yes, to the pooled bexotegrast group compared to placebo. Moving on to MRI parameters. So as we had mentioned, this trial included a Gadoxetate contrast using MRI, where we could evaluate the uptake by this contrast agent and by the hepatocytes and also the excretion into the bile ducts. So these measures are telling us how -- how -- a glimpse of hepatocyte function, but also bile flow. So all bexotegrast doses, including the 320-milligram dose saw small increases in relative enhancement compared to a decrease on placebo. And when we pooled the bexotegrast doses, this was statistically significant compared to placebo and in terms of time to arrival to the common bile duct, we again saw more better results for the bexotegrast group showing decreases in the 2 top doses, 160 and 320 in contrast to increased time to arrival on the -- in the pooled placebo group. And now alkaline phosphatase, focusing on the subgroup of patients with elevated values at baseline, and we see very mild changes here and some decreases in alk phos on the bexotegrast group relative to an increase in placebo. And when we pooled all the doses together, this difference was statistically significant for bexo relative to placebo. And with that, I'll pass it over to Dr. Gideon Hirschfield to give his overall impression of the study results and their implications. Gideon?

Thank you, Éric, and good morning to everyone. And first of all, I'd just like to thank the Pliant team for working so hard and diligently on this very exciting data for patients living with PSC. I think we all kind of underestimate the importance of developing anti-fibrotic therapies for our patients with this progressive biliary fibrotic disease. I'm really encouraged today, therefore, to have the opportunity to have seen this data which really is quite exciting because of the consistency of the message that was already presented from the prior analyses. I'm really pleased to see an ongoing safe profile for this drug over 12 weeks of use with no signals that would be of concern to patients. And indeed, with some signals to suggest that in the treated group, there were less relevant events for patients. I'm also pleased to see that as we add this dose arm that the message for this drug remains very consistent. It remains consistent with the biomarkers that have been already disclosed. And with the imaging and it appears that when one looks at the difference between treated and placebo group, that there's a drug effect. Certainly, this is early data. It's a 12-week study. Numbers are small. We recognize heterogeneity in this disease. But nevertheless, the multitude of different approaches with which the sponsor has investigated this drug, both clinical, biochemical and imaging is all very consistent with the proposed mechanism of action. And overall, my high-level review of what I've seen so far and no doubt there's further analysis from the sponsor is that this is a great launch pad for the future and hopefully, an opportunity to work out where to go with the next steps in developing this much needed therapy for patients. With that...

Thank you, Gideon. So we are obviously very pleased with these data as they mark another step forward in Pliant's development of bexotegrast, addressing the unmet needs of the PSC patient. I want to leave you with some takeaways from today's data and next steps for the program. And I think to Gideon's point, what is key is that we see a consistent effect across a number of different measurements and different endpoints that we have looked at. First and foremost, of course, bexotegrast continues to demonstrate a favorable safety and probability profile even at this high 320-milligram dose in a PSC patient population with suspected moderate-to-severe liver fibrosis. All those have shown now anti-fibrotic activity over a short-term treatment duration. And again, this is key, it's only 12 weeks. We're talking about a disease that develops over years. Contrast MRI suggested improved hepatocyte function and bile flow with bexotegrast treatment. All those have displayed improvement in the itch numerical rating scale at week 12 relative to placebo with notably statistical significance at the 2 higher doses. In terms of what these data now mean for us moving forward, we plan to prepare for regulatory interactions to discuss a path to registration with these data. And obviously, as you know, the 24-week data from this 320-milligram cohort are expected in mid-2024. We would like to thank our INTEGRIS-PSC investigators and their study teams for their dedication in 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 prominent program. So with that, let's open the call to questions, Chris.

Michelle, you can open up the call to the Q&A.

[Operator Instructions] The first question comes from Yasmeen Rahimi with Piper Sandler.

Congrats on the data. I have 2 questions. One is directed to the Pliant management team. Team, when you look at the totality of the data, did you see any differences in patients who were not on UDCA back on therapy in response with some of these key NIT biomarkers reported? And then the second question is directed to also Dr. Hirschfield. [indiscernible] Dr. Hirschfield, the team at Pliant is going to continue the 320-mg dose group data to 24 weeks. Could you maybe talk about what do we know about the progression of disease in PSC patients? And how we should be thinking about a continued treatment and what the impact of the additional 12 weeks of treatment would be on some of the biomarkers? I guess, in other words, what are biomarkers that are more sensitive to prolonged treatment? If you could share some thoughts around that, that would be great. And then sorry, one more last I want to squeeze in for Dr. Hirschfield is, could you maybe talk about how open the agency based on the work that you've seen they are towards use of NITs and registrational path?

Maybe, Gideon, you can start, if that's okay.

Okay. So 2 very important questions. I think that when you look at patients with PSC, particularly when you choose an enriched population, and that I think is one of the key facets of this particular trial is the fact that these are patients enriched for fibrosis. You do expect there to be a slow and steady progression in their disease over time. And what you don't know when you're developing new drugs for anti-fibrotic is at what point you will move to pushing back fibrosis to then actually potentially halting and reversing. And therefore, what you're looking for in these studies, which then go beyond 12 weeks is to see sustainability. So that's what we'll be looking for in the 24-week data and to also see whether or not you can start to see some shift into really pushing into so called the negative world where you're pushing back and you're actually reducing the fibrosis. So I think that's really something that's key. And I think for any mechanism of an anti-fibrotic drug, we don't know how long it will take to one of the points mentioned by Pliant, these are very -- diseases that last decades and therefore, when you develop a new therapy, we don't know what the pivot point is and how long you need the therapy to start to see that switch. That then sort of moves into that question that is always asked about surrogate endpoints and approval. And clearly, that's something for the FDA to comment on. But I think what is fair to say is that it's been clear from the public comments from the FDA that they are interested in rethinking how one develops clinical drugs for PSC. They are interested in not only the traditional pathways of a clinical end point, but the use of markets such as ELF and FibroScan to show benefits of new therapies. And their interest is in parallel with the academics and the patients who are committed to providing the data that's needed for the regulators to be able to move in their sort of pathways to developing safe but also effective drugs for these rare orphan diseases. So I'd say that there's never been a better time for the development of new drugs in PSC in that context.

Yes. Thank you, Yasmeen, for your question. This is Éric. I'll answer your question on the use of UDCA in that subgroup. So this was the smaller subgroup of course, in our trial, but the results were consistent with the overall results.

The next question comes from Ritu Baral with TD Cowen.

I wanted to ask a couple of questions to Dr. Hirschfield, specifically as a follow-up to your comment on the enrichment. As you manage PSC patients and as your colleagues do so, what percentage of the diagnosed patients do you think have this level of enriched suspected fibrosis? And is that a regular part of diagnosis? I guess I'm wondering if these patients are sitting at clinicians' offices with a file that suggests either mild disease with little fibrosis or that sort of high suspicion of fibrosis? And then I've got a follow-up on the functional biomarkers.

Yes. I mean that's a great question. And actually, whatever you do in a trial is a snapshot of practice and it's a snapshot of the patient's journey. And you could divide up a PSC patient into sort of 3 very big buckets, and this is pretty big buckets. But the patients with very, very early disease; the patients were very, very late disease; and the patients in the middle, which are the sort of patients that are included in this trial. And we, as an academic community struggle to know the exact top and bottom ends for ELF and FibroScan. But I'd say that more than 1/3 of our patients are sitting in this middle group. But that also remember, that means that the other -- there's the patients before that who will transition into that group. So the purpose of the inclusion criteria is to increase the chances of success in the clinical trial. It's not to exclude the total population that will need treatment. So that -- then to your point are we using these tools in practice. I think the answer is yes. Certainly, elastography by FibroScan and MRE is practiced across the U.S. and Europe. ELF score is used in Europe more so, although it is now available in North America. So I think clinicians are moving to this concept of understanding the risk stratification for their patients with PSC and where they stand today.

Great. And that actually -- that comment on ELF [indiscernible] is into my next question and would love Bernard and Éric's input as well. But as you think about the ELF score as a potential functional endpoint of import. How do you see sort of deltas of clinical meaningfulness in this disease as you follow patients in real life? And also, since we're seeing separation on cholangitis just a little bit. Is that an event that occurs enough to potentially contribute to pivotal design?

Go ahead, Gideon.

No, I was just going to say that it's a great question. And there is some evidence about delta ELF from bigger Phase III clinical trials which guides the conversation. And what clinicians will be interested in will be both the delta and what proportion of patients over longer term use stay in a lower risk category or don't progress to a higher risk category. So I think there are smart ways that you can use the ELF score in a larger study, which is powered and which is deliberately designed to be much longer duration. I mean we're talking 12 weeks here when you're thinking about later-stage trial development, you're going to be talking about much, much longer evaluation and that will allow us to see that classification.

And cholangitis?

Yes. So I can answer on cholangitis, so this is certainly an interesting end point because it is clinically meaningful and maybe Gideon will add a few words here. I know that there's also an effort to really standardize their criteria for defining ascending cholangitis if we were to use it as an endpoint and perhaps that's something that Gideon could add some more color to.

Yes. I mean it's a very relevant endpoint. It's very clinically meaningful. It does have some challenges in using clinical trials because of some subjectivity between a patient and investigator, but there is definitely another effort among validating ELF and FibroScan is also to try and improve the ability to define cholangitis. And this isn't the first trial where there's been an interest in cholangitis during the clinical trial. And that's why I think the spotlight will focus on how to capture what happens in clinical practice because clearly, we don't want our patients only being defined as having cholangitis if they have to attend the ER room when, in fact, they may be self-managing with their clinician in the use of antibiotics. So I think there is a way to better capture what happens to patients. And I do think that when one thinks about endpoints, which are clinically meaningful and have to be disease-specific, then cholangitis will become one of the endpoints in PSC trials on top of progression to cirrhosis or decompensation or need for transplant or MELD score that is very relevant, and it's very relevant to the physiology of the biliary tree and the physiology of drugs that change biliary function and potentially improve bile flow and reduce the chance of the development of cholangitis.

The next question comes from Brian Abrahams with RBC Capital.

Congrats on the data. Just 2 for me. First, I was wondering -- and I know you haven't met with regulators yet, but -- how are you guys thinking about ideally what a potential Phase IIb design could look like here with regards to the dose levels you may explore, the duration and the degree of patient enrichment? And then secondly, can you speak to some of the similarities and differences that the 320-mg placebo group had versus the earlier placebo group? It looked to us like these patients had much higher PRO-C3 levels and ELF scores at baseline versus the earlier placebo, and maybe some slightly different responses as well. I'm just kind of wondering how that might impact how we should be interpreting the 24-week data, if we should be sort of just looking at the 320-mg active arm itself maybe relative to natural progression or comparing it to that small placebo group carried out another 12 weeks.

Thank you, Brian. So I'll take the first question in terms of the Phase IIb design. And this is certainly -- right now as you know, we are -- we will be preparing for regulatory interaction. One of the things that we do want to ask the regulators is the importance of liver biopsy or histology as it relates to dose finding and whether a noninvasive endpoint could also satisfy that criteria, such as ELF. We know that from this study, it's hard to pick one dose. I think the study was too short and too small populations to be able to identify a winner, and we saw also activity at the lower doses, which could be explained also by increased exposure of bexotegrast in the liver compared to the lung. We've talked about that on previous calls. So I think for us, if we understand that there is an avenue where noninvasive could play a part in registration, that could really change how we build the next steps because in that sense, if you had to do still some histology prior to having your noninvasive being a pivotal endpoint then you'd rather do it maybe in a smaller study and provide some histology data to the regulators and then move on to Phase III with the noninvasive but if you can go straight to invasive, that would argue for the potentially straight to Phase III approach. So I think that regulatory interaction is really hopefully going to provide us some clarity on where the FDA currently sees the possibility of these noninvasives to be part of registration. And you alluded to also some of the differences. And I forgot to mention when going through the slides that we had seen that in the updated pool placebo group, which included 9 more placebo patients that were coming from the 320-milligram dose cohorts that adding these data has slightly reduced the elevation in ELF from baseline in that placebo group. So we expect that these patients did a little bit better in terms of increases in ELF compared to the other placebo patients that we reported earlier, but it was always the intent from our study as per the statistical analysis plan to compare each of the dose group to the entire pool placebo group, especially at week 12 since we have more data. And as you -- as you know, circulating biomarkers are prone to more variability when we reduce the sample size. So this is something that we were always intending to do, but we do think these 9 placebo patients seem to do a little bit better than the rest.

The next question comes from Pete Stavropoulos with Cantor Fitzgerald.

Congrats on the data. A question for Dr. Hirschfield. When you think about the improvement in bile duct flow, could it be related to improvements in the bile duct strictures? And is this possibly linked to the ALP improvements or stabilizations observed? And the reason I ask is those KOLs we've spoken to, they did not expect to see an effect on ALP in the short term but rather over longer-term dosing, where you could see the anti-fibrotic mechanism of action leading to liver function improvement. And a question for the team, and also for Dr. Hirschfield, you did report on itch which many of these PSC patients have. Can you just help us understand how itch affects this patient population and how the changes observed translate to a patient benefit?

Well, great questions, Pete. I mean -- so you're right that there's a complex interrelationship between the inflammation, the fibrosis, the biochemistry and the symptoms, and they're all actually linked at different points. And so certainly, a drug that is liver specific, such as this, where it's targeting specific integrins that we know are expressed in the biliary epithelium which are then related to the TGF-ß pathway, there's definitely sufficient concept to be positive in how one looks at the data that we see and in particular, how one looks at the functional data. The functional data is clearly a sub-study. It's clearly something that needs further work in terms of getting larger numbers and understanding the standardization. But for sure, one reasonable sort of hypothesis is that the drug is impacting those strictures where there's ongoing inflammation and fibrosis. And then to your point, the reason they're linked to itch is that, of course, itch -- cholestatic itch is a result of the failure to excrete bile adequately. And that's detectable by patients long before they're jaundiced and then circulating components are relevant to pruritus. And so actually, there's a lot of logic to link itch to the features seen on imaging. And then finally, I agree, alk phos is a very interesting biomarker. It gets both good press and bad press in PSC clinical trial, is definitely a marker that can be used for enrichment of risk of progression and it's definitely a market that we'd be looking for to see improvement. But generally, the improvement is likely in a mechanism such as this, as you pointed out, to be one that you'll detect the longer you give the drug successfully and you ultimately tackle the actual disease, which is the biliary stricturing. So that would be my sort of high-level thoughts on your comments.

And team, your perspective on how itch affects this patient population and how the changes you've seen can translate to patient benefit?

Yes. I think that's fair to say that there are differences certainly from -- when you compare PSC populations to PBC population. And again, I'll invite Gideon to comment on that. But when we look at the -- the baseline or the baseline disease characteristics, we didn't really have a very itchy population compared to some of the PBC trials. Nonetheless, we saw this increase in itch on placebo patients, which coincided with also these events of cholangitis, increase in alk phos. So that was an interesting finding that we want to study further certainly in late stage, but maybe I'll pass it on to Gideon just to talk about some of the differences here between different populations.

Different populations of disease or different populations in the trial?

Yes. Disease, I would say disease PSC and PBC, I think that's often a perception, especially with the data that's come out of the Phase III PBC trials that have been recently conducted that maybe itch might be something we want to look at further.

Look, I think I would always answer working backwards from what the patients consider to be very important. And if you are patients with PSC, the top 3 things they talk about are pain, itch and fatigue. Now the itch of PSC is cholestatic in etiology, like I said, it relates to the cholestasis and in the context of PSC, the progressive biliary fibrosis and biliary stricturing. That is different to patients living with PBC, where the inflammation is small bile duct more persistent and the itch is more stable. I mean it's more stable because it's not an itch so much of the obstruction of the biliary tree, but an itch of the inflammation from the small bile duct lymphocytic cholangitis. That said, mechanistically, they share a lot of similarities down the final pathways. And this study wasn't enriched for pruritus but that is something that you could do certainly as part of a later phase development because we have the tools, we've developed the approaches to understand how to measure improvement in itch. And clearly, therapies as has been seen in PBC that can tackle both disease and symptoms are even more attractive to patients seeking a change in their disease course.

Please stand by for the next question. The next question comes from Thomas Smith with Leerink Partners.

I guess first, just one on safety. I was wondering, are there any additional details you could provide around the -- on treatment discontinuation in the 320 mg group related to the elevated alk phos and transaminases, any relevant context you can provide on that patient would be helpful.

Yes, that -- thank you for the question. That patient that discontinued, really discontinued very late in the study. It was actually in one of the last visits that this mild increase in transaminases manifested and then the patient decided to withdraw from the study. So it was a mild elevation. And then this is the only discontinuation we've had. It was deemed not related.

Got it. Great. That's helpful. And then just maybe one for Dr. Hirschfield. I guess looking at the early data here, I'm thinking about the potential impact on fibrosis, are there other cholestatic diseases with fibrosis that are sort of top of mind that you would be particularly excited about maybe exploring [indiscernible]?

That's a good question. I mean, so I mean there are, but they have different mechanisms of fibrosis and a different fibrosis trajectory. And they're not as dominant, but the -- some of the progressive biliary fibrosis that we see in pediatrics we could have similar mechanisms. So if you think about atresia, where there's no treatments yet, that also actually leads to a biliary fibrosis. That's another rare orphan disease. I mean the other situations where we see this progress of cholestatic fibrosis, all are slightly -- slightly niche. So post liver transplant, recurrent PSC and biliary injury is very relevant for other biliary fibrotic conditions. I think for PBC, that's a disease where there's a lot of already interest in evolving therapies. And although those therapies are good, it is fair to say there is still a segment of the population of patients with PBC who've got fibrosis despite control of their cholestasis.

Next question comes from Alex Thomson with Stifel.

Maybe, Eric, a couple for you. Could you talk a little bit more about sort of the differences in exposure you've seen in the liver versus peripherally and how that's impacting your view of the data here and sort of thoughts on doses moving forward? And then maybe you could comment a little bit on the MRI subgroup population and how that compares to the broader population in the study as well, that would be helpful.

Thank you for your question. So in terms of exposures, we saw really generally dose proportionate increases in exposure across all these doses. So that's certainly something that really is consistent with our IPF study and our healthy volunteer work. And the point you made is something we've talked about is that from preclinical studies, we know that the drug has approximately 3x the exposure in the lung -- in the liver compared to the lung and also compared to plasma. So because it is primarily metabolized by the liver, so that could explain also the fact that we see this antifibrotic activity at lower doses. Certainly, here, it's -- I would say that we don't have the same target engagement tools in liver that we have in lung. You may recall that for the IPF indication, we had done PET imaging and things of the like, but we don't have that in liver. So it could be that we're maybe at the top end of the activity because of the higher exposures in the liver. But ultimately, what we need to do now is do more dose ranging in late stage to really pick a winner here when we have a longer duration and also more patients in each of the dose groups to really see what is the dose appropriate for Phase III. And the other question that you asked was concerning the MRI population. This was an optional sub-study so not all patients participated to this part of the study. However, in terms of baseline characteristics and demographics, this was overall comparable to the rest of the population.

Please stand by for the next question. The next question comes from Eric Joseph with JPMorgan.

Good morning. This is Noah on for Eric. Maybe just, could you talk about the individual components of the ELF score. I know you mentioned that there was one patient driving some variability with PIIINP, but just kind of noticing that PIIINP seems to be driving some of the differences in the score across doses. So just wondering if there are certain components of ELF that are more predictive of clinical outcomes than others?

So thank you for your question, Noah. In terms of the ELF, each of the components can affect the ELF score. If you -- you may know that the ELF is really based on a formula that gives a different amount of weight for each of these analytes, what we did see in this part of the study is that there was one patient, as I mentioned, on the description of the data, that had really sizable elevation in PIIINP and that probably drove the results for the group as well. And also that patient had increases in hyaluronic acid as well. So having effects on 2 components for that one patient is certainly expected to have brought the change of the group to a higher place. Having said that, I think that really begs for doing larger and longer studies because in 20 or so patients, you can imagine how one patient can drive the mean change. However, in larger patient populations that would be expected to have less importance certainly as we do further measurements along the longer course.

Please stand by for the next question. The next question comes from Joseph Stringer with Needham.

First one for Pliant management. Just given the complete 12-week data set that you have now, are you 100% certain that you'd move forward with bexo monotherapy in PSC? Or would you consider looking at some type of combo therapy. Essentially, would you consider splitting the bexo acid away from the IPF indication? And then second question is for Dr. Hirschfield, Follow up on the earlier question on the ELF score. What's your view on the 0.17 increase in the ELF score at 12 weeks for the [indiscernible]. There's, of course, the literature from previous clinical trials that suggest a 0.19 increase is predictive of clinical disease progression in PSC. So just given how close those two values are, how confident are you that the 0.17 change in ELF for the pools that so is a clinically meaningful result in this trial?

Maybe Gideon, you can go first.

I mean that's a good question. But again, I mean, we we're looking at only 12 weeks of therapy. And I'm interested to look at the difference between treatment and nontreatment. And I'm interested to see the consistency of effect in the treated arm versus the -- what we see for the ELF score in the placebo group and interested in as the groups have grown to see that, that message, that delta remains present. So do I know exactly what threshold I need to have for clinical significance? No. But I think Eric really hit the nail on the head. I mean, you need longer duration studies with larger numbers to really -- to tease this out. And you're going to reach the point where you have what you have in a 12-week study of this size. And actually, what you have is all pretty good. But now the next step is that nuance of working out what the study looks like for patients, but particularly then replicating the message over longer duration. And it's -- after a longer duration study where I think you'll be in a better position to comment on clinical significance.

Thanks, Gideon. And so coming back to your question, Joe, about combination therapy. Obviously, very interesting and definitely something that's top of mind for us as well. It's, I think, interesting to think about the combination of a direct antifibrotic such as bexotegrast, with an anti-cholestatic, for example, in treating PSC where you address two of the main components. And I think it's something we started evaluating in our preclinical models and notably in human tissue. And then we will continue to consider. But right now, the conversation is about bexotegrast and that's also what we want to kind of present to the authorities. But again, I think it's something that we will continue to consider and evaluate as we move forward.

Please stand by for the next question. Our next question comes from Ed Arce with H.C. Wainwright.

Congrats on the data. I have this question and I'd like to get a response, if I could, from both Pliant management and Professor Hirschfield. I'm trying to get a better sense for the totality of the data here so far, the 12-week endpoint. Clearly, you've seen positive and in many cases, stat sig improvements across function, in bile flow, fibrosis with PRO-C3, inflammation with cholangitis and even symptomatic improvement on pruritus. And yet, you have an ELF score across 4 doses that is clearly not dose dependent. I'm trying to get a better sense for how to we interpret that overall, how important is the ELF score in the overall totality of the data, especially since with the latest placebo group at 28 patients, none of those doses are any longer stats sig for the ELF score.

I can take the first part of this question and maybe depending on where this goes, we could involve Gideon. But I would say, thanks for your question. There's not a wealth of data for circulating biomarkers to see how accurate or discriminate they are in terms of dose response. So for us, it's -- are they -- maybe they can be more discriminate when you go out to longer periods, maybe with more individuals potentially in our study that was too short of a time to really expect a difference. I know that it's been seen in other trials, as you can see differences. But overall, I think the -- it's fair to say that the data is emerging in PSC for that. So I would say that for us, what's the most important here is that we do have evidence of antifibrotic activity in these PSC patients. And we've seen this evidence in IPF as well. So we know that the clinical data really is consistent with the preclinical data for our molecule. And we're happy to see this reduction in ELF overall compared to placebo, but it certainly as I mentioned before, this trial cannot answer which dose needs to get to Phase III, right? We really need to do more. And the approach that we'd be taking in late stage studies is also continue to evaluate multiple endpoints in terms of -- we need to have the question with the regulator to see which one would qualify as the primary endpoint for sure, but I think it makes sense for us to add other endpoints like transient elastography, potentially MRE, if we can, potentially MRI imaging like we did here. But that will help us really tease out a dose effect, I think, as we go out to longer duration.

The next question comes from David Lebowitz with Citi.

As we look forward to longer follow-up towards the middle of this year, with what dynamics should we expect to see in the data that varies from the 12 weeks in terms of what should we have -- what's your expectations be for the various biomarkers, but also for how the analysis will be carried out versus the 12-week?

Thanks for your question, David. So in terms of the 24-week finding for the 320-milligram dose, I would say the key value of these data will be the long-term safety similar to what we had seen in IPF patients, it's pretty much the same type of analysis that we'll be doing in terms of focusing on the 320-milligram dose group. And as you know, so in terms of the placebo group that was embedded in that dose cohort, there's only nine patients. And that limits our ability to very -- to have very meaningful comparisons with placebo. When you think about bexotegrast, again, circulating biomarkers don't tend to perform very well. I mean, there's more variability is what I mean to say here in small sample sizes. So we'll see what the data shows over the long term, but overall, the 12-week analysis that you're seeing here is the full dose ranging with comparable time points. And that pools with that larger placebo group allows us to have better comparison. So I would really say safety is what we're looking for. And if the favorable safety profile of bexotegrast continues to be what it is now at 12 weeks for that top dose, that will also provide a strong rationale to test the other doses for longer treatment duration in late stage.

With the question-and-answer session complete, let me turn the call over to Chris Keenan.

Thanks, Michelle. On behalf of my team here today and all of my Pliant colleagues, thank you for joining us this morning. 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 your participation. You may now disconnect.