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

Good morning, everyone. Thank you for joining us for Pliant's presentation of top line data from the INTEGRIS-IPF Phase II clinical trial evaluating PLN-74809 in patients with IPF. The press release that we will be referencing today is available under the Investors & Media section of our corporate website. The slides accompanying this presentation will be available on 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 PLN-74809 and our plans for the future development of PLN-74809 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 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; Dr. Éric Lefebvre, Chief Medical Officer; Dr. Gregory Cosgrove, Vice President of Clinical Development; and Scott Turner, Senior Vice President and Head of Research. Pliant team members will be joined by Dr. Toby Maher, who is currently Professor of Medicine and Director of Interstitial Lung Disease at Keck School of Medicine at the University of Southern California. Dr. Maher is a trained pulmonologist who has spent the last 20 years specializing in the management of all of pulmonary fibro -- in the areas of pulmonary fibrosis and orphan interstitial lung diseases. Dr. Maher will be joining us for 45 minutes of this call. Please keep that in mind when it's time for the question-and-answer session. Dr. Keith Cummings, Client's Chief Financial Officer will join us for the question-and-answer session. With that, let me 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 myself to share with you today the exciting and very compelling data that we announced last night from our INTEGRIS-IPF Phase IIa clinical trial of PLN-74809. Just as a reminder, PLN-74809 is an oral small molecule dual selective inhibitor of alpha v beta 6 and alpha v beta 1 integrins that's currently in development for patients with IPF as well as primary sclerosing cholangitis. Needless to say that the results from the INTEGRIS-IPF study have far exceeded our expectations. Before we dive into the data, I would like to take a step back to recognize something that many of you may know. The field of IPF drug development is a challenging one. At Pliant, we have built a solid foundation on science focused on interrogating the safety of our drug candidates and derisking our clinical programs. This is evident in the multiple meticulous studies and trials we have conducted in the past years from our live IPF patient [Indiscernible] to our pSMAD biomarker studies to the target engagement studies in IPF patients, I think we have built a compelling story, which leads us to the INTEGRIS Phase II data we are presenting to you today. Our safety database is extensive. To date, PLN-74809 has been dosed to over 450 human participants, including healthy volunteers, as well as patients with IPF or PSC, with no safety concerns. In addition, we have successfully conducted chronic GLP tox studies with no safety issues arising. Turning now to yesterday's news. The achievement of a primary endpoint in a clinical trial is great news. When that trial is in IPF patients, it's really great news. But when that 12-week IPF trial also shows those dependent improvements in forced vital capacity and quantitative lung fibrosis, which were our exploratory endpoints and IPF -- forced vital capacity being the current registrational endpoint in IPF versus placebo over 12 weeks of treatment, I think it's quite spectacular. We believe that today's data present a potential opportunity for a new treatment for what is a devastating disease for which there have been limited effective therapeutic options so far. Eric will begin with an overview of the INTEGRIS-IPF trial. Greg then will do a deep dive into the safety data. Eric will return to review the secondary endpoint of pharmacokinetics, and then Greg will then discuss the exploratory endpoints of the trial. So we'll discuss the biomarker data, and then we will hear from Toby on his starts on these results before I conclude with next steps and closing thoughts.

Thank you, Bernard. Good morning, everyone. So before I start on the resulting -- providing the summary of the results of the INTEGRATE-IPF study, I would like to remind the audience of the previous mechanistic work we had performed in the clinic with 74809. We had looked at target engagement in IPF patients and had seen that PLN-74809 achieved dose-dependent and exposure-dependent changes and target engagement in the lungs of these patients where the highest dose provided near saturation of alpha V beta 6 in lung. We had also shown that PLN-74809 was able to reduce TGF-ß activation in a dose-dependent manner. So now I'll turn to the study design and objectives of INTEGRIS-IPF. This was a multinational study, which enrolled a total of 90 patients, and there were 3 PLN-74809 dose groups, 40, 80 and 160 milligrams, which were dosed once daily, and this was in compared to placebo. We included patients that were either on or not on standard of care in our study, but it was stratified for use of standard of care or not. So the balance -- so the number of patients on standard of care would be balanced across the groups. The primary and secondary endpoints of our study were safety, tolerability and PK, respectively. And in terms of exploratory endpoints, we had change in forced vital capacity over 12 weeks. The high resolution CT-based quantitative lung fibrosis imaging, patient reported outcomes and also selected effect on selected biomarkers. The summary of the results is the following: 74809 was well tolerated over 12 weeks of treatment. Most treatment emergent adverse events were mild or moderate in severity. There were no discontinuations due to adverse events and no death or drug-related SAEs. 74809 treated patients experienced an 80% reduction in FVC decline over 12 weeks, so this was minus 15 milliliters in the pooled active group in contrast with placebo, which consisted mainly of patients on standard of care, that showed a minus 74% mL decrease over the same time period. The treatment effect was evident with and without standard of care agents. We saw an improvement of approximately 25 mL in the 80-milligram dose cohort and importantly, we saw a clear dose-dependent reduction in the proportion of patients with percent predicted FVC decline of greater or equal to 10%, which is a well-established predictor of death and disease progression in IPF. And for the exploratory -- the other exploratory end points, we saw dose-dependent antifibrotic effects seen -- based on QLF imaging with no progression in the 160-milligram group at week 12. And last, 74809 decreased serum biomarkers of collagen synthesis, which are PRO-C3 and PRO-C6 relative to placebo. We are excited about these encouraging findings which provide confidence to advance 74809 forward in development. With that, I will pass it to Dr. Greg Cosgrove, who leads our IPF program.

Thank you, Eric. Details of the study and operational aspects are illustrated here with 141 individual screened, a relatively consistent screen failure with other studies of just above 30%. And we randomized 90 individuals of which you see 67 to the active arm and 23 to the placebo arm. There are relatively small number of discontinuations in both arms of the study and the safety and efficacy and intent to treat analysis are similar. Of note, the number of individuals on standard of care was approximately 80%. And as an entire group, 50% approximately were on nintedanib and 50% on pirfenidone. The baseline characteristics of participants in the study were consistent throughout the different arms of the study. As you see, it is consistent with other IPF studies. It's male predominant. The age is appropriate given the characteristics of the disease, and the characteristics in terms of the time since diagnosis and the standard of care used are consistent throughout the different groups. Importantly, you see the duration of standard of care was consistent throughout the different arms as well. And the physiologic characteristics, again, consistent throughout the different groups. And we decided to assess an index of the disease severity with a GAP stage. And you can see the proportion of individuals at GAP Stage 1 and 2 were consistent throughout most populations. So for the safety analysis, the adverse event rates was comparable through the different dose arms of PLN-74809 and the placebo group. There were no study -- study drug-related serious treatment emergent adverse events related to drug. The withdrawal from study medication occurred only in the placebo group. And of note, there were no deaths related to an adverse event. As we broke down these adverse events and safety profiles from those with and without background therapy, you can see that the predominance of adverse events occurred in those on background therapy in contrast to those not on standard of care therapy. The most common treatment-emergent adverse event was diarrhea, and of note, this occurred in individuals on standard of care with 12 of the 13 participants having diarrhea taking nintedanib. All, but 1 event were mild-to-moderate in severity and diarrhea was of note recorded infrequently in our healthy volunteer study. To place this in context, in terms of other studies in the IPF space, you can see that the rate of diarrhea quite significantly larger in other studies of note in OFEV. And if you see in monotherapy in our current study, there was no evidence of diarrhea and the increased incidents occurred only on those on standard of care. In our study, there were no treatment-emergent serious adverse events related to study medication, and the serious adverse events that were reported were consistent with known features of the underlying diseases of those individuals. In conclusion, regarding the safety evaluation, I believe we can confidently say that PLN-74809 is well tolerated, and there was no dose relationship for the adverse events noted. There were no deaths or treatment-related serious adverse events, and no participants discontinued 74809 due to a treatment-emergent adverse event. As mentioned, the most frequent adverse event was diarrhea, but only seen in individuals on standard of care.

So then I will take it back. This is Eric, to describe the pharmacokinetic analysis, which were our secondary endpoint. So based on the sparse sampling we used in our study, the overall 74809 pharmacokinetics when we looked at total concentrations and unbound concentrations, which means free drug were consistent with that of previous studies. The concentration of 74809 increased approximately proportionally with dose, and the proportion of free drug was 0.3% to 0.5%, which is consistent with prior findings. So we have data now to build -- to put into our population PK model that was derived to project PK parameters, such as AUC0_24 and Cmax. I'll pass it back to Greg.

The enthusiasm for our results are suggested in the current slide, which the change in FVC from baseline to 12 weeks demonstrates what we believe to be a dose-responsive relationship and treatment effect from the 40, 80 and then up to the 160-milligram in contrast to placebo; further exemplified as we move from the left upward panel down -- or excuse me, across, you can see that effect is apparent in the pooled all 74809 group and then subsequently begins to emerge in the 40-milligram group. And in the 80 milligram, we see an inflection upwards or improvement beginning at 8 weeks. And then in the 160-milligram group, we see consistent separation of curves as we move forward. When we look at those on standard of care, we see a similar response. And then as we move forward to those not on standard of care, we again see a consistent, what we believe response there being notably in the 80- and 160-milligram group, acknowledging the reduced number of participants not on standard of care. Additionally, we wanted to look at important features such as a change in the forced vital capacity percent predicted and a decline of greater than 10%, which is a clinically meaningful, and I would argue, a registrationally important change in FVC percent predicted. As you can see and consistent with the absolute change in FVC or mL, there is a decrease, which appears to be dose responsive in the 80- and 160-milligram cohort in contrast to placebo. To summarize these forced vital capacity evaluations, we see that patients with 74809 experienced a benefit in terms of the change in FVC from baseline to 12 weeks with a minus 15 mL to the pooled group compared to the placebo group of minus 74 mLs. This treatment was evident in both those on standard of care, as well as off standard of care. And if we look and focus on the 80-milligram cohort, we see that improvement was approximately 25 mLs, so not simply a reduction of decline. This dose-dependent reduction in the proportion of individuals as we assessed with the percent predicted FVC, we believe, is an important feature and further supports the absolute change in FVC. As we move forward to QLS, we noted a similar phenomenon and consistent change with that of the physiologic change in FVC and that we assessed the mean percent change in QLF extent or percent QLF from baseline to week 12, we see again evidence that would suggest a dose responsive nature with the QLF not progressing in contrast to placebo in the 80 and then not progressing at all in the 160-milligram cohort. To further assess and categorically evaluate individuals, you can see we can determine the minimal clinical important difference of 2%. And if we assess greater than 2%, which would be worsening, minus 2% to 2%, which would be stable or less than minus 2% suggest an improvement. And as you can see in the 80- and 160-milligram cohort, there appears to be a treatment effect in contrast to placebo. That each individual patient is further identified in the drop plot. So these quantitative lung fibrosis data support that there is a dose-dependent antifibrotic effect based on QLF imaging. There was no progression in the 160-milligram group at 12 weeks based on mean change from baseline, and there were a higher proportion of participants who remain stable or improved in the 80- and 160-milligram group compared to placebo. Scott?

Great. Thank you. So here on this slide, what we're presenting are 2 biomarkers of larger panel of biomarkers that will be evaluated in the study, but these biomarkers importantly reflect collagen synthesis that's ongoing in the IPF lung. On the left, it's highlighting PRO-C3 which is the propeptide of type 3 collagen, a fibrillar collagen that is a component of the excessive extracellular matrix that accumulates in the disease. And what you can see very clearly is a dose-responsive reduction in the synthesis of type 3 collagen at 4 and 12 weeks with the highest reduction at 160 milligrams. On the right-hand side is PRO-C6, which is a basement membrane collagen also secreted excessively in the IPF lung with consistent reductions across all doses at 4 and 12 weeks. These markers are particularly interesting because they've previously been shown in large clinical studies to be elevated in IPF and also be further elevated in patients with progressive diseases.

Thanks, Scott. So it's my pleasure to -- now is Dr. Toby Maher's opportunity -- sorry, to share his perspective on this data. Toby?

Thanks. So thank you very much for asking me to be part of the call. And congratulations on the results. I think just to go over them, the safety data, I think, looks very encouraging. As everybody, I'm sure on the call knows the 2 existing treatments that we have nintedanib and pirfenidone have considerable tolerability issues. And we see significant drop-off rates in patients on treatment. So I think in comparison to existing therapies, the data from this 12-week study would suggest that this is better tolerated than either of the existing treatments. And then to move to the efficacy analyses, I think there are some very encouraging signals there. First of all, if we just look at the placebo group, the placebo group behave in the way we would expect an IPF placebo group to do so. They lose over 70 mLs of FVC in the 12 weeks, and that's comparable to many other studies that we've seen published and things that are being conducted in patients on background standard of care. So I think that reassures us that the placebo group is behaving realistically. And then if we look at the active treatment groups, we are seeing a reduction in the rate of FVC decline. Again, based both on the placebo in this study, but also on our historical understanding of [indiscernible] groups behave, to me suggest strongly that the drug is having an effective antifibrotic effect. And then if we move on to the more exploratory analysis, the QLF and the serum biomarkers with PRO-C3 and PRO-C6. Again, although we understand less well, how these measures behave in later phase studies, they are supportive of the FVC data in the sense that they're moving in the direction we would expect them to. So I think for a Phase IIa study, this provides a very compelling package of data to move forward with the compound.

Thank you, Toby, for your insightful comments. As you heard today, the team and I are extremely pleased with these data. And as they mark another step forward, implying development of PLN-74809 as an innovative approach to address the unmet need of the IPF patients. So I want to leave you with a couple of conclusions, program update and next steps for the program. So the results from the study obviously have exceeded our expectations, showing a favorable safety and tolerability profile and a treatment effect on both FVC and QLF. I think, importantly, the fact that treatment effect was also observed on top of standard of care gives us confidence that PLN-74809 has the potential to advance the treatment of IPF. We also recently completed enrollment in the 320-milligram cohort of the INTEGRIS-IPF Phase IIa trial. Interim data from this trial are anticipated in early 2023. And then finally, Pliant also intends on sharing today's data with the regulatory authorities in the near term to discuss the late-stage development plan for PLN-74809. Finally, we would like to thank our investigators and their study teams, as well as the members of the Pliant team for their dedication and support of the successful execution of this trial. But more than that, special thanks to the INTEGRIS-IPF clinical trial participants, their families and support networks for helping us advance this promising program. Okay. With that, let's open the call to questions, Chris.

The queue, Michelle, please go ahead and open up the queue to questions.

[Operator Instructions] Our first question comes from Brian Abrahams with RBC.

Congratulations on the data. My first one is for Dr. Maher, while he's still on. I was wondering if you could talk a little bit more about how these data overall fit in relative to other developmental IPF agents that you've seen with respect to the degree of promise. Might you expect potential improvements in FVC over time with an effective antifibrotic agent? And what would you be looking for here? What would you expect with even higher doses over longer durations with 809? And then I had a follow-up with the company.

And good questions. I think realistically, I think we're expecting an effective antifibrotic to probably stabilize lung function and prevent FVC decline. I think there is a potential that drugs could lead to a sort of small, but clinically important improvement over time, but I doubt we're going to get a drug that's going to truly reverse established disease. But I think aiming for stability and perhaps aiming for even a small improvement is realistic. Where does this sit in terms of other developments? We -- as you'll know, there are some Phase III programs ongoing. FibroGen have previously presented data with those suggesting some beneficial effects in Phase II [Indiscernible] now taken over by Genentech similarly showed a reduction in the rate of decline in FVC over a 12-month study. And then more recently, BI in a 12-week study showed a PD4 inhibitor appeared to prevent decline over 12 weeks. So these data are at least comparable to those that have moved forward into Phase III, and I'm sure everyone who's had any dealings with this field for a long time, will know there have been a lot of failures. So success at this stage is certainly not a guarantee and only really a small number of drugs have proceeded. So I think in the grand scheme, this is a very good result, and I think at least comparable to what into other programs that have moved forward to Phase III.

Got it. That's super helpful. And then in looking at -- maybe a question for management. And looking at the confidence intervals, it looks like they're relatively wide on FVC, not surprising given the endpoint and the duration here. But I'm just curious. Any impact do you think outliers may have had on mean FVC changes and maybe how some of those threshold analysis and any other analysis you've done on medians, for instance, might normalize for that? And then I have one more quick follow-up on safety.

This is Eric. So thanks, Brian. We have seen some patients who did better and some patients that did worse across all the treatment groups, I think. And when we look at given the size of the -- each of the groups, we've also looked at the median changes, which were consistent with the mean. So we think really the treatment effect of 74809 was definitely present in the 80- and 160-milligram dose groups, and it doesn't seem that outliers are explaining that.

Got it. That's super helpful. And then lastly, just real quick in terms of the diarrhea that you've seen. Can you expand a little bit about on, I guess, the manageability and how persistent versus transient that is? And any PK interaction you've seen or might expect with nintedanib that might further explain it?

Thank you. We don't expect any interaction with nintedanib because 74809 is not a -- does not have much DDI liability. It's mainly a substrate for different transporters in isoenzymes. But what's interesting, of course, is that 74809 is a substrate for CYP3A4 and PGP, and so is nintedanib . We will be conducting a formal interaction study, but we have not seen any excess toxicity in terms of the groups. We -- in terms of -- we know that there's more diarrhea in the combination, but we also saw that this was manageable as some of these patients use loperamide to treat and the duration of diarrhea was variable. So for some patients, it started later, some patients it started earlier. In some patients, mild diarrhea tend to persist. But importantly, none of the patients discontinued due to diarrhea.

Our next question comes from Pete Stavropoulos with Cantor Fitzgerald.

Congratulations on this positive data. So my first question is for Dr. Maher. Seems that this data that was presented and then sort of taking into account your clinical experience with the 2 approved agents for IPF, how do you see 74809 fitting into the current landscape or treatment paradigm? And the reason I ask is, I've spoken to a number of treating physicians, and many of them highlighted tolerability issues with the 2 approved agents, which leads to high discontinuation rates of treatment by patients. So when you think about 74809 where it sits mechanistically, sort of above TGF-ß activation and taken into consideration of tolerability profile, how do you sort of see implemented treatment in newly diagnosed patients?

Yes. And that's a good question. My strong suspicion with IPF, like many other complex diseases is that ultimately successful treatment is going for all combination therapy. But having said that, you also allude to the issue of tolerability that we have with existing drugs. So I think as I see it, existing therapies made a huge difference to IPF patients, it's making them live longer. But despite that, they are still dying of respiratory failure. They're still progressing, their diseases getting worse, they're ending up on oxygen. So there remains a need for better treatment. And I think for patients who are on this therapy, the authority would be put on to a second day [Indiscernible] to help ensure that they have disease stability. So I think one of the -- sort of the reassurances [Indiscernible] done on background standard of care. And so the data would suggest that it can feasibly be used as part of a combination treatment. But secondarily, given the fact that sort of 1/3 or more of patients end up discontinuing existing therapies because of tolerability issues, there is a huge need for sort of cleaner, much better tolerated drugs. And again, although it's a Phase IIa study, the early signal would suggest that perhaps this is such a drug where we would see far fewer side effects. So in all likelihood it would be an option for those patients who struggle with the current existing treatments. I think the final point of where would we be if we saw these data replicated in the Phase III study, I think the current challenge we have is that the FDA have not really been allowing trial designs that would allow you to place a new treatment as automatic first-line therapy. So I think if we fast forward 5 or 6 years from now, and imagine that this drug gets approved, then I suspect it would come into the market as an addition treatment on top of existing standard of care and would be used as monotherapy in patients who were intolerant of both existing treatments, and I think one would then want to design a Phase IV program to try and position the drug as automatic first-line treatment.

Thank you. Very helpful. So next question I have is, when you look at Slide 25 and 26, the 80-milligram dose, you sort of -- actually across the doses, you sort of see the change on, on versus off standard of care, it seems to be an inverted U-shaped dose response. Any reasons why? Is it mechanism of action, PK or just an artifact of a small end in the nonstandard of care cohort?

Thanks for the question. This is Eric. We believe it's really a question of small ends and because of course, the study was not powered to look at the efficacy endpoints, these were exploratory, but we think these could likely change with larger populations and certainly longer duration. But what we do think is really strong is the dose response that we see in the category -- categorical assessment of FVC. So that's the percent predictive of greater or equal to 10% where there's the fewest amount of patients progressing are the ones that are on the 160-milligram dose, and that's certainly consistent with what we saw in terms of benefits that we're seeing in terms of the QLF. So together, I think this gives us good confidence that there is a dose response, which we have seen in previous studies as well. They were mechanistic and also on our preclinical evaluation, so we'll just have to be really [Indiscernible]. We have -- we know that the drug is active and it has an effect on FVC and QLF. So we have everything we need to give the confidence to advance the program. And then as we design our Phase IIb study, obviously, this one will be powered adequately to be able to tease out the dose response.

Thank you. And along those lines, when you think about a registrational study, you do look at the responder analysis. It seems to reduce some of the potential confounding effects of the sample size. When you think about -- think about a longer-term study, would it be just a change versus baseline in FVC with regards to the primary endpoint? Or would you and possibly the agencies be interested in responder analysis and that it can be approvable beyond just the absolute change.

Yes. So both are important. So the change in mLs. The actual change in mLs is expected to be the primary endpoint given that that's the news for the other approved agents. But the other agents have also evaluated the 10% predicted FVC change because it is part of the clinical outcomes evaluation. So we will be providing data or evaluating both these endpoints as we move forward.

Our next question comes from Ed Arce with H.C. Wainwright.

Hi, good morning. Thanks for taking my questions and let me add my congrats on this positive data readouts. First question for me. Wondering if you could discuss, and this is for company management, the thoughts around dose selection. Clearly, you have the 320-dose cohort coming up early next year. But from what you have 80-milligram clearly has an absolute improvement in FVC while with 160, you have no progression in QLF. Just wondering if you could discuss your thought process and the criteria by which you would ultimately select 1 or 2 for the next study? And then I have a couple of follow-ups.

Thanks, Ed. So we have -- certainly, from the study results now, really good reasons to consider the 80-milligram and the 160-milligram as part of Phase IIb valuation. What will be interesting for us as we anticipate the results or wait for the results of the 320-milligram cohort, as it will tell us do we keep -- do we continue to see this favorable safety profile being manifested? Can we see even further changes in terms of FVC, also the categorical assessment of FVC and QLF because all these measures will be part of the evaluation at 320 milligrams, and based on this information, then this is going to be really important to see whether the 320-milligram dose could be included, should be considered in late-stage development. But right now, we have enough data -- positive data to really have interactions with regulators later this year to discuss the study design that we intend to pursue in late stage. So -- and then basically, the results of the 320-milligram cohorts will help us inform the dose selection, but will not be needed to be able to advance the program because we have great confidence in the results that we have today.

Right. Okay. And then related to that, Eric, with -- the next question is, would you necessarily expect an incremental improvement in response with the 320-milligram dose cohort, given that you saw at least on the absolute FVC measurement, a stronger response on the 80-milligram versus the 160?

So we -- it's going to be interesting to see that. I mean, obviously, 12 weeks is great findings to see these changes that we've seen in our study now at 12 weeks. And certainly, we're very excited about these results. The 320-milligram dose group will go out to a longer treatment duration, which is supported by the availability of the chronic safety studies -- preclinical safety studies. And so we'll have a treatment that will be administered for at least 6 months, and up to a year. So that's going to give us additional confidence on how really the projection of the curve, how we continue to see whether these, for example, improvements are stabilizing really throughout the 24-week period and longer. I think for us, we would be, I think, maybe we'll be well-served by looking at these data to really see -- to really further support the dose response we're seeing in the categorical change and also in QLF.

As we are coming up on the hour and have several callers in the queue, please limit yourself to one question. Our next question comes from Ritu Baral with Cowen.

Thanks for fitting me in while Dr. Maher is still on. Hi, Dr. Maher. Good to speak to you again after so long. I wanted to ask your opinion about the mechanism and target engagement. And whether you think that we're past the window of concern that was, I guess, first identified with the Biogen program toxicity, the mechanism and target engagement? And whether you think that we're past the window of concern that was, I guess, first identified with the Biogen program toxicity around alpha v beta 6. And I guess any additional details around that one end of IPF that did not resolve at the 160-milligram dose on the slide? Thanks.

It's been a long time since the days of [Indiscernible]. So -- and I think in terms of mechanism of action, we've always recognized that TGF-ß is a very important and integral part of disease pathogenesis in IPF, but at the same time targeting TGF-ß has been constrained by the knowledge that it plays important homeostatic roles, both in the lung and in other organs. And so the targeting of the INTEGRIS, particularly alpha v beta 6 has sort of looked like the most attractive route to damping down TGF-ß activation without interfering too much with homeostatic mechanisms. And I think as you alluded to with Biogen, particularly in the phase sort of Ib, IIa data that they presented, they certainly did seem to see sort of dose response that suggested a negative effect when they over -- when they have their maximal effect on TGF-ß activation. And I guess that's always been in the back of people's minds as a concern when it comes to the safety of this sort of approach. And I think that will remain a safety concern going into Phase III and Pliant particularly has done a huge amount of work, not just with this data, but with other data they've generated to try and alleviate concerns about the safety of this approach. And for me, that data has all been very reassuring. I think it's worth recognizing that this trial that we've heard about today is several times larger than the early Biogen trials where they were already beginning to see a negative signal. So for me, I think there's a lot of reassurance there that this is a pathway which can, with the right approach, be blocked safely. And as I said, I think it's a very important pathway in the pathogenesis of IPF. And importantly, it's not a pathway that is particularly inhibited by either of the existing treatment. So it really makes this drug complementary to existing treatments.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Congratulations on the X1 data. Two questions for Dr. Maher. Thank you for being with us this morning. The first one is, can you maybe comment on sort of expectation when we think about translating this data into a larger study? We have seen a number of failures when investigators run short studies in small population. So given the totality and the comprehensiveness of the data that Pliant has generated, how confident can we be as they will be running a Phase IIb study of a longer duration, more patients per arm, several doses. So if you could just comment on that and what evidence we have, that would be one. And then the second one is, would love to hear your thoughts on the data on the QLF that the company presented. What does this data mean to you in terms of establishing its anti-fibrotic effect? And how widely used is this measure currently in the clinic?

Thank you. So yes, so I think to answer your first question, the best example of a failure after promising early phase data is the sort of recent experience with Galapagos. But I think the difference between what Pliant have done and Galapagos has done is enormous. Whilst I was involved with the Galapagos program, it must be remembered that their first trial and the trial that led to the development of their Phase III program was really a 23-patient study, with only 7 in placebo and designed as a target engagement study with a single dose and essentially because the company were cash rich, they took the opportunity to move that forward very rapidly into Phase III without doing any further enabling studies, without doing any dose-ranging Phase IIb studies. I think, with the data, we're a million miles away from that. Pliant has done lots of target engagement. So we know the drug is hitting the target in the lung. And they have with this Phase IIa study tested a number of doses and to have got the associated PK data, et cetera. So I think in terms of following a logical developmental pathway, Pliant have really sort of ticked all the boxes. So for me, I think we can be in a much more confident position with this drug than we ever were with Galapagos drug, and I think if we compare to perhaps for success, it is similar to the pathway that was taken with nintedanib originally with dose-ranging early phase studies. And I think acknowledging that Phase IIa doesn't guarantee success at IIb or Phase III, I still think we have reason to be confident based on this data. Your second question -- it slipped my mind, whilst I talk.

That was the QLF.

Thank you, Eric. So yes, so I think, as I see it, the QLF data is sort of supportive of the FVC data. So QLF and again, I'm sure most people on the line have a reasonable understanding of this. But essentially, QLF is a computerized algorithm for trying to interpret change in imaging, unlike FVC, where we have a clear understanding of what FVC change means over time in terms of survival and what slowing of FVC change means. With QLF, we perhaps have a broad understanding [Indiscernible] preventing change in fibrosis severity on imaging is a good thing. But we are still learning how to quantify that, and we're still learning how to interpret what any amount of given change means. And so on the QLF data alone, I think it's very hard to understand exactly how that might translate into a Phase III study outcome. But for me, the fact that the data are heading in the same direction as the FVC is very reassuring. And I think the same is true of the serum biomarker data. We don't really understand what given change means. But from what we do know, changing things in the right direction is a positive. And so -- so for me, it's all supportive of the FVC data, and I probably wouldn't try and extrapolate it further than that.

Our next question...

So, I think we'll be losing Dr. Toby Maher at this stage.

Well, thanks for having me on the line, guys and congratulations again on the data.

Thank you.

Thank you.

Our next question comes from Jeff Jones with Oppenheimer.

Thank you, operator. And congrats again to the team on the excellent data. I guess 2 questions for the team. As we look forward, are there other secondary endpoints such as cough for IPF symptom scores we should be thinking about to help differentiate the product? And will you look at things like that in your Phase IIb ahead of the Phase III? And then in terms of timing around the Phase IIb, you've mentioned going to the FDA in the short term, ahead of the 320 mg data and of course, the 320 mg has the long-term readout as well. And so what are you thinking in terms of timing to start the Phase IIb in the context of having data around the 320 mg? And I'll hold there.

Thank you. So to address the first question, we will include patient reported outcome measures as part of the Phase IIb evaluation and also Phase III because these have traditionally been used. And certainly, we know that they're important to the payers and what have you and also to see if whether we can see some benefits from that perspective. So we will definitely be including that. In terms of our regulatory interactions, as I mentioned before, really what we're -- we have the data now in terms of the efficacy -- the strong FVC signal that we see with a favorable safety to meet with the agency and what we want to be talking about is really the strong man of our late-stage development plan where we really want to take the most robust, but also most expeditious path to NDA. And so this will require some discussion with the regulators in terms of what -- how they feel comfortable about our plan because we -- and that -- the reason -- their feedback will really help inform when Phase IIb can start. And I think that's all I'll say for now. But certainly, these regulatory interactions will be needed to determine the start of Phase IIb.

Our next question comes from Thomas Shrader with BTIG.

Let me add my congratulations. Just a quick question on who your monotherapy patients were? Were they all people who couldn't handle standard of care or were some of them treatment naive and there's a hint that some of your best treatment effects are in those patients. Do you think they'll try to get more patients just on your drug?

Yes. So the protocol allowed individuals to participate whether they were on or off standard of care. So these individuals would have been treatment naive for at least 3 months. Whether or not they previously were on treatment or not, we don't have those data readily available. But suffice it to say that the experience and the treatment benefit was in the absence of standard of care, which in total was approximately 20% in our study, but we will evaluate them in our advanced phase program, as we did in the Phase II.

Yes. And maybe just to add some color to that, we definitely are -- we'll be planning to include approximately 30% of patients not on standard of care as part of our Phase IIb evaluation. And we'll certainly be having the information whether they were pretreated and had to discontinue or whether they're truly naive. So this is information that we will have for late-stage studies.

Our next question comes from Joseph Stringer with Needham & Company. Joseph Stringer, your line is open. There are no further questions at this time. I'd like to turn the call back over to Chris Keenan.

Thank you, Michelle. On behalf of my executive team and all of my fellow client colleagues, thank you for joining us this morning. This is certainly a great day for Pliant and potentially for patients with IPF. My team and I look forward to sharing updates from across the Pliant portfolio in the near future. Have a good day, everybody.

This concludes our conference call. You may now disconnect.