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

Welcome to today's conference call hosted by Pliant Therapeutics. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to turn the call over to Vice President of Investor Relations, Christopher Keenan. Please go ahead.

Thank you, Shannon, and good morning, everyone. Thank you for joining us for Pliant's presentation of interim data from our Phase IIa clinical trial evaluating PLN-74809 target engagement using PET imaging in patients with idiopathic pulmonary fibrosis. During this call, we will be referring to the press release that included data charts that we issued this morning, which is available under the Investors & Media section of our corporate website at pliantrx.com. Joining me today with prepared remarks are Dr. Bernard Coulie, President and Chief Executive Officer; and Dr. Éric Lefebvre, Chief Financial Officer (sic) [ Chief Medical Officer ]. Joining us for the question-and-answer session will be Dr. Scott Turner, Senior Vice President and Head of Research; and Dr. Keith Cummings, Chief Financial Officer. 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 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. Now let me turn the call over to Bernard.

Thank you, Chris. Good morning, everybody, and thank you for joining us. It's my pleasure to give a short introduction to Pliant Therapeutics and provide context around the exciting interim data that we announced this morning from the Phase IIa PET imaging trial of our lead program, PLN-74809, and this in patients with IPF. PLN-74809 is an oral once-daily dual selective inhibitor of 2 integrins, avß6 and avß1. We are developing PLN-74809 as a potential treatment for patients with IPF as well as primary sclerosing cholangitis, or PSC. We have Orphan Drug Designation granted by the FDA for both indications. We are currently enrolling patients in the global INTEGRIS-IPF and INTEGRIS-PSC Phase IIa 12-week trials, which are randomized, placebo-controlled trials of PLN-74809. Pliant is the leader in the discovery and development of novel integrin-based treatments for fibrotic disease. Our approach to treating fibrotic diseases is based on an efficient biology-based drug discovery process. Since our founding, we have developed a broad portfolio of integrin targeting drug candidates across multiple fibrotic diseases. We have built a proprietary library of novel integrin binding compounds, which, to our knowledge, is unmatched in the industry. We also established a strategic collaboration and license deal with Novartis, focused on the development and commercialization of PLN-1474 for the treatment of liver fibrosis associated with NASH. So PLN-74809 targets the avß6 and avß1 integrins. These are selectively overexpressed in fibrotic organs such as the lung in IPF and in the liver and biliary tract in PSC. Both integrins drive fibrosis through the activation of TGF-ß, which is the master regulator of fibrosis. By blocking this integrin-mediated activation of TGF-ß, PLN-74809 has the potential to slow or even halt the progression of fibrosis without affecting systemic TGF-ß signaling. This fibrotic tissue specific approach is designed to avoid the many well-known toxicities associated with systemic TGF-ß blockade. Once-daily oral dosing of PLN-74809 will offer a convenient and patient-friendly approach. In order to fuel today's data in their proper context, let me provide you with some additional framework. Many of you may recall that we conducted a Phase Ib proof-of-mechanism trial. In that trial, we showed that healthy volunteers with plasma levels of PLN-74809 above the predicted 50% inhibitory concentration or IC50 experienced significant inhibition of TGF-ß signaling in their lungs. Based on those data, we predicted that a target engagement level of 50% or higher would be necessary in IPF patients in order to provide meaningful anti-fibrotic benefit. Today, I'm very pleased and excited to share with you that we surpassed the 50% threshold of avß6 target engagement at every dose tested. Moreover, the 2 highest doses approached full target saturation or 100% target engagement with 1 patient at 240-milligram dose achieving greater than 95% target engagement. These interim results are compiled from 6 post-dose scans taken from 4 IPF patients treated across single dose cohorts of 60, 120, 240 or 320 milligrams. Included in this morning's press release are 2 graphs that summarize the interim findings that I will now review. At the lowest dose of 60 milligrams, we saw 52% target engagement. At 120-milligram dose, we saw 60% target engagement. In the 2 patients receiving a single dose of 240 milligram, we saw a target engagement of 71% and 98%, respectively. And then finally, in the 2 patients receiving a single dose of 320 milligram, we saw target engagement of 83% and 94%, respectively. Note that target engagement with dose and plasma concentration dependent at a clear dose response was observed in the 2 patients that received 2 different single doses, so patient number 2 and patient number 3. Needless to say that these data have exceeded our expectations. Based on these findings, it is clear that PLN-74809 readily penetrates the highly fibrotic regions of the lungs in IPF patients, and that it binds to its target, the avß6 receptor. PLN-74809 achieved greater than 50% avß6 target engagement in the lungs of all patients across all single-dose cohorts with target engagement levels approaching saturation in the 2 top doses. Please note that the single doses of 60-milligram, 120-milligram and 240-milligram achieved peak exposures that correspond to the predicted peak concentrations of steady state of the doses that are currently being studied in our ongoing 12-week Phase IIa INTEGRIS-IPF and PSC trials. In addition, PLN-74809 was well tolerated across all doses with no serious adverse events reported in the trial. Previous studies with PLN-74809 have demonstrated proof-of-mechanism in human IPF patients as well as favorable safety, tolerability, pharmacokinetics and biological activity in healthy volunteers. With today's interim data, we have now demonstrated PLN-74809's ability to reach highly fibrotic regions of the lungs in IPF patients and achieve near complete inhibition of avß6, a major driver of TGF-ß activation and fibrotic disease progression. Obviously, we are extremely pleased with these results. Now let me turn the call over to Éric, our Chief Medical Officer, to review how these data inform our current and future clinical development plans. Éric?

Thanks, Bernard. As background, the primary goal of this ongoing Phase IIa open-label dose-ranging clinical trial is to measure the degree of target engagement by PLN-74809 on avß6 in the lungs of up to 12 patients with IPF as assessed by changes in avß6 PET tracer uptake before and after administration of a single dose. The trial includes 4 different dose levels to evaluate the relationship between PLN-74809 dose and exposure and the degree of target engagement achieved. PET scans are being obtained prior to treatment to determine baseline avß6 expression levels in the lungs and following a single dose of PLN-74809 at approximately 4 hours post administration to allow achievement of maximum drug concentration. Following a greater than 14-day washout period, patients can consent to receiving a second dose of PLN-74809 at a different dose level, followed by a second post-dose scan. Let me reiterate that these exciting interim results provide us with even greater confidence in our IPF program given the high level of target engagement and the -- and exposure response observed with just a single dose of 74809. With today's data in IPF patients, we believe that PLN-74809 has the potential to provide clinically meaningful anti-fibrotic benefit to patients affected by this serious and debilitating disease. As a reminder, PLN-74809 is a dual selective inhibitor of both the avß6 and avß1 integrins. So if you consider the encouraging interim data presented today on avß6 target engagement alongside the established published data showing that avß1 also plays a critical role in pulmonary fibrosis, you can understand our excitement. Given the encouraging dose response and the pharmacokinetic and pharmacodynamic correlation observed with these interim results, we are positively looking forward to the full readout from this trial. In summary, these interim data provide us with great confidence in the dose selection we are exploring as part of our ongoing Phase IIa INTEGRIS-IPF 12-week trial and to be tested in future late-stage trials. At Pliant, we are driven to advance novel treatments to patients in areas of unmet medical need with a focus on fibrotic diseases, and we truly believe that today's data takes us one step closer to delivering on our mission. Let me now turn the call back over to Bernard. Bernard?

Thanks, Éric. 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 PLN-74809 as an innovative approach to addressing the unmet needs of the IPF patient. With that, let's open the call to questions, Chris.

Shannon, please open up the call.

[Operator Instructions] Our first question comes from Ritu Baral with Cowen.

I just wanted to ask a little bit further about the tolerability and safety profile that you've seen. What were the most common AEs? And also, did you see any -- one, any dose-dependent increase -- clear dose-dependent increase in the most common AEs? And were there any even nonserious pulmonary or respiratory adverse events reported?

Thanks, Ritu. So for this specific PET trial, there were no reported AEs or no reported SAEs. Of course, this is a single dose in a limited number of patients, but it's actually the first time that we have unblinded patient data in terms of safety and tolerability. As for the drug itself, in terms of the Phase I studies or study that we have done evaluating safety, tolerability and pharmacokinetics in healthy volunteers, the AEs that were observed are very low in terms of frequency, and most of them are mild. I think most frequently reported AEs were headache and some constipation. There was no dose dependency going from 40 all the way up to 320-milligram multiple dose.

Got it. And nothing of a respiratory or pulmonary nature?

No, nothing. No -- what we would argue definitely not in the patients, but also not in the healthy volunteers, anything that would suggest on target safety considerations as it relates to TGF-ß blockade. And to your point, that could be, for example, worsening of symptoms in IPF patients or inflammation or anything like that. None of that was observed.

Very helpful. Great. And then just as you -- I know you only have 6 data points here. But as you think of dose selection, given what you said that the AE profile was not dose dependent in nature and that, as we previously discussed, you're getting sort of pSMAD saturation at around 50% to 60%. What do you think like do you need the 320 dose? Are you more interested in the 120 to 240? How should we be thinking about the rest of the doses in the study? And how you view the Phase IIb doses?

So for the PET trial itself, of course, we want to complete the study with the doses that we have now at hand. As for the ongoing Phase IIa IPF trial, the INTEGRIS-IPF trial, which is a global trial, currently, to your point, we are dosing 40, 80 and 160 milligrams, and we want to complete that study. Obviously, we have no safety data at 320 milligrams. And we are, I would say, evaluating the possibility of do a dose -- to do a dose extension in that Phase IIa study. But let me remind you, this would not affect at all the timing of enrollment and the timing of getting top line results for the ongoing study at the cohorts that are being evaluated at this point in time. If you look at the PET data, to your point, we see more than 50% target engagement at all the doses we have tested. And of course, we want to maximize our chances for success. But what is extremely, I would say, encouraging is the fact that even at the lower doses, which are corresponding to the lower doses in our ongoing Phase IIa trial, we are seeing that target engagement. So it means that we are within an anti-fibrotic range for all the doses that are currently being evaluated. So I hope that answers your question.

Our next question comes from Joseph Stringer with Needham & Company.

Congrats on the data. Just a couple of quick ones. Can you say, with the 2 patients who underwent the 2 different doses, were they step ups to the -- from a low dose to a high dose? Or was it vice versa? And was there any -- can you disclose any of the FVC baseline values for these patients? And I guess sort of looking towards the Phase II, the dose-ranging trial, you have FVC and you have various imaging measurements. How do you see some of the initial data kind of -- what the best measure of translatability into sort of the imaging readouts that you would see in the dose ranging?

Thanks, Joe. So in terms of the 2 patients that were dosed, in both cases, this was a step-up. So for patient 2, it went from -- first visit was 120 and the second dosing was 240. For patient 3 was 240. That was the first dosing and then 320, the second dosing. So it was a step-up in both cases. We can't step down as well as we move forward, but it happened to be like this. In terms of baseline characteristics, so I think the key point to remember here is that the patients in terms of inclusion criteria is based on FVC of 45% or higher, which basically delineates your patient population to mild -- to -- from mild to moderate. We didn't see any meaningful differences in baseline characteristics amongst the 4 patients. But of course, it's too early to kind of draw any conclusions because this is a very small sample population. So once we have the study completed, of course, we will report on the full set of patient characteristics. But so far, they are pretty similar at baseline. In terms of what do we expect? What is the exploratory endpoint? One would argue that could be determined to a certain extent to what we see today. I think we have 2 exploratory endpoints in our Phase II IPF trial that relate to disease and potential effect on disease. One is FVC, forced vital capacity, which I think is the clinical measure, but which I don't expect to be meaningfully changed by what we see today. This is really kind of fibrosis, and fibrosis and anti-fibrotic activity is measured by another exploratory endpoint that we are evaluating being QLF, quantitative lung fibrosis score. And so based on this, one could potentially anticipate there could be changes on QLF in terms of patients being treated with active versus placebo. Forced vital capacity is a measure that we take along in our Phase IIa study. But so far, nobody has ever been able to show significant changes in this specific endpoint in a small Phase IIa study that only lasts for 3 months, relatively small Phase IIa study for 3 months. You will need more patients, of course, and a longer duration, which we are planning to do in our Phase IIb. The impact of the current PET trial on that Phase IIb is obvious in terms of dose selection, right? It will help us to understand which doses are corresponding to the amount of target engagement and will help us to optimize that dose selection moving forward in Phase IIb and beyond.

Our next question comes from Tom Shrader with BTIG.

Congratulations on the data. You have a little bit of an embarrassment of riches in target engagement. As we think of the ongoing IIa study, should we now think of all of the doses of that study corresponding to very high target engagement? So maybe most appropriate to pool the 3 doses and maybe have a little better read on PD? Or is it too early to say?

I think it's a bit too early to say. I mean just as a reminder, the doses we're giving here in the single dose or that we are evaluating in the single dose of 60, 120 and 240 milligrams are corresponding to 40-milligram, 80-milligram and 160-milligram multiple dose in terms of peak exposure, as I've mentioned before. I mean it gives us, indeed, I would say, confidence in terms of mix that we are right in terms of dose selection with those 3 doses. And we want to kind of evaluate them further. In terms of -- if I understand the question right, in terms of pooling it, I think that's what you were specifically asking for, stopping here. Is that what the question was, Tom?

Well, just with the half-life of your drug, which is very long, sort of, a back of the envelope calculation says the 40 mg dose is already going to be very high target engagement at steady state.

Yes. So I think we want to kind of evaluate it and get it through, and that's what we want to do. And we want to continue in our ongoing IPF PET trial as well to just kind of add more dots to the curve that you see in the press release to kind of make the predictive power of this PK/PD model even more robust than it is already. But yes, I mean we are very confident that the 40-milligram will already kind of generate some significant anti-fibrotic activity. But of course, if we can kind of continue dosing to higher doses, we want to kind of optimize towards success there.

Okay. And then just 1 quick question. You'd given us average target engagement. What we see or are there detailed scans to get a sense of whether very fibrotic areas are equivalent to less fibrotic area? Is there more structure to come that we'll see at a medical meeting? Or is the average readout what we're going to see?

No. The full analysis will contain more data in terms of how highly fibrotic regions are selected, and that's based on concurrent CT scans that are taken at the same time as the PET imaging scan is taken. So there are more data. The data set will be richer than what we have today. But we -- the initial analysis was focusing on understanding target engagement -- percentage target engagement in these highly fibrotic regions, pre and post -- I mean obviously, post dosing. There's more data that are in this pretty rich data set.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Congrats on the data. I have a number of questions for you. Maybe the first one to start off would be to talk about the variability and receptor occupancy between patients. So if you look at the 240-milligram dose group, you see a delta difference of almost 27%. I guess what I want to understand is, is this variability and receptor occupancy at the same dose within expected? And given that the 60-milligram and 120-milligram has only 1 patient data, how do we feel comfortable that maybe as you add additional scans to these -- to the data that we continue to stay above 50%? So if you could just maybe comment on that. And then the second question for you here is, what does this data set mean based on your modeling on the level of pSMAD changes that you would be seeing? And then I have a follow-up.

Okay. Thanks, Yas. So in terms of the variability, to your point, there is variability between the two 240s and actually there's also variability between the two 320s. This variability that we observe is basically inherent to the measurement and the image acquisition and analysis as well as a PK from a single dose administration. There's -- none of the doses given are exactly the same in terms of the plasma concentration -- corresponding plasma concentration. So I think what is important here is the fact that we have a clear dose response in the individuals that received 2 different single doses. So you're referring to patient 2, for example. There is a clear increase going from 120 to 240 and the same in patient 3 going from 240 to 320. Although that's not a big delta in terms of dose, we still see a corresponding effect in terms of target engagement. What is our confidence that we will remain over 50% target engagement? I think we need to complete the study. I think what we have seen we were extremely surprised and positively surprised to see already 50% at 60 milligrams. That needs to be confirmed. And so it's our intention to have at least 3 scans on a per cohort basis. So we only have 1 at 60 and 1 at 120. So we want to add 2 more at least in each of those cohorts. And so basically, I think -- I mean it's hard to predict, but I think based on what we have seen, I'm quite confident that we will remain around the target engagement levels that we have seen so far. But again, we need to increase the end value. So the second part of your question relates to the connection, if I may call it like that, between our pSMAD studies in healthy volunteers versus what we see today. I think if you think about it, it's remarkable how well the current interim target engagement data connect with those data that we observed in our Phase Ib study. So from the Phase Ib study, we concluded that the threshold for inhibition was the IC50 concentration, which is very close in terms of free plasma concentration to the EC50 that we observed in our target engagement study. So it's very much in the range there. And moreover, it turns out that the same plasma concentrations that lead to 50% target engagement of 50% inhibition in our preclinical models that we have used, including human IPF tissue. Again, these concentrations are very, very close to each other. So it seems that we are able to connect the dots between our cell-based systems or human IPF tissue systems where we look at pro-fibrotic gene expression or pSMAD study in healthy volunteer and now ultimately also in our target engagement study in IPF patients.

Very helpful. Maybe another question for you is do you -- can you comment on sort of enrollment progress in the IPF study? Are you on track to finish enrollment by year-end? And should we be expecting probably another data set from the target engagement with more patients on it over the next few months by year-end? So if you could comment on that, that would be helpful for us.

So in terms of enrollment for the IPF trial, we are on track to complete enrollment by the end of the year. For the PSC trial, we are on track to complete enrollment first half 2022. We do not provide guidance in terms of timing of finishing the ongoing PET trial to measure target engagement for the simple reason that I just cannot predict it. It's a complex trial where it's in a single center. And just that acquisition and overall image analysis takes time. So we don't provide guidance in terms of the exact timing of completing this trial.

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

Thanks, Shannon. On behalf of my executive team and my fellow Pliant colleagues, I would like to 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, everybody.

This concludes today's conference call. Thank you for participating. You may now disconnect.