All right. Good morning. Welcome back to the JP Morgan Healthcare Conference. I'm Eric Joseph, Senior Biotech Analyst with the firm. Our first presenting company this morning is Pliant Therapeutics, and it's my pleasure to welcome and introduce CEO Bernard Coulie to talk to us a bit about the company. There'll be a Q&A after the presentation. There'll be mics circulating around the room. For those joining online, feel free to submit any questions through the digital conference book. So with that, Bernard.
Thanks, Eric. Good morning, everybody, and thanks for joining us so early in the morning. I want to thank JP Morgan for giving us the opportunity to present the company. At Pliant, we are focused on developing novel treatments for fibrotic diseases, and to that end, we have developed an industry-leading fibrosis platform. The platform itself is based on inhibition of integrin-mediated TGF-beta activation. TGF-beta, as you may know, is a key regulator in initiating and propagating fibrosis. Out of this platform, we have developed a number of drugs that have been shown to be safe and, in case of our lead program, have a clear anti-fibrotic effect. What I will discuss today are two programs. First, bexotegrast, formerly known as PLN-74809, which is currently in phase II-A for IPF and PSC.
We will go over the data that we presented in the summer of 2022, showing that the drug was well tolerated in a phase II-A setting over three months of treatment, with a clear effect on FVC and a number of biomarkers for fibrosis in patients with IPF. Secondly, I will discuss also a new program called PLN-101095. The IND was submitted late last year. This is a potential first-in-class selective αvβ8, αvβ1 integrin small molecule inhibitor addressing immune checkpoint inhibitor resistance. We are in a strong financial position. Our balance sheet at the end of the third quarter had $360 million in cash.
That's both non-dilutive from our collaboration with Novartis, as well as a follow-on financing in the summer of last year of $230 million, catalyzed by the positive data. This is our development pipeline. Beyond bexotegrast, which is a dual inhibitor of αvβ6 and αvβ1, and PLN-101095, we have PLN-101325, which is a allosteric activator of a muscle laminin binding integrin called α7β1. This is a program that's aimed at muscle diseases, notably muscular dystrophy, as well as fibrosis in the muscle. IND filing is expected by the end of this year. Of course, we have PLN-1474, which is owned by Novartis. This is a program focused on treating NASH-associated liver fibrosis through inhibition of αvβ1.
Again, this is a program that will enter phase II testing, but has, you know, is being conducted by Novartis. In terms of anticipated milestones for 2023, in terms of the bexotegrast INTEGRIS -IPF program, we will have 320mg data coming up. Interim data, 12-week interim data, early first quarter, that's a matter of a couple of weeks from now. In the second quarter of 2023, we will have our 24+ week final data of this cohort. In terms of the INTEGRIS- PSC study, it's enrolling very well, we anticipate top-line data for 40mg, 80mg, and 160mg in the third quarter of this year. The phase II-B in IPF with bexotegrast is anticipated to start mid-2023.
For PLN-101095, we will start phase I, first in human in patients, early second quarter, 2023. We have a year filled with a number of catalysts, sequential catalysts, so quite excited about that. Going back to bexotegrast and trying to understand a little bit the IPF commercial opportunity here. We did quite some work in trying to understand how we can position this program, you know, versus the approved programs. The current commercial landscape in IPF is basically driven by Esbriet as well as Ofev. Both generate over $3 billion in revenue in 2020 alone, and it's still growing. There is. It's changing. Esbriet went generic in 2022, and Ofev will lose market exclusivity, at least in the U.S., in 2025.
There's also a significant need for new therapeutic options in the sense that Esbriet and Ofev display only a slow, or a modest slowing of IPF progression, with no improvement in terms of patient quality of life or survival benefit. On top of that, and I think this is the key issue, there is a significant tolerability issue related to notably GI side effects. Bexotegrast offers a preferred treatment option based on four characteristics. First, its anti-fibrotic mode of action. There is a direct anti-fibrotic effect in tissue through the active inhibition of TGF-beta, which we have shown in our phase II-A study. Also, based on the data from our phase II-A study, we've shown that the drug works both in monotherapy as well as in combination treatment with the approved programs.
This is once-daily dosing of a pill versus the existing programs where our existing approved products where you have multiple pills over multiple administrations per day. Finally, I think last but not least, from a safety and tolerability perspective, the drug is well-tolerated. We have no GI side effects whatsoever when we compare it to the approved treatments. Going back to the basic biology. bexotegrast blocks both αvβ1 and αvβ6. Those are two integrins that are selectively upregulated in fibrotic tissue, and they're responsible for the upstream activation of TGF-beta, which is, of course, the master regulator of fibrosis. bexotegrast blocks the interaction between these two integrins and latent TGF-beta, thereby blocking the activation of TGF-beta upstream of its receptor. As a consequence, we see a significant reduction of pro-fibrotic genes and ensuing fibrosis.
What is key to understand it is that these two receptors are selectively upregulated only in fibrotic tissue. Basically, we block TGF-beta, but only in fibrotic tissue without affecting systemic TGF-beta signaling. Thereby, the drug is devoid of any of the typical toxicities that you will see with systemic TGF-beta blockade. Why blocking both? We did a number of experiments, what I show here is human tissue work, in patients' tissue, patients with IPF undergoing a lung transplant, we get fresh tissue in the lab, we basically run these assays looking at our drugs and effects compared to, for example, competitor programs. What you see on the left is the expression levels of COL1A1, which is one of the key pro-fibrotic genes, in response to a number of treatments. These are tissues from five different IPF patients.
What we see is that with single inhibition of αvβ1 or αvβ6, you see some reduction in COL1A1 expression levels. If you combine both or you look at bexotegrast, we see a significant reduction down to 50%. Blocking both gives you kind of an additive effect in terms of anti-fibrotic activity. This is not just on COL1A1, but actually on a whole spectrum of pro-fibrotic genes, we see that same effect. Turning to safety now. When we look at our GLP studies that we did actually with all our compounds, not just bexotegrast, we see no single evidence for any systemic TGF-beta blockade-related toxicity. You see some of these typical toxicities on the left-hand side, such as cardiotoxicity, specific skin cancers or bleeding.
With our drugs, we haven't seen any of that. If we look at the overall safety profile in our GLP tox studies, repeat those tox studies that have been done up to nine months in monkeys and six months in mice, there are absolutely no findings, and the NOAEL has been set at the highest dose testing. There are no pulmonary infiltrates, there are no bladder cancer. There was a recent report on that. There's absolutely no evidence for any toxicity. We don't have to do any additional repeat dose tox between now and the NDA. If we look at safety pharmacology, no findings. Genotox, no findings. Reprotox, no findings. At least based on our known clinical tox studies, the drug seems to be very safe.
We have dosed up, I think, over 600 human participants to date, both patients and healthy volunteers, up to 640 mg as a single dose or 320 mg multiple dose. Again, there are no safety concerns so far. Before I dive into the phase II-A data, just as a reminder, these are target engagement data that we generated using a PET ligand against αvβ6. This was in collaboration with Stanford. These are data that we released, I think it was in the fall of 2021, showing that with increasing doses, we have increase in target engagement in a dose and plasma concentration dependent manner. This is critically important because it looks like we are able to kind of fully saturate the target at the higher doses.
320mg . This is a single dose administrations, 320mg on this slide corresponds to about 300mg , I would say, at the peak concentration level in a multiple dose setting. It kind of approaches the higher dose that we are currently testing. 240mg as a single dose on this slide corresponds to about 160mg in a multiple dose setting, which is the highest dose tested so far in the data I will show you in a minute. The INTEGRIS-IPF study read out in the summer of last year, we looked at three different doses, 40mg, 80mg, and 160mg compared to placebo. Primary endpoints were safety, tolerability, and pharmacokinetic properties of the drug.
The exploratory endpoints included change in Forced Vital Capacity or FVC, effect on QLF or quantitative lung fibrosis as a measure of lung fibrosis through high-resolution CT, and effect on selected biomarkers for fibrogenesis. The treatment duration was three months. 90 patients in total were randomized and treated, 67 active, 23 placebo. Very low discontinuation rate in general, and we had no discontinuations in this study due to drug. What is key here is at the very bottom is that 80% of patients across all the different cohorts were on standard of care with kind of equally balanced between both Ofev and Esbriet. This was important because it allowed us to measure the effect of the drug on top of standard of care, but also to measure the drug in monotherapy setting. This is the summary of the data.
Bexotegrast was well-tolerated over 12 weeks of treatment. Most adverse events were mild or moderate in severity. No discontinuations due to AEs, no deaths or drug-related SAEs. The treatment itself resulted in 80% reduction in FVC decline. This was beyond expectations. We had never expected to see this kind of effect on FVC, notably in such a short study with such a low number of patients. In a pooled analysis, there was a 15mL decrease in FVC decline in FVC, sorry, versus 74 with placebo. What is key here is that the effect was evident with and without standard of care. Actually, in the 80mg dose group, we saw an improvement, so a + 24mL improvement in FVC. There was also a dose-dependent reduction in the proportion of patients having an FVC percent predicted increase beyond 10%, and I will come back to that.
This is an important predictor or prognostic marker for progression and mortality. We saw similar treatment effects on a number of imaging and serum markers for fibrosis, so QLF, PRO-C3, and PRO-C6. These are the FVC data change from baseline to week 12. As you can appreciate, at 80mg , we actually had an increase in FVC. At 160mg , we had a decrease of 25mL compared to placebo, which was 74mL in total. 80% of these patients are on standard of care. If we look at the time course of the event, what is notably in the pooled analysis as well as at 80mg and 160mg , is how quick the drug works. We see a separation of the curve already at four weeks.
To remind you, we reach steady state with this drug, we reach optimal concentrations around day seven. Looking at the proportion of participants or patients with an FVC percent predicted decline of more than 10%, we see a clear dose response. At 160mg , there was only one patient that progressed beyond 10%. This is a strong predictor of disease progression and mortality. We look at QLF, quantitative lung fibrosis, which measures the amount of fibrosis in the lung by means of a high-resolution CT, we see that at 160mg , there's no progression of fibrosis over a 12-week treatment period.
Finally, if we look at some biomarkers for fibrosis or fibrogenesis, such as PRO-C3 and PRO-C6, we see already at four weeks for PRO-C3 a dose-dependent reduction, similarly at 12 weeks. On PRO-C6, we saw a reduction versus placebo as well, but there was no dose dependency there. At 12 weeks for the 160mg PRO-C3 reduction, it was nearly significant. One of the big issues with the current treatments that have been approved for IPF are GI side effects. If you look at the historical data of diarrhea incidents in these trials, in these placebo-controlled randomized clinical trials, you see with Ofev, 26%, 62%, sorry, with Esbriet at 26%.
Recent data from a new Boehringer drug, a PDE4 inhibitor in monotherapy, showed 17% incidence in diarrhea. That doubled when combined with standard of care. In our case, bexotegrast monotherapy, 0%. There was no evidence for diarrhea. Only when combined with standard of care, we saw numbers that, you know, increased because of standard of care. The 320mg cohort is ongoing, very similar design as the 40mg, 80mg, 160mg, except for the fact that we will treat for at least six months, up to 48 weeks. Just, as kind of a interim analysis, I would say all patients have passed six month treatment mark, have been dosed beyond six months. We had two DSMB reviews. The, Sorry.
The DSMB also sees this data, SAEs, any SAEs, on a monthly basis. So far there's no concern whatsoever. The 12-week interim data will be presented early first quarter. That's a matter of a couple of weeks. What we will present is exactly the same as for what we have presented before. Safety, PK, tolerability, as well as a number of exploratory endpoints, including FVC, QLF, and biomarkers. The 24+ week data, the study will stop when the last patient, last visit happens at six months, will be released or the top-line data will be presented in the second quarter of this year. The bexotegrast is also being studied in PSC. The INTEGRIS-PSC study is recruiting well. We had some initial delays in terms of, you know, pickup of patients.
With the recent stopping of the Gilead trial, we saw significant influx of those PSC patients into our trial. Anticipated top-line data will be third quarter. What we will present are three month data on the 40mg, 80mg, and 160mg . What is key here is that one of the exploratory endpoints is PRO-C3. As you know, I showed the data, we had a dose-dependent effect on PRO-C3 already in IPF as a sign of clear anti-fibrotic activity. I think this bodes well for this study as well.
Switching gears now to our second program, which is a dual selective αvβ8, αvβ1 integrin inhibitor aimed at reprogramming the immune-suppressive tumor microenvironment of solid tumors. We know that αvβ8 drives TGF-beta activation very much like αvβ1 and αvβ6, except it's expressed on immune cells, on T cells. It has a central role in immune suppression in solid tumors. Our drug is a highly selective inhibitor of αvβ8, but also αvβ1. This dual mode of action, blocking αvβ8 on T cells and αvβ1 on fibroblasts, is quite different from some of the existing programs that are in the clinic, which are antibodies against αvβ8. It's also oral dosing because it's a small molecule, obviously.
No major findings in a 28-day GLP tox, so no AL set at the highest dose tested. IND was submitted in December. We anticipate to have it open by the end of this month, and first-in-human study will start March or April. This will be in patients. Some data here. PLN-101095 basically kind of rebalances the gene signatures, TGF-beta versus Interferon-gamma. We know that patients that are resistant to anti-PD-1, this is driven by a high TGF-beta signature, low Interferon-gamma signature. What we see with the drug is that we tip that balance towards high Interferon-gamma, low TGF-beta, thereby resensitizing the tumor against anti-PD-1. High β8 gene expression, be it on tumor cells or infiltrating T cells, is linked or correlates with worse prognosis, and this has been published before.
When we look at some of our data, this is single agent activity, albeit in a short-term study in EMT6 breast cancer model. We see a reduction in tumor volume as well as an infiltration of CD8 positive T cells into the tumor. When we look at some of the gene signatures in this specific experiment, we see a reduction in TGF-beta activity, an increase in a number of genes that are regulated by Interferon-gamma, including Granzyme B, Interferon-gamma itself, CXCL9, and notably PD-L1. In combination with an anti-PD-1, we see a significant reduction in tumor growth. This is again in the EMT6 breast cancer model. We see a significant increase in survival. We saw the same data in a pancreas tumor model showing a significant reduction.
in combination with an anti-PD-1, in terms of tumor grow, a reduction in TGF-beta signaling, as well an increase in CD8 positive T cells. All of these data have been presented at SITC. There was a poster. I think it's available on our website. There's much more data there. Summarizing what we have seen, we have an oral αvβ8 β1 inhibitor that has activity in multiple PD-1-resistant tumor models. We see actually, I didn't show those data, but it's available on the poster, a greater reduction in TGF-beta signaling compared to an αvβ8 antibody alone or even a TGF-beta antibody. We also saw a significant reduction in tumor fibrogenesis. As I mentioned, the first in-human study will start second quarter 2023. That concludes my presentation. Thank you for your attention, and happy to take any questions.
Well, thanks Bernard . I guess I can start off while mics are circulating. Just picking up on the data presented so far from INTEGRIS-IPF, I mean, a common question we get is sort of the expectation around dose responsiveness as you dose escalate up to the 320mg dose, right? I guess the trend is supportive of dose responsiveness looking at FVC percent predicted of greater than 10% decline, but not so much when looking at excuse me, mean FVC change going from 80mg- 160mg . I guess how do you sort of square that circle, that knot a little bit?
I guess your confidence that you're not approaching sort of a biphasic pattern as you dose escalate to 320mg?
Yeah, absolutely. Thanks, Eric. That's obviously a question we get a lot. I mean, that's a disadvantage of showing an effect on FVC in the first place, which we didn't expect. I think couple of things. First, based on our, all our preclinical work, target engagement work in patients using the PET approach, actually also looking at TGF-beta signaling in lungs in healthy volunteers, we consistently saw a dose response. There is no evidence for kind of a reduction in effect at higher doses. Again, here in this study, it's also shown on actually PRO-C3. We see it on FVC percent predicted more than 10% increase in terms of proportion of patients getting there, and QLF.
I would say three out of four, at least in this study, was dose-dependent in terms of the endpoint changing. Part of the issue is the variability and the noisiness of FVC, I think. The fact that we see a positive effect on 80mg , I mean, that's great, and a little bit less on 160mg , but I think most of that can be explained by the fact that FVC itself has, is just a variable endpoint. You need many more patients and a longer duration, I think, to kind of really confirm a dose response moving forward. We're not worried about that at all. I think. One of the key questions we get all the time is what do you expect in your 320mg ? Is this going to be kind of even less effect?
I think what will be good for us, what we will consider as kind of the, a good outcome of this study is that an effect with 320mg that is within that same range as 80mg and 160mg, and confirm safety. That will definitely drive selection of that dose moving forward together with 160mg because our phase II-B study, will study two doses. Right now, based on what we know, it's 160mg and 320mg, of course, we have to wait for the data.
Right. I'm sure another common question you get, and which you addressed in your presentation is the safety profile, particularly as you're, as you're looking to dose escalate with 320mg. There's plenty of discussion around a recent publication about the, I guess, the pro-tumorigenic activity of αvβ6 inhibition, related to bladder cancer. How, I guess, any concern or have you investigated, directly, bexotegrast activity on that potential outcome, I guess, in a similar model? I guess from a mechanistic standpoint, does αvβ1 perhaps, you know, interact or compensate for any of this pro-tumorigenic activity, purported with αvβ6 inhibition?
Let me start with the publication itself and what we saw. For those who haven't read the paper, this was a paper published by AbbVie, and it's a Morphic compound. These data go back actually to probably 2018, 2019. The compound never went into the clinic because of that toxicity. This was a 28-day GLP tox study in non-human primates showing already after 28 days of test or dosing, at the higher doses, 2mm lesions, I mean, cancer that was invasive into the lamina propria. We have dosed the exact same monkeys, so these are mainland Asian cynomolgus monkeys for nine months and didn't see anything. We went back to the slides and revisited everything.
We don't see any bladder cancer or any epithelial lesion or hyperplasia whatsoever in any other organ. If that would have been the case, there was no way that we would get the IND at the end of 2018 and then move into the clinic. The FDA saw these data from AbbVie and Morphic. Morphic actually reported on this in their 10-Q third quarter 10-Q 2019, that they had a pre-IND meeting, and because of the tox findings, couldn't move forward. The FDA was aware of this. They have seen all our data. There was never a concern. We ran a study. In that specific paper of AbbVie, they also referred to hyperplasia of epithelial cells, notably in bile duct, in a specific model, a DDC model of bile duct fibrosis.
We ran that model a couple of years ago, looked at the same markers of hyperplasia, didn't see anything. There was absolutely no evidence for cholangiocyte hyperplasia or proliferation. Ultimately, I think the most potent αvβ6 out there, I mean, stopped meanwhile, is the Biogen antibody. They did their chronic docs. They never saw bladder cancer. We are convinced that this is not on target. We are definitely convinced this must be off target. Second part of your question, Eric, whether αvβ1 may contra compensate some of that. I mean, to be quite honest, we have no data except for the fact that αvβ6, in our opinion, does not drive bladder cancer.
All right. Just coming back to the utility of the 320mg dose cohort. I suppose, you know, we already talked about sort of the potential for sort of additional dose responsiveness and perhaps maybe the, one of the more informative aspects of that cohort would be the longer term exposure going to 24 weeks, and perhaps beyond.
I guess, anything from preclinical modeling that sort of sets where you might have an informed expectation as to where FVC or sort of fibrosis improvement could go with longer term exposure, perhaps, you know, also just thinking mechanistically, any compensatory mechanisms that sort of might counteract or impede the initial benefit that you're seeing so far, clinically at with 12 weeks exposure, 12 weeks of treatment?
Yeah, I think, I mean, again, we saw a dose response effect in all the different systems that we tested, including in patients, using the PET study. If you look at those target engagement data that I showed, in my presentation, you do see kind of a saturation at 160mg, 320mg. Whether you're going to generate additional benefit is something that remains to be seen. I think the reason we want to study 320mg, if it's safe, is, and we are convinced there is no kind of blunting or kind of reduction in efficacy, is because we can, right?
It's 7x still below NOEL, and it will allow us to kind of minimize, I would argue, risk for a variability, whether it's PK exposure, et cetera, moving forward in this, you know, hard to treat patient population. I think one of the reasons we want to do it is that Maybe there is additional benefit, notably in a monotherapy setting. That's definitely something we want to study in our, in our phase II-B study, where we will power sufficiently to have a monotherapy group that will allow us to evaluate that effect in that specific setting. We will have 30% of patients in our phase II-B design that will be on, you know, on just our drug and no standard of care.
For us, again, there's no evidence, nothing that, you know, would suggest that 320mg is not a good dose to be studied from an efficacy perspective. I mean, the only thing that would stop us, of course, is if there is a safety signal. To your point, we will have six month and beyond data that will notably be important to kind of deal with that, you know, safety question. Yeah.
Will it necessarily be, sort of a fair apples-to-apples comparison, comparing the 320mg cohort data with the lower dose cohort data that you presented so far, in terms of, you know, aligned, baseline patient characteristics?
Yeah. I mean, we don't expect it to be much different from the study that I just presented because basically, we continued, you know, using the same centers. It's not that there was an interruption of the study. Once, actually the lower doses were enrolled and the study was completed, the 320mg started enrolling, so in the same center. We don't anticipate. There was not like a time lag, it's basically the same center. I don't anticipate much change in patient characteristics, be it on standard of care, time of diagnosis, number of years on standard of care, things like that. We don't anticipate that to be much different. We will be able to compare apples to apples.
For the 12-week data, we will use the placebos also of the existing 40m, 80mg, and 160mg , and we'll pool those, right? We put extra power into the study. It's not just seven patients. Sorry. For the six month data, of course, we will only have a small group of placebo patients because we didn't treat our lower doses...
Yeah.
-beyond three months. Again, that will be very much kind of a safety evaluation. so.
Okay. Okay. Okay. Just on the regulatory piece leading up to the start of the phase II-B trial, I guess, any additional interactions with agents, FDA or other regulatory bodies, that you plan to have ahead of starting that study?
Not anymore. We had those interactions, and we discussed a number of different development plans, or at least designs for a phase II-B. One of which was a seamless phase II-B, phase III design, and the other one being a phase II-B standalone. The FDA recommended to do a standalone phase II-B study followed by a phase III study with an end of phase II meeting in between. It will allow us to start earlier than anticipated, so mid this year and to complete the study also quicker. In terms of duration of that study, Eric, our Chief Medical Officer and his team are still working on that, but it would be anywhere between 36 weeks and 48 weeks probably.
Okay. Okay.
As I mentioned, we will have 30% of patients that are not on standard of care in that study.
Okay. There is a defined monotherapy.
Absolutely.
-group within that.
it will be powered.
Okay.
to show effect. Yeah.
Okay. Just pausing for any questions from the floor. Maybe a couple questions on the PS, on PSC, just given upcoming data in the third quarter from INTEGRIS-PSC. I guess, you know, just generally speaking, what would sort of clinically meaningful data set look like in that study? Also just generally speaking, around sort of what does the ultimate registration path look like in the indication right now, just given that there really hasn't, there isn't, an approved precedent at the moment?
The first part of your question is way easier to answer than the second part. What will be success is if we see an effect on a number of these fibrosis biomarkers, notably, that will be success. Unlike in IPF, in PSC, a biomarker such as PRO-C3 is actually predictive or correlated with clinical outcome. PRO-C3, higher levels of PRO-C3 basically have a negative impact in terms of transplant-free survival. If we see a reduction of PRO-C3 and some of the other fibrosis biomarkers such as ELF, I would say that's success. We don't do biopsies, so there's no histology. It's only three months. We know that these biomarkers, based on our IPF experience and also published data, respond quickly.
As you saw in our IPF trial, we had response after four weeks already. If we see that same happening, same effect happening in our PSC trial, I think that's success. On top, of course, safety. We have some imaging there as well. Whether we see morphologic changes within three months remains to be seen. You know, that's part of the measurements we do. What is beyond that? I think that's a whole conversation that is happening and that we also will have with the regulators is, like, are we going to focus on histology endpoints and the noisiness of that? You know, it's a risk. Are we going to kind of look at some of these validated biomarkers and use them as at least co-primary endpoints?
We know that, you know, histology in NASH is, for example, quite challenging, but at least in NASH you have fibrosis that affects the entire liver in a kind of diffuse way. PSC is way more patchy from a liver fibrosis perspective. A biopsy, there's a high risk or a high chance for missing any changes in fibrosis. You know, the FDA is aware of that, and I think that's part of a conversation that we and others are having, in terms of trying to think with them, like, can we replace this or at least can we have co-primary endpoints that include serum biomarkers that have been validated for fibrogenesis?
Okay. All right. I think we may leave it there for time if there are no questions from the floor. Bernard, thank you very much for your time this morning. Great presentation.
Thank you.
Yeah. Thank you.