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

Alright, good morning. Welcome back to the JPMorgan 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 about the company. There'll be a Q&A after the presentation. There'll be a mic circulating around the room. And 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 JPMorgan 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. And 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 antifibrotic effect. So what I will discuss today are 2 programs. First Bexotegrast, formerly known as PLN-74809, which is currently in Phase IIa 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 IIa setting over 3 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 alpha(v)beta8, alpha(v)beta1 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 nondilutive 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. So this is our development pipeline. Beyond Bexotegrast, which is a dual inhibitor of alpha(v)beta8 and alpha(v)beta1 and PLN-101095, we have PLN-101325, which is a allosteric activator of a muscle laminin binding integrin called alpha7beta1. 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 alpha(v)beta1. Again, this is a program that will enter Phase II testing, but is being conducted by Novartis. So in terms of anticipated milestones for 2023, in terms of the Bexotegrast INTEGRIS-IPF program, we will have 320 milligram data coming up. So interim data -- 12-week interim data, early first quarter, so that's a matter of a couple of weeks from now. And then in the second quarter of 2023, we will have our 24-plus week final data of this cohort. In terms of the INTEGRIS-PSC study, it's enrolling very well, and we anticipate top line data for 40 milligrams, 80 milligrams, and 160 milligrams in the third quarter of this year. The Phase IIb in IPF with Bexotegrast is anticipated to start mid-2023. For PLN-101095, we will start Phase I first in human and patients early second quarter 2023. So we have a year filled with -- we have a number of catalysts -- sequential catalysts, so quite excited about that. So 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 versus the approved programs, the current commercial landscape in IPF is basically driven by Esbriet as well as Ofev. Both generated over $3 billion in revenue in 2020 alone, and it's still growing, but 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. So Bexotegrast offers a preferred treatment option based on 4 characteristics. First, its antifibrotic mode of action, so there is a direct antifibrotic effect in tissue through the active inhibition of TGF-beta, which we have shown in our Phase IIa study. Also based on the data from our Phase IIa study, we've shown that the drug works both in monotherapy as well as in combination treatment with the approved programs. But 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. And then 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. So Bexotegrast blocks both alpha(v)beta1 and beta6. Those are 2 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 2 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 profibrotic genes and ensuing fibrosis. What is key to understand is that these 2 receptors are selectively upregulated only in fibrotic tissue. So 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 and what I show here is human tissue work in patients' tissue, patients with IPF undergoing a lung transplant, and we get fresh tissue in the lab, and 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 profibrotic genes in response to a number of treatments. These are tissues from 5 different IPF patients. And what we see is that with single inhibition of alpha(v)beta8 or beta6, you see some reduction in Col1a1 expression levels. But if you combine both or you look at Bexotegrast, we see a significant reduction, down to 50%. So blocking both gives you an additive effect in terms of antifibrotic activity. And this is not just on Col1a1 but actually on a whole spectrum of profibrotic 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. So 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 stock studies that have been done up to 9 months in monkeys and 6 months in mice, there are absolutely no findings and the NOAEL1 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. And so 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; repro tox, no findings. So at least based on our nonclinical tox studies, the drug seems to be very safe. We have dosed I think over 600 human participants to date, both patients and healthy volunteers, up to 640 milligrams as a single dose or 320 milligram multiple dose. And again, there are no safety concerns so far. Before I dive into the Phase IIa data, just as a reminder, these are target engagement data that we generated using a PET ligand against alpha(v)beta8. This was in collaboration with Stanford. These are data that we released I think it was in the fall of '21 showing that with increasing doses we have increase in target engagement in the dose and plasma concentration dependent manner. This is critically important because it looks like we are able to fully saturate the target at the higher doses. 320 milligram, and this is a single dose administration, 320 milligram on this slide corresponds to about 300 milligram I would say at the peak concentration level in a multiple dose setting. So it approaches the higher dose that we are currently testing. 240 milligram as a single dose on this slide corresponds to about 160 milligram in a multiple dose setting, which is the highest dose tested so far and the data I will show you in a minute. So the INTEGRIS-IPF study read out in the summer of last year. We looked at 3 different doses, 40 milligrams, 80 milligrams, and 160 milligrams 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 3 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 equally balanced between both Ofev and Esbriet. And 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. So this is the summary of the data. First, 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. So in a pooled analysis, there was a 15 milliliter decrease in FVC versus 74 milliliter with placebo. What is key here is that the effect was evident with and without standard of care. Actually, in the 80 milligram dose group, we saw an improvement, so a plus 24 milliliter 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. So these are the FVC data change from baseline to week 12. As you can appreciate, at 80 milligrams, we actually had an increase in FVC; at 160 milligrams, we had a decrease of 25 milliliters compared to placebo, which was 74 milliliters in total. Again, 80% of these patients are on standard-of-care. If we look at the time course of the event, what is notable -- notably in the pooled analysis as well as at 80 and 160 milligrams is how quick the drug works. So we see a separation of the curve already at 4 weeks. Just to remind you, we reached steady state with this drug, so we reached optimal concentrations around Day 7. 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 160 milligrams, there was only 1 patient that progressed beyond 10%. Again, this is a strong predictor of disease progression and mortality. If we look at QLF, so quantitative lung fibrosis, which measures the amount of fibrosis in the lung by means of a high-resolution CT, we see that at 160 milligrams, there's no progression of fibrosis over a 12-week treatment period. And then finally, if we look at some biomarkers for fibrosis or fibrogenesis, such as PRO-C3 and PRO-C6, we see already at 4 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 160 milligram 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 62%, with Esbriet 26%. Recent data from a new Behringer drug, a PDE4 inhibitor in monotherapy showed 17% incidents in diarrhea. That doubled when combined with standard-of-care. In our case, Bexotegrast monotherapy zero percent. There was no incidence for -- there was no evidence for diarrhea. Only when combined with standard-of-care, we saw numbers that increased because of standard-of-care. So the 320 milligram cohort is ongoing. It's a very similar design as the 40 milligrams, 80 milligrams, 160 milligrams, except for the fact that we will treat for at least 6 months up to 48 weeks. Just as an interim analysis, I would say, we have now passed -- all patients have passed 6-month treatment mark, have been dosed beyond 6 months. We had 2 DSMB reviews. The DSMB also sees this data SAEs -- any SAEs on a monthly basis, and so far there's no concern whatsoever. The 12-week interim data will be presented early first quarter, so that's a matter of couple of weeks. What we will present is exactly the same as for what we have presented before. So safety, PK, tolerability, as well as a number of exploratory endpoints, including FVC, QLF, and biomarkers. The 24-week plus data, so the study will stop when the last patient -- last visit happens at 6 months -- will be released and the top line data will be presented in the second quarter of this year. Bexotegrast is also being studied and PSC. So the INTEGRIS-PSC study is recruiting well. We had some initial delays in terms of pickup of patients. With the recent stopping of the Gilead trial, we saw significant influx of those PSC patients into our trial. So anticipated top line data will be third quarter. What we will present are 3-month data on 40 milligrams, 80 milligrams, 160 milligrams. What is key here is that one of the exploratory endpoints is PRO-C3. And as you know, I showed the data, we had a dose-dependent effect on PRO-C3 already in IPF. That's a sign of clear antifibrotic activity, so I think this bodes well for this study as well. Switching gears now to our second program, which is a dual selective alpha(v)beta8, alpha(v)beta1 integrin inhibitor aimed at reprogramming the immune-suppressive tumor microenvironment of solid tumors. We know that alpha(v)beta8 drives TGF-beta activation, very much like alpha(v)beta1 and alpha(v)beta6, except it's expressed on immune cells, on T cells, and it has a central role in immune suppression in solid tumors. Our drug is a highly selective inhibitor of alpha(v)beta8 but also alpha(v)beta1. So this dual mode of action blocking alpha(v)beta8 in T cells and alpha(v)beta1 on fibroblasts is quite different from some of the existing programs that are in the clinic which are antibodies against alpha(v)beta8. It's also oral dosing because it's a small molecule, obviously. No major findings in the 28-day GLP tox, so NOAEL 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. And this will be in patients. So some data here. So PLN-101095 basically 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 beta8 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 reduction in TGF-beta activity, an increase in the number of genes that are regulated by interferon gamma, including granzyme B, interferon gamma itself, CXCL 9, and notably PDL1. In combination with an anti-PD-1, we see a significant reduction in tumor growth. This is again in the EMT6 breast cancer model, and we see an increase -- significant increase in survival. And 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 growth, 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. But summarizing what we have seen, we have an oral alpha(v)beta8, beta1 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 alpha(v)beta8 antibody alone or even in 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. So that concludes my presentation. Thank you for your attention and happy to take any questions.

Thanks, Bernard. I guess I can start off while the mics are circulating. So, again, just picking up on the data presented so far from INTEGRIS-IPF, the common question we get is the expectation around dose responsiveness as you dose escalate up to the 320 milligram 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 mean FVC change going from 80 milligrams to 160 milligrams. I guess how do you square that -- circle that knot a little bit? And I guess how do you -- I guess your confidence that you're not approaching a biphasic pattern as you dose-escalate to 320 milligrams.

Yes, absolutely. Thanks, Eric. That's obviously a question we get a lot. 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 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. So there is no evidence for a reduction in effect at higher doses. And again, here in this study it's also shown actually PRO-C3, we see it on FVC percent predicted more than 10% increase in terms of proportion of patients getting there and QLF. So I would say 3 out of 4, 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. And the fact that we see a positive effect on 80 milligrams, that's great and a little bit less on 160 milligrams, but I think most of that can be explained by the fact that FVC itself is just a variable endpoint, and you need many more patients and a longer duration I think to really confirm a dose response moving forward. So 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 320 milligram. Is this going to be even less effect? I think what will be good for us, what we will consider as a good outcome of this study is an effect with 320 milligrams that is within that same range as 80 and 160 milligrams and confirm safety. And that will definitely drive selection of that dose moving forward together with 160 milligrams because our Phase IIb study will study 2 doses. And right now based on what we know, it's 160 and 320 milligrams, but, of course, we have to wait for the data.

All 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 320 milligrams, there's plenty of discussion around a recent publication about the pro-tumorigenic activity of alpha(v)beta8 inhibition related to bladder cancer. I guess any concern or have you investigated directly Bexotegrast's activity on that potential outcome, I guess, in a similar model? And I guess from a mechanistic standpoint, does alpha(v)beta1 perhaps interacts or compensate for any of this pro-tumorigenic activity reported with alpha(v)beta8 inhibition?

So let me start with the publication itself and what we saw. So 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. And this was a 28-day GLP tox study in nonhuman primates, showing already after 28 days of dosing at the higher doses, 2 millimeter lesions, cancer that was invasive into the lamina propria. We have dosed the exact same monkeys. So these are mainland Asian cynomolgus monkeys for 9 months and didn't see anything. And we went back to the slides and revisited everything. We didn'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 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. And then ultimately, I think the most potent alpha(v)beta6 out there, I mean [indiscernible] meanwhile is the Biogen antibody. They did their chronic tox. They never saw bladder cancer. So 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 alpha(v)beta1 may [ contra ] compensate some of that, to be quite honest, we have no data, except for the fact that alpha(v)beta6 in our opinion does not drive bladder cancer.

Just coming back to the utility of the 320 milligram dose cohort. I suppose we already talked about the potential for additional dose responsiveness and perhaps maybe 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 sets -- where you might have an informed expectation as to where FVC or fibrosis improvement could go with longer-term exposure? Perhaps also just thinking mechanistically, any compensatory mechanisms that might counteract or impede the initial benefit that you're seeing so far clinically with 12 weeks exposure, so 12 weeks of treatment?

Yes, I think, again, we saw a dose response effect in all the different systems that we tested, including in patients using the PET study. But if you look at those target engagement data that I showed in my presentation, you do see a saturation at 160 milligrams, 320 milligrams. So what are you going to generate additional benefit is something that remains to be seen. I think the reason we want to study 320 milligrams, if it's safe, and we are convinced there is no blunting or reduction in efficacy, is because we can, right? It's 7x still below NOAEL, and it will allow us to minimize I would argue risk of variability, whether it's PK exposure, et cetera, moving forward in this 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 and that's definitely something we want to study in our Phase IIb study where we will power sufficiently to have a monotherapy group that will allow us to evaluate that effect in that specific setting. So we will have 30% of patients in our Phase IIb design that will be on just our drug and no standard-of-care. So for us, again, there's no evidence, nothing that would suggest that 320 milligrams is not a good dose to be studied from an efficacy perspective. The only thing that would stop us, of course, if there is a safety signal. And to your point, we will have 6 months and beyond data that will notably be important to deal with that safety question. So, yes.

Would it necessarily be a fair apples-to-apples comparison comparing the 320 milligram cohort data with the lower-dose cohort data that you presented so far in terms of aligned baseline patient characteristics?

Yes, we don't expect it to be much different from the study that I just presented because basically we continued using the same centers. And so it's not that there was an interruption of the study. Once actually the lower doses were enrolled and the study was completed, the 320 milligrams started enrolling in the same center. So we don't anticipate -- there was not like a time lag and it's basically the same centers. So 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. So we will be able to compare apples to apples. Moreover, for the 12-week data, we will use the placebos also of the existing 40 milligrams, 80 milligrams, 160 milligrams, and we'll pull those. So we put extra power into the study. It's not just 7 patients. For the 6-month data, of course, we will only have a small group of placebo patients because we didn't treat our lower doses beyond 3 months. And so again that will be very much a safety evaluation.

Okay. And just on the regulatory piece leading up to the start of the Phase IIb trial, I guess any additional interactions with the 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 IIb, one of which was a seamless Phase IIb, Phase III design and the other one being a Phase IIb standalone. And so the FDA recommended to do a standalone Phase IIb 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 and 48 weeks probably.

Okay.

And as I mentioned, we will have 30% of patients that are not on standard-of-care in that study.

Okay. So, there is a defined monotherapy group within that.

And it will be powered to show effect, yes.

Just pausing for any questions from the floor. Maybe a couple questions on the PSC just given upcoming data in third quarter from INTEGRIS-PSC. I guess just generally speaking what would clinically meaningful dataset look like in that study? And then also just generally speaking around 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?

So the first part of your question is way easier to answer than the second part. So 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 biomarker such as PRO-C3 is actually predictive or correlated with clinical outcome. So PRO-C3 or higher levels of PRO-C3 basically have a negative impact in terms of transplant-free survival. So 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 3 months. We know that these biomarkers, based on our IPF experience and also published data, respond quickly. So as you saw in our IPF trial, we had response after 4 weeks already. And so 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 more morphologic changes within 3 months remains to be seen, but 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, it's a risk. Are we going to look at some of these validated biomarkers and use them as at least coprimary endpoints. We know that histology in NASH is, for example, quite challenging, but at least in NASH you have fibrosis that affects the entire liver in a diffused way. PSC is way more patchy from a liver fibrosis perspective. So a biopsy, there's a high risk or high chance for missing any changes in fibrosis. And 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 coprimary endpoints that include serum biomarkers that have been validated for fibrogenesis.

Okay, all right. Think we might leave it there for time if there are no questions from the floor. So, Bernard, thank you very much for your time this morning. Great presentation.

Thank you.