Good morning, everyone. Thank you to those of you in the room, as well as those dialed in on the webcast. My name is Faisal Khurshid. I'm one of the senior biotech analysts here at Jefferies. We're here live at the Jefferies Global Healthcare Conference in New York. Really pleased to have with us today management team of Tvardi Therapeutics, joined here on the stage by CEO Imran Alibhai. Imran, really great to have you here with us. Could you start by introducing the company? Yeah. Great. First, thanks for having us doing this fireside chat. Tvardi Therapeutics is a biotech company founded in 2018, and our focus has been STAT3. STAT3 is an incredibly well-known transcription factor, where we have known that it sits downstream of all the signaling cascades we hear. When you think about an inflammatory or proliferative disorder, you think about the cascades that drive those, whether they be immune modulation, whether they be cytokines, whether they be growth factors, all of which are signaling to the cell. Every one of those targets have been interrogated previously, and we have drugs to almost every one of those targets. What's interesting is there is redundancy in all those targets, and they all signal into STAT3. STAT3 has been this holy grail type of target which people have been going after for about 20 years now, which is a transcription factor. Once it is activated by these external signaling cascades, moves into the nucleus and drives the not only intrinsic proliferation and inflammatory steps that we see, but extrinsically in the immune compartment, we see immune dysregulation. That is something that is common in malignancies, but also common in a variety of inflammatory disorders. The company was founded on the basis of one of our co-founders, a guy named David Tweardy, who actually identified STAT3 30 years ago. If you ever wanted a KOL in the field of STAT3, it's him. What we identified and what we developed was a small molecule that's orally delivered, which we've now tested in, oh, God, well over 300, going into 400 patients now. I'm excited to tell the story from where we were, which was a pre-clinical company five, six years ago, into a company that's treated many, many patients to learn tremendous amounts about what it is to drug a STAT3 inhibitor. Got it. Excellent. Thank you for the overview. You had two programs here. There's TTI-101, which is your more first-gen program, and then TTI-109, which is your next-gen program. For 101, you evaluated this in REVERT-IPF. Can you talk to us about the key findings from there? If I can just be blunt about it, tell us what went wrong. Yeah. No. What are you doing to come back from that? Yeah. No, no, it's great. It was a bit of a disappointing outcome, we've actually gone back through and looked at the work, and looked at what happened in that trial, and we actually learned some pretty interesting things. As a background, we decided to go, we have a parallel path, one in oncology and one in pulmonary fibrosis, initially for our first generation molecule, TTI-101. 101 was really the proof of mechanism in the pulmonary fibrosis space. Then we said, "Hey, our next generation molecule, 109, would be used to address that," used to basically move forward there and retain 101 for oncology. What we did in that study and what we had shown pre-clinically is that we could actually reverse fibrosis in animal models, and it was quite interesting, and restore lung function. We thought, "Okay, let's go ahead and do this trial." The trial was an all U.S. trial. It was a blinded trial in two arms of our drug versus placebo on top of the standard care of nintedanib. We reported out data in October, when we originally had the data, the initial set of data, and there were two really confounding factors. One, we saw in the placebo arm, in every other trial that we been tested the same, or been tested with the same patient characteristics that we had, we didn't see the placebo drop. Normally, when you look at IPF trials, you look at a forced vital capacity, and what we saw normally is anywhere between 70-110 mils over a 12-week period. There was only a 22 mil drop. That conflated things. The other issue, which is an issue for everybody in the IPF field, is that particularly on top of nintedanib, we saw a higher than expected discontinuation rate. That led to having much smaller numbers than we had anticipated of patients who completed. Really the majority of those dropouts were really driven by GI events. When you look at nintedanib, we already know if you look at the phase III data for nintedanib, 62% of those patients get some sort of GI or diarrhea. The conflagration of those two events together made comparisons difficult. We did do another analysis, which was actually quite intriguing. We went back and we said, "Okay, yes, we had a higher discontinuation rate, but if you did complete trial, what happened to you?" We looked at what are the quantitative markers we can look at. You know the IPF space as well as anyone, and we normally look at FVC as our endpoint. FVC is even intra-patient, there's changes. When we said, "Okay, what other quantitative markers can we look at?" For the patients who completed trial, we went back and we looked at fibrosis, and we looked at a marker that's incredibly well-known in the STAT3 pathway, which drives a lot of disease, which is IL-6. What we saw was a pretty encouraging event, and that is in animals, we could say, "Hey, we could therapeutically reverse fibrosis." Then in humans, we actually saw the same thing. We saw that there was a 7% placebo-adjusted rate of fibrosis reduction. The way we measured fibrosis is pre- and post-treatment, and we looked at high-res CTs, and we looked at them independently and in a blinded fashion. It was encouraging because every other trial we've ever seen in this space, or that I'm aware of anyway, has always said there is an increase in fibrosis in the placebo arm, and then in the treatment arm, we prevent that increase. This is the first trial I'm aware of that, particularly over a 12-week period, where there is an actual decrease in the fibrosis. That, again, ties to what we had seen pre-clinically. Similarly, we saw a very nice trend in the exact same fashion with IL-6. Yeah. A couple of questions on that. Yeah. Yeah. Please. The idea of kind of evaluating the trial on the basis of the patients who completed the trial. Yeah. I think you get it, like for a lot of investors. Yeah. They hear that and they're like, "Well, is that legit? Yeah. Can you kind of defend the. Yeah. Can you defend that a little bit? Yeah. No, no. I think you're right. I think is, what are we doing when we're looking at a post hoc analysis? I think you can't fudge, let's say, a quantitative score, right? When you look at those patients who complete a trial, you're saying, okay. We're just looking at because those are the only patients where we can get both pre- and post-fibrosis numbers, right? Or we can get pre- and post-IL-6 numbers. I think the differentiation is not only are you seeing a difference, but the difference is in a scale that others have not shown before. I think that's really where the differentiation was, is that, look, pre-clinically, we've shown this, and now clinically, this proof of mechanism has been repeated. I think particularly the trend of how it occurred. It wasn't like, oh, we prevented an increase in fibrosis. It seemed to be that those patients on treatment were actually showing decreases in fibrosis. I think I am, like I said, unaware of anyone who's shown anything like that, particularly whether it be a 12-week trial or a 52-week trial, but particularly in a 12-week trial to see that change was very encouraging to us. If you had actually said to me, "A priori, do you think you would see this?" I'd be, "Probably not. It's too short of a time period. To have something that we can quantitate was encouraging to us. Are we saying, "Look, this is the end all, be all. We're going to move straight to a phase III?" No. Right? We understood that there was limitations about what had happened in this trial. It gives us actually a really nice conduit into with our next generation molecule, which we think will address some of the issues that we saw. Yeah. In this trial. Yeah. To kind of simplify. Yeah. Is the argument, which I think I can get along with. Yeah. The argument you're essentially making is that analyzing the trial on a completers basis is valid for a super objective measure, maybe less so for something like FVC, but more so for something like HRCT fibrosis measurement. 1,000%. I think that's exactly right. Right. I think that's true not only for HRCT, but also other blood measures like IL-6, which again, is complete quantitation. Yeah. There's nothing we can't say, hey, there's some change here that would have intra-patient change in a smaller time period like FVC does, or diffusing lung capacities where you're basically blowing into a tube. Right. Right? Yeah. If that's the argument, can you maybe just remind us and explain to us the level of validation that exists for fibrosis quantification? How do you quantify this in the study? How well validated is this? Just kind of give us some confidence in that actually being an accurate and objective measure. I think that we use the same, every time an IPF patient comes into a trial or into a doctor's office, there is a methodology to assess basically components of their fibrosis. This is the same methodology we use. This isn't anything that was a methodology that isn't distinct. This is the same fibrosis score that every physician uses when they have a patient come into a trial. The way we did it, again, is to say that we took patients pre-treatment and then post-treatment. All of the scans were read independently. They were read on a blinded fashion. There couldn't have been, from that perspective, anything that we could change or any way manipulate to come to an answer. I think, again, I'll say it one more time, what we've seen previously is in other trials. Not many folks report fibrosis, I don't think people can showed, we haven't been able to showed disease modification. In the IPF space. We've shown really good shows of changing symptomology, right? We still see patients continue to do worse over time. To really change the trajectory of an IPF patient, we really need to change the basis of the disease. This is the first trial that I'm aware of anyway, that actually shows a decrease in fibrosis as opposed to others that said, "Hey, we just prevented the increase in fibrosis when you look at the trial." That, again, why it's encouraging to us is because that's exactly what we saw in the models, in the animal models. That is that gold standard model where therapeutic treatment can, in our hands anyway, show the reversals. Got it. Makes sense. Maybe, I know I'm giving you a hard time. Yeah. Please. Yeah. Please. Maybe one last- Yeah. Hard question. We'll go to. Yeah. Anytime. Yeah. I'll go to what you're doing next. Yeah. In terms of the overall trial execution. Yeah. Obviously for investors, one important thing to consider here is when you're thinking about the path forward, thinking about trial execution, and kind of fixing that going forward. Yeah. In terms of the very high discontinuation rate. In the study, can you just walk us through how was that not caught earlier, and what are you doing from a trial execution basis to address that going forward? A couple things, right? The trial was overseen by a safety monitoring committee, which is composed of folks who've been in the IPF space for decades, right? We had consistent meetings with them over time, and we asked that exact same question, and we said, "We were blinded to the data, and we were blinded to the information on what was occurring." We asked them, and they were like, "Well, the discontinuations were diarrhea." Right? "We see this in nintedanib patients. This is not uncommon for us." There was no life-threatening reason to pause the trial. I think the other thing that they said to us that was very interesting, and when you look at the data, we could oversee discontinuation rates overall for the trial, and those numbers stayed stable. Interestingly, we referred back to us the nintedanib phase II trials, which the rates of discontinuation of the placebo arms were in the mid-to-high 20s, and the rates in the treatment arm for nintedanib was in the low 30s, basically. We sat there the whole time. It was until, throughout the whole period of the trial, we're watching, looking at the overall rate, and it stayed stable even into April, which was the last time we had our SMC meeting, where, again, we were blinded to the data. Again, from our perspective, from a blinded perspective, we weren't seeing this. Clearly, towards the end of the trial, it has been a much, there was a much higher rate of discontinuations, particularly on top of nintedanib, and I think that was one of those idiosyncrasies of that trial, and even the SMC said to us, they were like, "It's really surprising. To see what you saw in your trial, particularly, it was very unexpected to see why these patients weren't showing decreases in placebo because if we'd shown those decreases in placebo, I think we're having a different conversation here. Yeah. Right. Yeah. Yeah. I guess part bad luck as well is kind of what you're saying? Yeah. I think if you were to go back into an IPF trial, it needs to be a longer trial. Yeah. Right? I think that's one of the issues. The other issue is you're facing a backbone therapy where everybody's struggling with, right? We are actually talking to the same SMC members about what their experience is with the newest drugs. With nintedanib and Jascayd now, the new drug by the PDE4 inhibitor- Yeah. The people are really struggling to keep patients on nintedanib and Jascayd at the same time. Yeah. Yeah. I think that's another issue that people are struggling with. I think IPF is great. We have new drugs that are now going to be available. It's become very, very expensive, but the backbone therapies cause a lot of issues in the first place, you have to think about, "Okay, if I'm going to incorporate into that into a future trial, let's see how we manage that appropriately. Yeah. Makes sense. You went back to the drawing board. Yeah. You have TTI-109. Yeah. Tell us about what TTI-109 is, and I think you have some data coming up, like any day now? Yeah, exactly. We'd said that the data would come out in June, so we didn't go back to the drawing board because of this. We went back to the drawing board years ago. Yeah, you've had it all along. Yeah. We'd always told the street, our board, and everyone associated with the company that 109 was our go-forward molecule in the non-oncology space. The reason we liked 109 is that a few years ago, we looked at 101, and we looked at the structure, and we said, "This is a really interesting molecule. It has everything we want in the fact that it has PK, it has PD, and we've seen activity in oncology studies, we had seen activity across every model that we've tested this in." We looked at it, and when you look at the structure, you can see it's a small molecule. It's under 500 kDa. What was really interesting is that it is incredibly insoluble and very apolar, which makes it difficult to formulate. We went back to the drawing board on the simple basis of saying, "Hey, can we generate a molecule that is easier to handle and would give us a better drug from the perspective of how do we deliver this molecule orally?" We actually found that if we simply added a phosphate group to this molecule, now this molecule, what we termed 109, was inactive. We gave that, and it turned into, again, orally delivered. The idea was with 109 is that once it is ingested and then passes through the gut and then into the blood, where we have all these phosphatases, that it would then convert into the active moiety. What did that give us? What it did, and what we showed in our animal studies, in our IND-enabling work, was something very interesting is that, one, we showed that 109 converted into 101 very rapidly. We have data, and it's in our published decks, that show in a rat and in even in a monkey, at even the highest dose, that within two hours, you can see a small amount of 109 left, but almost well over 95% of it has converted. But the other benefit. That's after first pass GI metabolism, or? Yeah, exactly. From what we can tell, right? Because we're looking at blood exposures. The other thing that we saw that was really interesting, exciting, is that we know 109 is inactive. Right? We know that has no activity. What that did is it solved two different problems. One, it made a drug much easier to formulate and deliver. It also gave us patent protection for a new chemical entity. But also, I think the thing that was exciting to us is that you're basically getting no exposure of the active moiety in the gut itself, on the luminal side. It's going to where you want it to do once it passes through into the cells of interest and into the blood, right? I think the one issue, again, in the IPF study that was really detrimental was GI. A lot of that's delayed based on the background of what you're taking. Now having this, removing that aspect potentially could be very, very intriguing, as we go into other indications or into indications general in the non-oncology space, where we either have to deal with background therapies or as a single agent. Got it. When you say that 109 is inactive, you mean against STAT3 inhibition? Yeah. What was the tox that you saw? Was that mediated through STAT3, or was that due to some other idiosyncratic off-target? Yeah. That's a good question, right? That's a good question. We have seen that if you look at other inhibitors that relieve immune suppression, for example, think of PD-1, CTLA-4 inhibitors. A lot of those have background diarrhea as well. I think in this instance, what we're expecting is that because you're not having any of the active moiety in the gut, but you're passing through it, and you're getting the activation, then you see that. I think in our preclinical work, which we'll be putting out here very, very soon, we'll be able to show you that, look, we retain activity, but based on the way of the mechanism of the molecule, because we know that the 109 is not active towards STAT3 at this point, that we should potentially be in a better situation than we were before. Got it. The phase I data that you have coming up, just clarify for us, that is phase I healthy volunteer data? Right. The idea there was is in rats and in monkeys, we had shown that, hey, this molecule rapidly converts into the active moiety. It has no tox, just like 101 had no tox in the IND-enabling studies, and that we could show a dose-dependent increase. The more 109 we gave, the more 101 we got in the blood. We actually went to the FDA and the oncology division and said, "Hey, could we move this forward?" They were like, "Yeah, go right ahead. You could go into an Optimus design." We as drug developers said, "We want to repeat these experiments in humans. We want to show the same things we've shown in rats and monkeys in a human being." That's exactly what we've done. It's a three-part study. It's a study where we have a SAD study and a MAD, a single ascending and multiple ascending. Very common. Everybody are pretty accustomed to that. The other thing that we're looking at in this study is effectively a bioequivalence, where we're looking at intra-patient, where a patient gets 101, or they get 109 a few days later, or 109, or their 101, and vice versa, and showing, hey, intra-patient, do we see, when we give molar equivalents of the drug, do we see similar exposures? The idea there is not only on a PK perspective are we able to show what we need to show, which is rapid conversion as well as equal exposure. More importantly, we can also say we're going head-to-head. We're saying, look, we have placebo arms, we have treatment arms, and then those treatment arms are composed of 101 versus 109 to look at not only safety, but then to look at pharmacodynamics as well. Every one of those components will feed into then saying, "Here's a story. Here's why we think this is a differentiated molecule from our first-generation molecule, and one then we can push forward into a variety of different indications," which we can talk about. Got it. Makes sense. Super interesting on the PK side. You're looking basically at conversion from 109 to 101. Yeah. You're looking at comparability between 109 to 101. Yeah. 101 just given by itself. Yeah. Safety, you want to check that box. Yeah. What about PD? Are there inflammatory markers like IL-6 or anything downstream of STAT3 that you can look at, even in a healthy volunteer setting? There is, and that's something that we're excited to talk about and walk through with folks when we release the data. One of the things that we can look at, and one of the things that we're incorporating into this trial is looking at FACS. Which is basically looking at immune profiles of patients. Can we change, even in a healthy volunteer, immune profiles of certain cell types that we think are important? We've actually shown that in mice. For example, when you look at a mouse, you can take a mouse and you can treat a normal mouse with our molecule, and you can show down regulations of specific cell types and immune cells that are relevant in disease. That translates beautifully when you go to a diseased mouse. I think the same idea here is to look at those similar immune cell types and say, "Can we show a decrease here?" What does that portend for disease indications where we know those are drivers of the disease? Got it. Yeah. With respect to that, are there specific benchmarks for some of those immune cell changes that investors should be thinking about or prepared to see? Yeah, I think it's a healthy volunteer, right? If you had STAT3 activated in the blood of a human being, that's a problem. You have lymphoma, right? You're going to have a leukemia. I think what you're looking for and what we hope to show here is to actually show, look, is there a modulation where you would expect that? Again, what's compelling to us is we've seen this in animals. We've seen it in a healthy mouse that we can down-regulate certain immune cell types. Again, when we go into a diseased mouse, or one being induced disease and inhabit that, those same populations change as well. I think it is indicative of what will occur. There is no absolute threshold. If we knew absolute thresholds, we'd be pre-treating everyone, right, on how to prevent a whole variety of disease types. Got it. Pharmacologically from your preclinical data for 109, you actually had a few different disease models that you looked at, not just a pulmonary fibrosis or bleomycin type of situation. Yeah. Are you still expecting that IPF would be the main indication for this, or what does that look like? I think IPF is a changed space, right? I think you have to definitely do longer studies. I think that was one of the take-homes from this trial. I think also you have a multitude of other drugs, or a couple other drugs that have now will be or are approved. It makes for a more challenging landscape. I think what we've actually pointed to and publicly released, because it's all published, is data that across a variety of modalities where are inflammatory and proliferative, that are immune dysregulated, and we've highlighted published papers that are across the board. Things like diseases of the colon, of the GI tract, excuse me, everything in the IBD space, from ulcerative colitis to Crohn's disease. Similarly, we've shown diseases where there's skin proliferation, where we know that where there's an inflammatory and proliferative response, also where there's immune dysregulation across the board. We think that's interesting. The reason we think these are interesting indications, because some of these indications you don't have to be on a background therapy. Like oncology, we switch from one therapy to the next. You don't have to stay on the background, so which solves one of the major issues that we believe from the IPF trial, which is having nintedanib as a background. The other thing is that when we compare ourselves, there's a lot of these other disease indications. You're talking about injectables, you're talking about IV therapy or injectables long term. We're an oral inhibitor, you compare ourselves to what are the other oral inhibitors in spaces currently that we're interested in, they're usually things like JAK inhibitors, right? JAK inhibitors have a whole set of issues, right? They're oral molecules, they seem to be functional, they have black box warnings, they cause a whole variety of cytopenias and thromboembolic events, and even cardiovascular events. Now over, well, almost to 400 patients, we've not seen any of that. We don't see these spontaneous and different strange infection types that we see with JAK inhibitors and even, you look at other molecules. You just mentioned this. This is the data that came from Abivax, which is fantastic outcome, we saw a propping up of oncology issues, or cancer risk. If anything, we know STAT3 inhibitor, which we know the mechanism, treats cancer. Yeah. It's not like we're going to cause cancer. I think from our perspective, there is a need for oral drugs and oral drugs that hit a pathway where all the pathways coincide with. We've done a really good job with antibodies of hitting individual cytokines, but hitting individual cytokines doesn't shut off the whole pathway. I think if you could find something that at where, at the coalescing of node point, like a STAT3 inhibitor, that could be very interesting. Got it. If it is can a like- Yeah. Spell it out for investors in a way, right? Like one way to be convinced on this is that you can understand that REVERT-IPF study had challenges, but the fibrosis improvement is sort of undeniable. Yeah. You can understand from a PK basis, 101 to 109 is simple tweak. The phase I healthy volunteer data check the box on that, then put the whole story together. If you're now telling me like, "Well, we want to go into fibrotic Crohn's disease instead," you've ruined the thread for me a little bit. No. Can you defend that? No, no. Absolutely. I think you have to think about how do you execute a trial, right? How can a small company like ours execute into a trial where we can say and point to you, "Here are all the different indications where we know STAT3 is dysregulated," right? Can we then take from our data from a healthy volunteer, translate that Look in and pick indications or indication that makes sense, where STAT3 is also dysregulated, where we can take what we've learned from these other trials and this healthy volunteer data and say, "Does that convert? Does that translate?" Does this suggest that if we were to take not only markers of pharmacodynamics from this ongoing trial, but also have clinical efficacy endpoints that make sense, that you could actually hit that point. I think, look, it's because we haven't disclosed it, we haven't publicly disclosed what these indications will be, and we will do that, and we're just compiling that data as we speak. You'll see the story comes together, we believe quite nicely, to suggest a path forward in indications where we know that STAT3 is incredibly important. Got it. The tweak to my layered pitch. Yeah. Is basically that consider IPF, your initial IPF trial, and the finding on fibrosis there as kind of almost just like a test model or proving ground that this drug is antifibrotic, and then you can string the rest of it together. Yeah. Is that a fair- Yeah. Take? I think, yeah. Simplified, but potentially, I think it's beyond just fibrosis. I think the idea is that can you show, hey, can you change models of inflammation? Can you change immune dysregulation? Can you change proliferative markers, right? I think everything that we've shown, whether it be across the board, suggests all that. When we put all that together, what indications make sense for us, whether that be other new indications or going back into IPF. Got it. That's helpful. Yeah. We're at time here. Yeah. Just one last question. Yeah. Can you just remind us the funding status of the company? We have capital into Q4 of this year that we have both readouts coming up. We have a readout here with 109 in June. Obviously, we don't have enough time. We have our phase II liver cancer study, frontline, second line, third line, reporting out in the second half of the year. We expect that we'll have plenty of capital to get through those readouts. We'll take it from there. Got it. Sounds good. Well, thank you so much, Imran, for joining us. Yeah. Thank you. Thanks.