All right. Welcome, everyone. For our afternoon session here, we have Imran Alibhai from Tvardi Therapeutics. Welcome, Imran. My name's Gautam. I'm a Biotech Analyst here at Chardan. We have about 15 minutes, so let's just jump into it. Can you give us a quick overview of Tvardi today? You had a busy year from the IPF failure to your healthy volunteer data, your post-hoc analysis. Walk us through what happened, what have you learned? Yeah. Well, first of all, thank you for the invite this morning. Gautam actually initiated on us, so really nice report and appreciate actually the transparency and the balance there. Tvardi Therapeutics is focused on STAT3. STAT3 is an incredibly well-known transcription factor. Put it in the PubMed, there's only 45,000 papers that show up talking about its centrality to not only immune dysregulation but inflammation and proliferation, hallmarks of a variety of I&I disorders. We initially started in oncology. In oncology, across the board, we showed PK/PD of activity and tolerability in a phase I trial in solid tumors, which actually led the program into a phase II trial in liver cancer, which we'll report out later this year. Then earlier this year, we actually had data from our IPF trial. Now in our IPF trial, that was really demonstrated there is. The background of that was we know that STAT3 is intrinsically important in fibrosis as well as inflammation. In our models, we could actually show reversals of fibrosis, not just stopping it, but actual reversals of. We went into a trial, this was an all U.S. trial, a trial where we enrolled patients that were on background. Majority of our patients, vast majority, were on background nintedanib. Now background nintedanib, 68% of those patients have diarrhea— Right. —in their phase III trial. We actually saw, unfortunately, a higher rate of discontinuations than we would've expected when combining our 1st- generation molecule TTI-101 with nintedanib. From that perspective, it didn't. I wouldn't call it a failure, but it did not meet our goals. But what was interesting is, after the fact, we went back and we looked at the completers, so the patients who completed trial, and we saw an incredibly interesting trend. The main mark we look for is forced vital capacity. And forced vital capacity can be actually quite variable, even intra-patient, particularly for our 12-week trial. Even though all the other trials suggested you would see a decrease, we actually didn't see a decrease in the placebo arm, so that was a confounding factor. But so we went back and said, "Look, we know FVC can be indeterminate. Right. Let's look at other pre-specified endpoints that could be very interesting." One of those was IL6. IL6 correlates with inflammation. It directly sits upstream of STAT3 reactivation. We looked at that, and we actually saw a more than fourfold difference in the decrease of patients treated with TTI-101 in IL6 relative to placebo. That was pretty encouraging. What we were very encouraged by was the data in fibrosis. The way we measured fibrosis in the trial is how everybody measures it. You look at high-res CT pre-treatment and post-treatment, and after 12 weeks, we saw an actual decline in baseline fibrosis. Most trials don't even report fibrosis because they don't see a change in fibrosis. We know a variety of molecules like JAK inhibitors and the molecules that are currently available, they don't show changes in fibrosis. What we actually saw was a 7% placebo-adjusted rate in the decline of fibrosis. Most folks, when they show their fibrosis data, they'll say, "Well, we prevented an increase. We didn't actually see a decrease." From our perspective, that was very encouraging because it actually replicated our pre-clinical data. In the background, we'd told the street that we were always wanting to move our next- generation molecule forward in I&I. It had been IPF, and the reason we wanted to do that is because we had identified years ago that we could make a very bioavailable molecule known as TTI-109 or TTI-101's prodrug available. That was the phase I data that we reported out earlier this year. What is interesting about our next- gen molecule is that TTI-109, again, is the prodrug, but it's inert. Right. It has no activity. It's once at doses we're giving it to humans, and it's designed to pass through the gut, and because of all the phosphatases in our bloodstream, it would rapidly convert into the active moiety. We have systemic distribution, but we wouldn't have any exposure in the gut. That potentially would obviate any GI adverse events. The phase I data we reported showed exactly that. The phase I data showed we had converted quickly into the active moiety systemically. Two, it showed GI tolerability that looked like placebo as opposed to what TTI-101 looked like, and we ran that trial in the healthy volunteers across three arms. The most encouraging data from my perspective, and I think overall the company's perspective, is we had pharmacodynamic data. Right. We were actually able to show that in healthy volunteers, in the published populations that are pathogenic in UC across T cells and B cells, that we could show reductions in a healthy volunteer. We know those populations are pathogenically expanded in a diseased population. Right. For us to show it in a healthy volunteer really portends well from the perspective of ulcerative colitis. That was one of many reasons we will talk about why we really wanted to get into now the next-gen trial for us. Yeah. For TTI-109 will be ulcerative colitis. Let me take one step back. Yeah. Historically, STAT3 drugs have failed, right? I can think of Otsuka. I am sure there are pretty bunch of others. Yeah. What do you think went wrong there, and how are you differentiated? We were founded actually by David Tweardy. David actually is the Head of Internal Medicine at MD Anderson, but in my mind, his real claim to fame is he identified STAT3 30 years ago. He was one of the first three groups to actually identify the molecule, and he understood you can't go after the protein. You just want to prevent its activation. What we have developed at Tvardi is a non-covalent inhibitor that binds and prevents STAT3's activation but has no effect on the protein. We've published this previously. What was very encouraging about our data, and where Otsuka and others have failed, is that they go after the protein, and they try to remove the protein from the system. For example, Otsuka had a covalent inhibitor. It bound up all of its phosphorylation sites, and we believe that caused it to aggregate, get ubiquitinated, and removed from the system. Why is that important? Because STAT3, the protein, is part of the electron transport chain in the mitochondria as well. Right. That's part of the scaffold. What they saw in their clinical trials was, yes, some activity, but where they suffered is they saw mitochondrial toxicities like lactic acidosis and peripheral neuropathies that wouldn't go away. Right. Across 400 subjects that we treated with TTI-101 and our next-gen molecule TTI-109, we've not seen one example of a drug-related mitochondrial toxicity. We've proved it in vitro, but the proof in the pudding, from our perspective, is the fact that we haven't seen it, and it's an Adverse Event of Special Interest. We track it everywhere, and we just don't see it, and we think that's credit to the founders. Perfect. We have five minutes or so left, right? I want to get to the gist of it, right? Yeah. You're going into UC. Yeah. Now, tell us quickly on what is the relevance of the Th17, Tfh, and B cells that you saw went down. Yeah. How are they related to UC biology? Let me also ask you this, right? How are you going to ensure that the epithelial STAT3 is not going to be affected? Yeah. Therefore the gut lining and all that is protected? Absolutely. STAT3 is essential for the formation of Th17 cells as well as autoantibodies. Right. Those are the pathogenic centers in ulcerative colitis. In our healthy volunteer data, we actually demonstrated specific reductions of those pathogenic cell types, both from a cellular response, i.e., T cells, and a humoral response for the B cells. Right. If those levels are homeostatic in a healthy volunteer, we know they're pathogenically expanded in a diseased population. We think that portends very well. Now, you bring up an important point. STAT3 has multiple roles, and one of them has been considered, well, they may have a role in wound healing, for example, right? Right. If you go back to the genetic data, it's actually not chronic wound healing STAT3 is implicated in. It's in acute wound healing, right? If you go back and you look at all of the data, you look at our animal data in the mouse models, we see no change. We've done that in acute models and chronic models. Then go to the nine-month monkey toxicology data that we have. We see no changes. If there were changes, you would have captured it in those models. Then we have had patients on treatment for up to two years with this drug, and again, we haven't seen acute wound healing issues or chronic wound healing issues. That would have popped up if you were expecting changes in the mucosa, you'd start seeing mucositis, for example. Right. That hasn't been an issue for us. I think because we're not eliminating STAT3, the protein from the system, we don't believe that we're going to be having the same sorts of issues. If anything, the data we just published recently in long-term mouse models show that we can change gut dysbiosis and the microbiome. Okay, that's awesome. You have proposed what the phase I study's going to look like for UC? No, it would be a phase II study. Phase II study, yes. It's to be patients who are refractory to front or second-line therapy, and it would be studying not only QD doses but BID doses versus placebo. Yes. We would look not only at endoscopic remission, but we would look at pharmacodynamics. The reason this is important, it's not our data, it's other people's data. Yeah. Tofacitinib and olamkicept, two separate trials demonstrated when STAT3 goes down, activated STAT3 goes down, they saw clinical remissions. If it didn't go down, they didn't. They've gone through and said, "Hey, can we hit the external cascades that drive STAT3? We're going after STAT3 directly." I think that data in and of itself validates why we're going after this, after STAT3 as a target, particularly in second-line ulcerative colitis. If we're able to show that data, give you clinical remission rates and pharmacodynamic data, that opens up a wide variety of data points for us for the front line or even later lines like disease processes where they're more fibrotic, like Crohn's disease, for example. Okay, perfect. We have about one minute or so. I'm going to just ask you about the HCC data that's coming up. Yep. Just frame to us what would a win look like and what the strategy is in that indication. Yeah. We actually have really nice data from TTI-101 in the phase I trial. That came out in 2025. We have interim data from that trial, the one we went public. In that setting, we are studying front line in combination with checkpoint inhibition, and second line also in checkpoint inhibition, and then third line as a monotherapy. We're excited. If we are able to maintain the rates that we've previously shown, it could really be quite interesting from that perspective. A last-line trial would allow us to go directly into an accelerated potential approval trial. These are 100% trials. In the front line, if we were to actually see some activity there where we maintain the remission rates or the objective response that we've seen, we could actually do a front-line trial. Those are only 350- person trials. We expect TTI-109 to be our go-forward molecule in the I&I space and retain TTI-101 in oncology, where we haven't seen the same sorts of issues in oncology, where we have published trials, that we've seen with TTI-101 in the inflammatory and I&I space. Perfect. I think that's all the time we have, Imran. Thank you so much. Well, we still got a little. Oh, we do, yeah. I think it's like 1:45 P.M., right? Yeah. Yeah. Okay, perfect. All right. Thank you, sir. I will call you.