Good morning. Welcome to the Tvardi Therapeutics Investor Webcast. At this time, all attendees are in a listen-only mode. A live question and answer session will follow the formal presentations. To our covering analysts, please use the raise hand feature to be added to the queue. As a reminder, this call is being recorded and a replay will be available on the company website following the conclusion of the event. I will now turn the call over to PJ Kelleher of LifeSci Advisors. Please go ahead, PJ. Thank you, Wilson. Good morning, everyone. Earlier today, Tvardi Therapeutics issued a press release announcing data from its phase I healthy volunteer study of its next generation STAT3 inhibitor, TTI-109. A copy of this press release is available on tvarditherapeutics.com. Joining me on today's call is Imran Alibhai, Chief Executive Officer of Tvardi Therapeutics. Before I turn the call over to Imran, I would like to remind everyone that this discussion and the accompanying press release will contain forward-looking statements, including statements concerning the anticipated benefits of Tvardi's product candidates, the potential benefits of TTI-109 as compared to TTI-101, Tvardi's ongoing and planned future clinical trials, and anticipated timing of reporting data from such trials, potential indications for its product candidates and Tvardi's development plans and such indications, discovery and development of its product candidates, its anticipated cash runway, and other statements regarding management's intentions, plans, beliefs, expectations, or forecasts for the future, as well as matters that are not historical facts or information. For a list and description of the risks and uncertainties that Tvardi faces, please see the reports Tvardi has filed with the Securities and Exchange Commission, including its most recent annual report on Form 10-K for the year ending December 31, 2025, and subsequent filings with the SEC. This conference call contains time-sensitive information that represents management's judgment and intention and is accurate only as of today, July 7, 2026. Tvardi undertakes no obligation to update or revise any forward-looking statements except as required by law. I will now turn the call over to Imran Alibhai, Chief Executive Officer of Tvardi Therapeutics. Imran? Thank you, PJ, and thank you for everyone for joining this call this morning as we review new and exciting data from our TTI-109 development program. Before I begin, I'd like to point out that the slides that accompany this call are available on our website with an appendix that includes additional material, including more in-depth data from our preclinical program in model systems that are the backbone of our translational program, as well as the data we presented earlier this year, from our phase II IPF study, which we will highlight today. That brings us to STAT3, which is what we are focused on. STAT3 is an incredibly validated convergent node. If you drop it into PubMed, only 45,000 papers describe its role as a central mediator in inflammatory and proliferative disease. What we have demonstrated over time is that preclinically, we can downregulate activated STAT3, which then leads to downregulation of immune dysregulation, inflammation, and proliferation. We can now show you that we've confirmed these findings in patients in that we can show target engagement, downregulation of the cellular and humoral responses, as well as actual validation of decreases in inflammation and proliferation. That brings us to 109. This is our next generation STAT3 inhibitor, which is a phosphate prodrug of our first-generation molecule. Today, we will demonstrate that TTI-109 met the design objectives that in that it rapidly converts with predictable dose proportional PK and has improved GI tolerability to our first-generation molecule. Beyond this, we will show you mechanistic pharmacodynamic data of reductions in disease-associated immune populations, specifically T cells and B cells. Seeing this kind of pharmacodynamic data signal in healthy volunteers, we believe portends well for patients with chronic and inflammatory diseases in the dermatologic and GI space that exhibit STAT3-driven immune dysregulation, inflammation, and proliferative tissue remodeling. If you take a step back and think about all the signaling pathways that have been individually targeted in the past, which include growth factors, cytokines, even non-tyrosine kinases, all of these converge in STAT3 and induce the protein to become phosphorylated. It then homodimerizes, moves into the nucleus where it drives the transcriptional cascades of immune dysregulation, inflammation, and proliferation, the common hallmarks we see in dermatologic and GI indications. What we've developed at Tvardi are non-covalent oral small molecule inhibitors that simply inhibit STAT3's ability to become phosphorylated. This prevents homodimerization, its movement into the nucleus, and the transcriptional cascades we associate with disease. What we do not do, and what we have published on the bottom left, and have demonstrated now in patients, is have any impact on STAT3 in the mitochondria. This has been an issue previously for other molecules in this space. From our perspective, not only do we have the in vitro data that suggests that STAT3 is not affected, that we don't affect mitochondrial STAT3 function, we now have 400 patients worth of data across our two molecules that demonstrate we've not seen one example of a drug-related mitochondrial toxicity. The reason all this is so important is really here in the middle of the page, that STAT3 has a dual mechanism. Intrinsically, we know that STAT3 activation drives the inflammation and proliferation we see in the cellular compartment. Extrinsically, and maybe equally important, we know that STAT3 activation also drives immune dysregulation. What we have demonstrated in vivo, in vitro, and now clinically, is that intrinsically, in the cellular compartment, we can down-regulate the inflammatory and proliferative cascades. Simultaneously, we can show you extrinsically in the immune compartment that we can restore humoral and cellular immunity. The basis of our program is on our first-generation molecule, TTI-101, which is the clinical foundation for the development of TTI-109. Our first in-human study was actually an oncology study in which we demonstrated PK, PD, tolerability, and activity, and shown here is that pharmacodynamic effect. That is that we were able to take biopsies from patients pre-treatment and on treatment, and we were able to demonstrate that in every patient, we saw a decrease in activated STAT3. The overall decrease was 55%, and in patients with clinical benefit, it was almost 80%. Earlier this year, we presented data from the IPF study called the REVERT IPF trial, which was a phase II study in which we demonstrated that in patients treated with TTI-101, we could decrease one of the hallmarks of inflammation and fibrosis, and that is IL-6. What you see in the top of this panel is that patients treated with TTI-101 had a greater than fourfold difference in the slope of the line versus patients on placebo to IL-6. The thing that was really encouraging to us is potentially early signs of disease modification in these patient populations. In that, in the bottom of the panel, you can see a difference in fibrosis. We measured by CT fibrosis pre-treatment and post-treatment. What you see is a 7% difference in weighted fibrosis score, an actual decrease in fibrosis. We are unaware of any other trial, whether they be a 12-week trial like this or if a 52-week trial, that has actually shown a decrease in fibrosis relative to the starting point of the patient population. Finally, from an overall safety profile, we've tested TTI-101, our first-generation molecule, across 300 subjects. We've demonstrated we do not see any of the mitochondrial toxicities observed with other STAT3 inhibitors like peripheral neuropathy and lactic acidosis. Commonly, we are compared to JAK inhibitors. Similarly, we do not see the safety signals that we see with JAK inhibitors. We don't see serious infections. We don't see major cardiovascular events or malignancies. These are all black box warnings. Nor do we even see the cytopenias. The most commonly reported adverse event with TTI-101 has been diarrhea. Based on this foundation, we wanted to basically maintain this mechanism of action and observed clinical activity of 101, we wanted to improve its drug delivery and diminish its GI exposure. We built TTI-109 on the left-hand side. Now, TTI-109 is the phosphate prodrug of TTI-101, interestingly, 109 is inert. It is like 101 delivered orally, once it passes through the gut, it is designed to convert to the active moiety in the blood because of all the phosphatases we have in our blood. What that allows us to do is generate a very soluble molecule that's easily formulated. Two, because it has no activity, we're diminishing any of the GI exposure of the active moiety in the gut. What we have demonstrated in our GLP results, IND-enabling GLP results, is that like 101, there were no tox findings with 109. Two, for the prodrug, we show that at equal or near equivalent doses of 109 and 101, we had equivalent exposures. Finally, what we needed to show for this prodrug to be what we expect it to be is that 109 had to rapidly convert to the active moiety 101. That's exactly what we see. In the bottom right-hand corner, what you're looking at is the highest dose we tested in a GLP primate study. What you can see, within two hours, 109, which is in orange, has now rapidly converted, and the vast majority of it is converted into TTI-101. To that end, we wanted to replicate these findings in human beings. What we did is we ran a three-part study. Part A was a SAD portion of the study. In this portion of the study, we wanted to demonstrate that like in rats and monkeys, 109 rapidly converted to 101. Part B was a bioequivalence crossover study in which we gave patients 101 or 109 to start, washed them out, then gave them the alternative molecule. We wanted to show that equivalent doses of the molecules gave equivalent exposures, again, like what we had shown in rats and monkeys. Finally, Part C was three arms combined. In that, we looked at placebo, TTI-109, and TTI-101 at the recommended phase II dose. What this allowed us to do was look at steady-state exposures, safety and tolerability, really then demonstrate pharmacodynamics of 109. First, from the SAD portion of the study, here on the left-hand side is the data I just showed you. This is the primate study, where we saw that 109 rapidly converted to 101. Here's the human data. What you can see, again, very similar to the animal data, is that 109 in a human being rapidly converts to 101, again, at two hours, greater than 95% of 109 is converted to 101. The next part of the study was giving near equivalent doses of 109, having a washout period, then giving 101, or reversing the order, demonstrating equivalent exposure. That's exactly what we saw. When we gave equal molar dosing, confirmed equivalent exposures of the active moiety of 101 versus 109. The final part of the study was really understanding the exposures. In the SAD portion of the study, what you can see is the higher the dose of 109 we gave, the higher the dose of 101 we got. At all of the active doses, we were well above the IC50. This compares favorably to what we saw at steady state in the MAD portion of the study. What you can see, in green and in purple, the same dose, we can see similar pharmacokinetic profiles at day one and day 21. We see a predictable dose proportional PK increase at steady state. What's interesting is those exposures are all above the STAT3 IC50. The next part of this study, after we'd now checked the boxes for exposure, was to really demonstrate a differentiation in a healthy volunteer from a safety perspective. What you can see is the overall profile for these three molecules. For placebo, for TTI-109 at different doses, then a head-to-head comparison of 109 to 101. What you can see, the overall, the safety profile appears favorable. The incidences of TEAEs are broadly similar across the groups from placebo to 109 to the recommended phase II dose of 101. Interestingly, we did see at near molar equivalents of 109 and 101, and potentially improved profile of 109. Important to note, at the dose level 2 of 109, we observed one subject who discontinued due to an episode of isolated transaminitis. However, it's unlikely related to TTI-109 as the lab values begin to improve while she was on treatment and prior to treatment discontinuation. In addition, we saw no changes in bilirubin, so there was no indication of DILI. It was theorized that an alternative etiology for this could have been a passing of a gallstone, as it shared much of the same symptomology. Importantly, the study demonstrated no SAEs, no dose-dependent pattern in adverse events, and no clinically relevant changes in vital signs or ECGs. As detailed in the prior slide, we built TTI-109 to improve on the GI tolerability of 101. This slide highlights that improved tolerability. Overall, the TEAE rates were similar, but we observed an important distinction between 109 and 101. When diving deeper into the characteristics of diarrhea, the duration of diarrhea for TTI-109 was comparable to placebo. It was transient and resolved without treatment, very placebo-like, in contrast to TTI-101. At the recommended phase III dose of TTI-101 versus TTI-109, you can see quite a contrast. TTI-109 had a duration less than placebo, actually, and much less than what we see with TTI-101. Interestingly, we had three patients exhibit diarrhea, and one patient had a grade one event in the 101 arm that actually led to his discontinuation. From our perspective, not only had we shown you from a pharmacokinetic perspective, we had achieved our goals, but also this data demonstrates to us that we had achieved our goals in improving the GI tolerability with 109 that had placebo-like activity. The final part of the study was really understanding pharmacodynamics. We had a specific hypothesis rooted in biology. STAT3 is essential for Th17 and B cell function. We know this from genetic knockout studies where T cell and B cell specific STAT3 knockout mice are Th17 deficient or can't produce autoantibodies respectively. What we have demonstrated previously, and this was a study done years ago, when you give TTI-101 to a healthy mouse, what you can see is a 50% reduction in Th17 cells, both in the blood and the spleen, which portends quite well for diseased mice. That when, again, we know in diseases like in IBD, these animals upregulate IL-17. What you can see is that when we therapeutically treat with our molecule, we can reduce these IL-17-producing cells back to near baseline. Our expectation going into this healthy volunteer study was, can we see the same thing? Can we demonstrate in a healthy volunteer a decrease in these immune populations? Not only can we see it in maybe Th17 cells, can we also see it in other immune cell populations that we know that are related to STAT3? That's exactly what we saw. At the active doses, which are the 250 mg and up doses, these were the doses, as you recollect from the previous slides, that were above the IC50 for STAT3. We saw reductions in Th17 cells, reductions in T follicular helper cells, and in B cells. Not only did we show it for simplicity, we were just showing these three cell types and the core cell types. We can show you, and have demonstrated, that we saw reductions across 16 cellular and humoral immune subsets recognized as pathologic markers of the inflammatory and proliferative dermatologic and GI diseases, all of which were sustained over the active dose range. From our perspective, what we had demonstrated in a healthy population is downregulation of cellular and humoral immune populations, which portends really well for disease populations. The take-home from our perspective, as we think about all the clinical data that we have generated across 101 and 109, is this. With 101, excuse me, we've shown target engagement. We've seen decreases in diseased populations of inflammation and proliferation. Now the 109 clinical observations build on this, in that in the PK portion of the study, we showed rapid conversion with dose proportional exposures above the STAT3 IC50. Beyond that, from a GI tolerability perspective, we saw that 109 was similar to placebo in incidence and duration of diarrhea, and improved versus TTI-101. Finally, actually exceeded our own expectations is that in a healthy volunteer, we were able to show decreases in cellular and humoral disease-related immune population, which portends well for a variety of STAT3-driven dermatologic and gastrointestinal indications. Over the next four slides, I will walk you through why we think these two therapeutic areas are key and could be well interrogated by 109, excuse me. That is that both these indications are driven by STAT3. In these indications, we see immune dysregulation, we see inflammation, and we see proliferation, all STAT3 driven. You'll see this common theme across the next four slides, is that we'll walk you through both the dermatologic space and gastrointestinal space preclinical data, and then how that preclinical data has translated into clinical data, and why this, we think, portends well for the [ZTD's populations. First, let's look at activated STAT3. There are two models that we've interrogated in the dermatologic space. One is a chemically induced inflammatory skin model in which the animals are delivered bleomycin, and we see inflammatory increase in proliferation in these models. Second, we have a genetically induced model known as a tight skin-1 model, and this is a growth factor-dependent increase in inflammation and fibrosis. What you can see is that when we therapeutically treat with our molecules, we return activated STAT3 back to baseline levels. Similarly, when we go to GI models, whether they be models that are focused on the innate immune axis or the adaptive immune axis, we see the exact same phenotype. That translates to what we've seen clinically. Again, in our oncology study, we saw reductions with paired biopsies of activated STAT3. When we look at immune dysregulation across the dermatologic and GI space, we see increases in cellular responses. For example, in the dermatologic space, whether it be hidradenitis suppurativa, systemic sclerosis or scleroderma, or even dermatomyositis, we see inductions of pathogenic Th17 cells. Similarly, when you go to the GI space, when you look at either UC patients or Crohn's disease patients, we see induction of Th17 cells. When we go to these models and we look at Th17, we can see that all of these models, like in humans, we see an induction of the Th17 response. In the presence of our molecule, we can therapeutically return the IL-17 producing cells back to baseline. Our conversion, clinically, is that we've showed you in a healthy population, we can actually downregulate this, not only Th17 response, but even the humoral response in a healthy population, which portends well for a diseased population. When looking at inflammation, the second hallmark of dermatologic disease, you can see across the chemically induced model and the genetically induced model, we return inflammation looking at IL-6 back to near baseline levels. Similarly, the way we measure inflammation in an animal in the GI models is to look at colonic inflammatory scores. Again, you see reductions with therapeutic treatment back to baseline levels. That ties with what we'd seen clinically in our IPF study when we actually showed reductions in IL-6, which is the key cytokine involved not only in inflammation, but the later stage proliferation. The final commentary here is on proliferation. That in both of these models, and I don't show all the data, it's in the back of this deck, you can see that when we therapeutically treat, we can not only show reversals of this proliferative or fibrotic step, but we can also show you that we downregulate all of the indices related to this inflammatory pro-fibrotic transcripts, and this includes everything from CTGF to TGF-β to fibronectin to COL1A1 across the board, not only are we seeing reductions in the fibrosis, but we're seeing those in the markers that we associate with these populations. Similarly, when we look at GI models, we see the same thing. With therapeutic treatment, we can see, and this is an example from the innate immune axis, that we can actually retain colon length and morphology in these animals. Again, the final step of this is that we see we can reduce fibrosis in a human. That's how we've translated that from our IPF study. To wrap up here, I think what we've learned from our perspective is that we know STAT3 as a transcription factor is genetically validated. What we've demonstrated pre-clinically is we can downregulate this in both the inflammatory and proliferative spaces in both the dermatologic and GI space. We've confirmed that not only in a healthy volunteer, but also in diseased populations. We believe 109 is now well-suited to interrogate these populations where we know they're STAT3-driven, and that STAT3 drives both a cellular humoral immune response, inflammation, and proliferative tissue remodeling. That leads us to my last slide, and that is that today we've reported out our top-line data. We anticipate, incumbent on filing our INDs and funding for these indications, we can initiate these studies in the first half of 2027. Depending on the size and scope of the data, we expect to be able to quickly wrap these studies and further validate and provide more proof of concept for our data so that we can eventually move to confirmatory spaces. Also at the end of the year, or the second half of this year, we will also provide the top-line data from our initial oncology study in HCC, which we'll report across three lines. We believe we've developed a diversified pipeline, with multiple data catalysts, which we can drive long-term value for our investors. With that, I thank you for all your time, and I'll open the door for questions from the audience. Thank you, Imran. At this time, we'll be conducting a live Q&A session. As a reminder to our covering analysts, please use the raise hand feature to be added to the queue. Kindly hold for a brief moment while we pull for questions. Our first question comes from Yasmeen Rahimi with Piper Sandler. Please go ahead, Yasmeen. Yas, you may be on mute. Can you hear me? My apologies. We can hear you. Can you hear me? Yeah. Yep. Okay, wonderful. Sorry for my annoyance. Congrats team on the data, and thank you for really connecting the data, the product profile, and also the opportunity of expansion in dermatology and gastroenterology. I think my question for you is just sort of maybe a little bit more granular in terms of how soon can you get the IND filed. Dermatology and gastroenterology is quite wide spaces. What point will you be in a position to kind of fine-tune as you think about which indications you're interested in pursuing? Also a reminder, if you do move forward to a phase II study, with these, given your tox coverage, I'm assuming you could rapidly expedite going into a phase II-B study or a phase II-A. If you could just crisp out a little bit the way you envision the next steps, that would be really helpful. Sorry. Yeah was a mini multi-part question. No. These are all great questions. From our perspective now that we've completed the nine-month monkey tox studies for 109, we anticipate that there are no other preclinical experiments to do here. We've now wrapped up with phase I. We'll have the complete study report within the next few months. That allows us to rapidly move into an IND. We believe we can file an IND for a phase II program in one or both of these spaces by the end of the year. We could get, as I mentioned, a study, advanced or initiated in the first half of the year. For lead indication, they're beyond the therapeutic areas, that selection remains ongoing. It's really informed by kind of a number of important inputs, and those include our board, the KOLs, our external consultants, and importantly, our investors and the broader competitive landscape. We expect to announce the lead indication once we've completed that alignment process and have the appropriate funding in place to support this future development. Our priority is to select an indication where we know there's an unmet need, the competitive environment is there, and we have a capital-efficient clinical trial design that allows us to create meaningful value for patients and shareholders. I think, we actually identified some of those indications in the dermatologic space. You could pick very small indications where we've seen dermatomyositis, to very large indications like hidradenitis suppurativa, all of which share the clinical features of STAT3-driven disease, which then leads to inflammation and proliferation, and then immune modulation. Similarly, in the GI space, where you could pick very small indications, or smaller indications, not small, things like Fibro- stenosing crohn's disease, all the way to frontline ulcerative colitis. What we think is interesting across these spaces is that when you think about all of the drugs that are approved, even in these spaces, they hit singular pathways. Where STAT3 is multimodal, we think we'll be able to hit all of these consecutive things. I think once we have alignment and support and the funding in place, we think we can rapidly move into these phase II studies. Is that fair, Yas? Yeah. That's very helpful. Thank you. Thank you for your questions, Yas. Our next question comes from Steve Seedhouse with Cantor. Please go ahead, Steve. Yeah. Thanks. Good morning. Thanks for hosting the call and for the update. Wanted to just first ask if you could clarify, and maybe signal to the market, how much money do you think you'd need to raise to get to some sort of signal finding data in one or more of these candidate indications? In different financing scenarios, are you sort of ideally hoping for parallel track development in a couple of these, or are you really going to narrow it down to one and update the market at some point before the study initiation? Yeah. No, absolutely. Let me ask, and it all depends on the studies, right? Because of the parallel nature of both of these therapeutic areas, we think that we could absolutely run these in parallel, and we have the resources to do so, and I think the funding would be important. I think when we look at these trial designs that if you ran them in parallel and run phase II studies, it could be $100 million, but we could also run that for half that cost for one indication for smaller trials. It really depends on having alignment from investors on the indication or indications that would allow us to move forward across the board so that we could put this data out there, have the ability for people to digest the data, then work on developing indication-specific protocols that would allow us to rapidly enroll trials within a short timeframe, get interim proof of concept data. Beyond that, have clinical evidence of that so that we could rapidly move into confirmatory trials. Is that fair? Yeah. Thanks, Imran. Just want to also follow up on the grade three transaminitis case. Yeah. I think you mentioned maybe that an alternative hypothesis or a hypothesis for what happened was this patient might have had a gallstone. Was that a formal diagnosis, or is that just a hypothesis at this point? Yeah. How certain are you it's not drug-related? Yeah. No. I think important to note is that while the patient was on treatment, we saw an increase in her transaminitis, a decrease while she was still on treatment. We believe it's very unlikely that it was drug-related. Again, there was no change in bili. It wasn't a formal diagnosis, but it did share some of the same symptomology from that perspective. That's why we think this was not related to our compounds. All right. Thank you. Thank you for your question, Steve. Our next question comes from Julian Harrison with BTIG. Please go ahead, Julian. Okay. Great. Good morning. Congrats on this update, thank you for taking the questions. First, on phosphorylated STAT3, sorry if I missed it, but just wondering how that compares between 109 and 101. Second, I'm wondering if you could talk more about your decision not to revisit IPF, considering just how much the GI tolerability seems improved with 109 versus 101. Yeah. It's no different. Sorry if it wasn't made clear. 109 is the prodrug of 101, the purpose of 109 is to basically, 109 is inert. Once it passes through the gut and into the bloodstream, it converts into the active moiety 101. We know, and we have data that's demonstrated how 101 works, and 101 works by non-covalently binding STAT3 and then preventing that phosphorylation step that causes homodimerization and its movement into the nucleus. Empirically, once 109 is converted to 101, which we demonstrated that that seems to be occurring quite rapidly, there is no difference in how this prevention of phosphorylation is occurring. Does that make sense, Julian? Yeah, it does. Yeah. Yeah. No. Look, on the IPF, I think from our perspective, the IPF study provided important clinical proof of mechanism for STAT3 inhibition, right? What we've been able to show, as you mentioned, is decreases in the IL-6 population and STAT3. That said, when we look at the IPF trials, these trials are longer trials, we know that the validated FDA endpoint in IPF is now forced vital capacity, and that, even in itself, has a tremendous amount of variability. It's clear that these studies need to be really six months or potentially even a year. Also you have to take into account that we have new drugs, and that are now available in this space beyond what we had with Esbriet, OFEV. Now we have the PDE4 inhibitor and potentially inhaled treprostinil. That landscape has changed dramatically in the last year or two, which is great for patients. We don't believe that these mechanisms are disease modifying, but they have changed FVC values, running a trial like that in the U.S. or even ex-U.S., would take a lot of time and actually be quite costly because we would have to fund the background in these indications in ex-U.S. studies. Where here in the United States, that's paid for because of insurance, but ex-U.S., you fund all of the components of these indications. The final component of this is that with GI studies and derm studies, we take biopsies. Quite common. That allows us to have interim data, to provide that initial step that allows us to show, hey, we're hitting these canonical cascades by looking at activated STAT3 and looking at inflammatory and fibrotic markers in the skin and in the GI. Whereas you can't do that in IPF. I think, for all those reasons, it's something that we would happily revisit, and some of the indications in these spaces have ILD components. I think at this time, where we want to be capital efficient and move quickly and move from proof of mechanism to proof of principle, is really to pick indications where we can get interim data and then move forward with clinical efficacy endpoints and do that in a shorter order than doing what would potentially be a very long-term and expensive study in IPF. Make sense? It does. Thank you very much. Yeah. Thank you, Julian. Our next question comes from Debanjana Chatterjee with JonesTrading. Please go ahead, Debanjana. Hi. Thanks for the presentation, and congrats on the data. You mentioned that biopsy-driven interim proof of concept would be very interesting. Would you be able to help us frame the expected timeline to clinical POC, if you're pursuing the derm opportunities versus ulcerative colitis or IBD? Yeah. I think both would be similar, honestly, right? We believe in both indications that we would be able to get started in the first half of 2027. We think that interim data could be available in both studies in the first half of 2028. This all depends on size and all these other components, but we think that in a modest phase II trial, we'd be able to have data in 2029 from this. It would build a nice set of inflection points that would validate what we've seen with TTI-101, using TTI-109 into indications in the derm and GI space we haven't interrogated in the past, but have this interim data sets, where we know that there are markers that are diagnostic for the disease that we then can move forward, in early 2028, and then that would validate and really give us the clinical endpoints within a year from that time point. Make sense, Deb? Yeah. A quick follow-up. If you ultimately prioritize a Th17-driven derm indication, how should we think about the risk-reward trade-off between pursuing dermatomyositis, HS, or the classic Th17 disease, like psoriasis? Yeah. I think each is interesting. Each has its own components that we have to think about, right? Dermatomyositis, the valid trial, really nice data. The drug there is a JAK inhibitor. We saw an increase from 1% to 10% in infections in that population, something we don't see with our molecule. As we talk to folks, it may be that baricitinib actually become the standard of care, and you might have to run your trial on top of that. When you look at other diseases like hidradenitis suppurativa, those indications is where patients can fail, where we see the ceiling about 30% of efficacy with either a TNF-alpha inhibitor or the IL-17 inhibitors. Once they fail, they can then move to another therapy, so you don't have to have background therapy in this space. In both of those indications, you're able to take biopsies to validate your findings and then move forward. I think the larger indications like a psoriasis and others. Those are big trials. In our feeling, those are more inflammatory in nature. Where we're interested is really looking in disease populations where there is not only an inflammatory component, but a proliferative component, and that's where STAT3 is critically involved. We know that STAT3 drives both inflammation and the proliferative steps. I think when we think about where we can make the biggest impact in the shortest timeframe, that's how we think about the overall cascade. Then being able to run these trials efficiently in the U.S., but also ex-U.S., and making sure that we can hit our regulatory timelines as well as our clinical and interim data points. Thank you. I'll hop back in the line. Yeah. Thanks, Deb. Thank you, Debanjana. Our next question comes from Ryan Deschner with Raymond James. Please go ahead, Ryan. Thanks. Good morning. Congrats on the update. I'm curious how you interpret the discontinuation in the 101 cohort due to diarrhea, which appeared to be from a grade one adverse event in that table. For your new target indications and maybe for your potential derm indication in particular, would you anticipate having to use a higher dosing level than what was used for IPF? Okay, let me answer that in reverse. No. What's interesting, we've seen this across all of our models, whether this be the tumor models that we've run in the past, whether they be the GI models, whether it be the pulmonary fibrosis model. We actually see at least a four to one, sometimes much higher, ratio of our drug in the plasma of these animals relative to the disease tissue. That's common. We see target-dependent engagement, and that's clear. We do not believe that we will have to see this. For example, there was a study just put out recently by one of the co-founders that we saw a greater than eightfold increase in the target area and the disease, which was a GI study, relative to what we saw in plasma. We do not believe that, and we've seen this commonly from that perspective. We think the recommended phase II dose of 101, which was 400 mg BID, or 800 mg total, the equivalent dose is basically 1,000 mg or 500 mg BID of 109. We don't anticipate having to ever go above that. That's from that perspective, what we see. To your first question around the grade one. It's interesting, right? I think when you look at that data set, it's right here. These are healthy volunteers, right? When you look at the 109 data, it is clear that it looks placebo-like. Particularly when you look at diarrhea duration, it's when you then look at 109 and you compare it at the top doses, that the duration is placebo-like for 109, but much longer for 101. I think that really demonstrates that there is some distinction here. Even in a healthy volunteer, that we're seeing some changes that by eliminating the GI exposure of 101 with 109, that there is some sort of differentiation. I agree with you, it is grade one. It was a grade one discontinuation. I don't know how to elucidate that any further. I think even if we didn't see the discontinuation, I still think the duration of the time, which is placebo-like of 109 relative to what we're seeing for 101, is favorable. We achieve what our goal was here, was really showing a distinction between the two, even in a healthy volunteer, from that perspective, where grade one diarrhea is sometimes just considered loose stool. Thanks a lot. Fair. Okay. Thanks, Ryan. Thank you, Ryan. Our next question comes from Jay Olson with Oppenheimer. Please go ahead, Jay. Jay, you may be on mute. He's coming. Okay. Well, I think we'll take the next question just while he un-mutes. Okay. Yeah. Our next question comes from Etzer Darout with Barclays. Please go ahead, Etzer. Hello, can you hear me? This is Etzer, Barclays. Hey. Hey, Etzer. Hey, how's it going? Thanks for taking the question. Just wanted to know if you could maybe characterize the abdominal pain associated with 109. Is it equivalent to what you saw with 101? Any distinctions that you could make there would be helpful. Then in terms of proof of concept, would you be leaning more towards maybe monotherapy proof of concept, or would this be in combination maybe with standard of care, best supportive care, and the indications that you're thinking about? Thank you. Yeah. Really, the abdominal pain, there was nothing there that we can tell. I know that the number seemed more, it's grade one, but there was nothing there that seemingly was differentiated from the placebo in this situation with 109. If there's anything additional, we'll follow up on that point. I think it's a really interesting point that you bring up about combination versus. Depends on the disease. It depends on the indication, and it depends on the type of funding. For example, in ulcerative colitis, or Crohn's disease, there is a sequential stepping, where patients would come off their existing therapy and take 109 monotherapy. You could also perceive that with potentially hidradenitis suppurativa. In dermatomyositis, as I mentioned earlier, we see a new drug coming to space, and that might be on top of a JAK inhibitor, on top of IVIG. In scleroderma, you might be on top of mycophenolate. It really does depend, but I think they're well-defined populations. We understand what these diseases are doing. Then you would put in the requisite placebo arm, depending on the type of trial you are, so that you could potentially differentiate if you are on top of the standard of care. I think one of the key things, Etzer, for us is being able to pull biopsies and using those biopsies to show that, hey, there's a change, not only in activated STAT3, but markers that are indicative of the disease. We see that across the space where there are those markers, so that provides that kind of proof of concept. We'll expect that those phenotypes within manifest into clinical activity, when we have the full data set. Great. Thank you. Yeah. Thanks, Etzer. Thank you, Etzer. Our next question comes from Jay Olson with Oppenheimer. Please go ahead, Jay. Hey, Imran. Congrats on these results, and thank you for providing the update. Based on the full analysis of 101 and these new findings for 109, would you anticipate including any prophylactic measures in your future clinical development plans, or does 109's superior tolerability profile obviate any particular GI concerns? I had a follow-up if I could, please. Absolutely. I think at this point, it'd be disease specific, but we do feel like we've been able to obviate a lot of what we are seeing on the GI side. Again, I think that would be informed study by study. If you look at the initial studies, everybody was prophylactically given loperamide, I think it was, and they still saw two-thirds of their patients having diarrhea. Something we didn't do in the IPF study. So it will be very disease specific, depending on what is the disease itself and if you're on top of background therapy, even though we believe we have obviated, it may be just to be assured, that won't be an issue, and we're not seeing that issue. Again, we think there's quite a distinction with what we've shown here, 109 relative to 101. I think for the most part, we feel pretty comfortable about our data, about our indications. If there is, we'll definitely let you know, as part of the trial design. Okay. Thank you. Yeah. That sounds great. If I could please sneak in a big picture question. Yeah. Sure. Yeah. Between, let's see, dermatology, GI, and other potential indications, what area do you feel fits most closely with your vision for Tvardi, especially with your company's substantial oncology pedigree and the existing oncology development program for 101? It's a great question. I see us as a STAT3 company, we go where the data takes us. I think in oncology, we saw that there was a really nice signal in liver cancer coming out of the phase I study. Now with 109, we see a really nice signal across the board for immune dysregulation, which is validated by what we saw in inflammation or proliferation. Because STAT3 sits at, like this slide shows, a convergent node, there are a multitude of indications that this could be interesting in. The way we look at it is, where is STAT3 necessary and sufficient? The oncology trial is built to demonstrate that. As well as these trials in the future, in the dermatologic and GI space, we think we'll do the same. From our perspective, I would say these are dual paths because now we have two molecules. What we saw with 101 in oncology, which we've reported that phase I data. That was published in early 2025. We did not see the GI discontinuations like we saw with IPF. I think as we think about a path forward is really identifying disease is where we don't believe that what we were seeing was necessarily 101 specific. We really saw, even in the IPF study, the majority of our discontinuations were GI related, and it was top of intended. I think what we're seeing here is dual pathways to have STAT3, where we know it's necessary and sufficient in the non-oncology space, in the GI and derm space, and then a separate arm of the company focusing on oncology with 101, which was well-tolerated in oncology in that space. It really is a dual path. Having two molecules to interrogate multiple pathways, is I think, a way to build value for the company and be de-risking for the company over time, and as well as important for patients. Because no one's been able to get a STAT3 inhibitor across the line. Having a STAT3 inhibitor could really allow us the convergence of signaling cascades that drive these proliferative and inflammatory diseases. Great. Super helpful, Imran. Thank you so much, and congrats again on all the progress. Thanks, Jay. I appreciate you. Thank you, Jay. Our next question comes from Sara Nik with H.C. Wainwright. Please go ahead, Sara. Hey, Imran. Congrats on the data. Thanks for taking the questions. Kind of wanted to get a little more granularity on the PD part and specifically to start. Were the immune cell population reductions you saw reversible on washout? How quickly did those populations recover, if you have? As a follow-up to that kind of recognizing that this is still early and cross-study, do you have any internal benchmarks for how the magnitude of the population modulations that you saw stack up against biologics on the same, like Th17, TFH, B-cell subsets, even any directional speculation? Thanks. Yeah, no. Fantastic question. The first part, we didn't do the washout part of the study. That's a great point. These were FACS analysis done pretreatment at basically day zero, and then after the last doses at day 21. That's the information we have. What is interesting, you highlight it, is that not only did we see these changes in the core populations, we saw them in subpopulations. Let me delve into that a little bit. In the subpopulations, these were populations of Th17 cells, of T follicular helper cells, and B cells, which have been published to be pathogenic in disease populations. For us, that was quite remarkable, because we know that in our peripheral blood, all these cells are circulating, and then those cells in a disease state become expanded. What we showed in preclinically, to ask about the magnitude is that, for example, on the Th17 side, when we looked at a healthy mouse, we saw about a 50% reduction. In a healthy mouse, we saw a 50% reduction in the blood, and that led to very nice data preclinically in diseased animals. That's both in the dermatologic and the GI spaces, where Th17 is measured. When we compare to what we've seen in other phase I studies, there are really not that many people who do this. It's not trivial thing to say, because you have to take the blood, it has to be fresh, it has to be done immediately. You can't freeze these cells because then you lose these signatures. You can't do flash versions necessarily, from what we were told. We've only saw a few, maybe one really honestly, and that was with the JAK inhibition. With JAK inhibition, you would expect that they have their own sets of black box warnings, and one of those is you would expect a potentially massive decrease in neutrophils. We didn't see that. From our perspective, that's very encouraging because that ties to what we've seen now across 400 subjects, is that we're not seeing those changes that would tie to toxicity. We did see similar trends in some of the populations where we know that JAK is related to STAT. What I think is important is that there are a multitude of signaling cascades, even downstream of IL-6, that aren't independent of the JAKs. For example, when you see IL-6 induction, that leads to a multitude of other pathways that are JAK independent. When you can hit the node, you would potentially get a more dramatic effect in reducing these diseased populations without getting some of the black box warnings. It's hard to do cross comparison because very few folks have done the kind of work we've done to demonstrate what we've done here. I think when we look at the populations and then the subpopulations that have been implicated in pathologies of UC and GI, and to see a consistent trend we saw in some of these greater than 60%. For simplicity, we are just showing the 3 core. We feel pretty encouraged. I think the other point on this, I'm harping on this, there's a lot of work that was done here, is that because we can modulate both the humoral response and the cellular response, when you look across the space, both of those are important, and folks are focusing on one or the other, and being able to hit both simultaneously to us is pretty encouraging. No, thank you. That was very helpful. It's a pretty deep dive, and we've had lots of conversations with KOLs on how to resolve the data. We have to show it, I have 23 minutes to walk people through decks, here's the top line. Absolutely. Discussion. Yeah. Definitely appreciate that. Thanks, Sara. Yeah, thank you. Thank you so much. Our final question comes from Christopher Liu with Lucid Capital Markets. Please go ahead, Christopher. Hi, Chris. Hey, Imran. Thanks for the question and congrats on the data. On the reductions in disease relevant immune cells, based on the magnitude of reductions that we see, in your mind, do you think that there's a stratification between which diseases could be higher probability of success or lower probability of success for 109? I think what it suggests, that's hard to say, right? No one's done this kind of work before that I'm aware of. That would say, "Hey, okay, here's this inhibitor in a healthy population. Let's see what happens in a diseased population." That doesn't happen, so we can't see that perfect translatability, and saying, "Okay, now we can say this one works versus that one." I don't know honestly if that has been demonstrated, and that's something we'll look into, and I'll follow back up with you on that purpose. I do think that there are clearly indications where both are important and driving the disease, and they work in tandem, honestly, because we see across a variety of these disease types that have an autoimmune component that the conversion of the B cells with the aid of T follicular helper cells turning into these plasma autoantibodies on top of the Th17 component. I don't think, and I'm not aware, and let me just put it that way. I'm not aware of anyone who said, "Okay, hey, this is driving this is driving that, and that's why you should pick one or the other." We're looking for potentially convergent nodes that allow us to hit all of these simultaneously, and that's why we think STAT3 is in that mechanism. When we dive deeper, well, I'll definitely follow up with you, and see if there's additional commentary there as we identify indications. Got it. Maybe one other question. Yeah If I may. Yeah, please. There was the 60% reduction across these immune cells. Just wondering if there's any literature to kind of gauge where that is, in terms of how efficacious that might be. Again, well, it's interesting. We have the data. We've shown it, right, and it's right here. Right? We've shown that, hey, in a healthy mouse, we can reduce IL-17 producing cells by 50%. Go look at all of our animal data, right, across the board that we see downregulation of a cellular and humoral response. We see downregulation of inflammation, downregulation of fibrosis. I think you just can't, say, pick on one thing. It's the compendium of the data. What you can see are in the UC and the CD data, that the clones look the same, even though we've therapeutically treated them. Or in the least proliferative skin models, whether they be genetically delivered or inflammatory, we see reversions of fibrosis, and that ties to our other sets of data. I think it's a compendium. Focusing on just one is interesting, and it's an interesting thought experiment, I think you really have to take a step back, and I know we all get excited by, hey, can one piece of data turn into everything else? I think you have to take it in as a holistic component to look at the data. I am not aware of anything that says, "Okay, if you get 50%, you get this immune activity." I'm not aware of that on top, our data certainly suggests that preclinically. Got it. Thanks. Thanks, Chris. Appreciate your question. Good question. Thank you for your questions, Chris, and to all of our analysts. I will now turn it back to Imran to close out the call. Yeah. Thank you all. Thank you for listening. I think we identified this molecule years ago, and to now come into fruition and be able to really demonstrate across all vertices of where we think 109 can be interesting. We've hit this PK, the safety, and really validates where we could potentially be in a variety of disease types. We look forward to keeping you all informed of where we're going. Thank you for your time. Appreciate you guys.