Good morning, and welcome to the Tvardi Therapeutics KOL webinar on the potential of TTI-109 in ulcerative colitis. At this time, all attendees are in a listen-only mode. A live question and answer session will follow the formal presentations. To the 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 made available on the company website following the conclusion of the event. A copy of today's presentation is available on Tvardi's website at tvarditherapeutics.com. 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, 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. Various risks may cause Tvardi's actual results to differ materially from those stated or implied in such forward-looking statements. 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 31st, 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, August 19th, 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. Please go ahead, Imran. Thank you, Tara, and thank you to everyone joining the call this morning as we review our TTI-109 development program in ulcerative colitis. Our discussion has four parts. Dr. Longman will open with the evolving ulcerative colitis treatment landscape and the case for targeting STAT3. I will then present TTI-109, our next-generation STAT3 inhibitor, the rationale for ulcerative colitis as its initial indication, and the phase I data we released in July. I will follow with our proposed proof- of- concept trial design, and Dr. Longman will close with his perspective on the potential clinical role of STAT3 inhibition in UC. For those newer to the story, Tvardi is a clinical-stage company developing novel oral small molecule therapies targeting STAT3, a convergent node downstream of multiple signaling pathways that drive immune dysregulation, inflammation, and uncontrolled proliferation, particularly in conditions like ulcerative colitis. To that end, I would like to introduce Dr. Randy Longman. Dr. Longman is the Director of the Jill Roberts Center for Inflammatory Bowel Disease and Professor of Medicine at Weill Cornell Medicine. He is a gastroenterologist and a mucosal immunologist. His research focuses on the mechanisms driving IBD, with a particular emphasis on translating disease biology to new diagnostic and therapeutic approaches for medically refractory disease, and he has served as a principal investigator in numerous IBD clinical trials. His work has been published in leading journals and is supported by the NIH and major IBD foundations. In other words, he sits precisely at the intersection where our program lives. Dr. Longman, thank you for joining us. The floor is yours. Okay. Super. Good morning. Can you hear me okay? Yep. Great. Okay. Good morning. Just as Imran said, I'm the Director of the IBD Center here at Weill Cornell. We are a very high-volume IBD center, so we see a lot of referral cases. The majority of what we see is moderate to severe IBD, and just as Imran said, we have a lot of experience in different phases of clinical trials, particularly phase II and phase III. Today we're talking about ulcerative colitis. Many of you are familiar with ulcerative colitis and IBD pathophysiology, and we'll go through this quickly. It is a chronic intestinal inflammation. The pathogenesis, as we'll touch on, really spans many layers, and I think that that's really the focus of today. A lot of the features of how we stratify ulcerative colitis are based on clinical presentation. The clinical presentation of ulcerative colitis is usually diarrhea, rectal bleeding, increased frequency, and these are patient-reported outcomes that we use to clinically track disease activity, and that's meaningful because that's the basis of our metrics for many of these clinical trials. The diagnosis is based on colonoscopy and biopsy. Here you can see pictures of different stages of disease, and these are different endoscopic scoring systems. These are what we find to be really the most valid clinical metrics as outputs, right? We know that the PRO2 stool frequency, rectal bleeding is very good. Fecal calprotectin as a biomarker is also very good. But really having the endoscopic score and having evidence of histologic response is some of the most meaningful data that we have for clinical studies. Treatment spans many different types of treatments over the years, and you guys are probably familiar with many of these. For mild and mild to moderate disease, we can start with 5-ASAs or steroids. But once we move into moderate to severe disease, we are really talking about a span of biologics, and we will talk about those and the therapeutic need. End-stage disease or very severe disease can be treated with colectomy. Next slide, please. This is just a high-level slide sort of highlighting the multilayers of inflammatory bowel disease pathophysiology. Ulcerative colitis, in particular, is an ulcerative disease, and so this is an ulceration of the mucosal layer. Although it could start with that, and obviously that is the diagnostic criteria that we are looking for, in contrast to Crohn's disease, which would be a transmural inflammation, there is inside- out signaling. What do I mean by inside- out signaling? Essentially that there are immune signals. Some of these T cells and B cells now that we know play a role, and some of the macrophages that are able to now release these cytokines and result in inside- out inflammation resulting in ulceration. Ultimately, this leads to chronic mucosal inflammation, which is the thing that we are trying to break, right? We are trying to figure out a medicine here that is going to allow us to break the cycle and to prevent recurrence of disease and allow for maintenance of remission. As we have touched on, disease phenotype is important to think about as we characterize ulcerative colitis. So we talked about different types of patients who can have a single flare and then go into remission. Some that have sort of this chronic relapsing, and some that are very acute and get very sick right away. Immune dysregulation is the different types of immune cells that could be contributing, and we will talk a bit about this, and Imran will highlight some of the preliminary data that they have looking at specific cells. But then also thinking about this in the context of a genetic and environmental susceptibility as well. Next slide. What is the treatment paradigm as of today? Once we confirm ulcerative colitis, patients are stratified into mild to moderate or moderate to severe, more on the severe side. For the mild disease, as we mentioned, oral therapies, including 5-ASA, which are non-immunosuppressive, can be first-line therapies. But once you get past that and you really move into the moderate to severe or ASA refractory disease, we are talking about advanced therapies. As of now, all of those advanced therapies, including steroids, which we are trying to minimize because that is the one medicine that really has the highest risks in patients with ulcerative colitis and IBD, are immunosuppressive therapies. These are all TNF-α inhibitors, anti-integrins, IL-23. These are all medicines for which we have to check for hepatitis exposure, for tuberculosis, and we counsel patients on different risks of reactivation of different infections. That is for first-line therapy. First-line therapy for many years was dominated, I would say, particularly in our practice, by alpha 4 beta 7 blockade. We have seen a shift in that practice, particularly to IL-23 inhibitors as first-line therapies. Kind of moved away from TNF-α blockade given the black box concerns and some of the safety concerns with respect to hematologic malignancies. Although they certainly do have a role, particularly with respect to speed of treatment. We do think that those are one of the medicines that can act more quickly. When we talk now about second-line therapy, particularly in the moderate to severe, now you're talking about medicines that you would use as second-line therapy. We really don't use anti-integrin therapy as a second-line therapy. This is really IL-23 and JAK inhibitors, which take the cake primarily in this category. Next slide, please. This is just sort of a list of that and what we talked about, some of our conventional therapies, which are also our older therapies, 5-ASA really for mild disease. And then the immunosuppressants, including corticosteroids, these are the older medicines. They do work in a pinch, and we do know from pharmacy data and from payer databases that they're still overused. We certainly have an unmet need in this area of early treatment that is not being captured. These are also some of our least safe and least effective medicines, certainly not for maintenance as well. Biologic agents, we talked about TNF-α, IL-23, and anti-integrin. We talked a little bit about the positioning of those. I would say second-line therapy JAK inhibitors are somewhat the go-to here. They do have black box warning, including blood clots, and also safety concerns with respect to reactivation of viral infections in particular. S1P modulators exist, particularly VELSIPITY, but I would say that that's more in sort of the mild to moderate sort of category, particularly for first-line. Next slide, please. This is sort of just visually reflecting the unmet need here, right? And many of you know about this therapeutic ceiling that we talked about. We see it across the board with the different medicines that are available, including JAK inhibitors. There seems to still be a lot left on the table. What is the nature of that pathophysiology that is left on the table? I think three things that are highlighted here sort of reflect that. One, secondary loss of response. So this is the situation where you get anti-drug antibodies. The mechanism shifts, right? We have data suggesting that people who are treated with TNF-α maybe shift their disease towards an IL-23-dependent mechanism or other types of cytokines that are able to now sustain inflammation. Two, we have heterogeneity of disease, right? There can be multiple factors, genetic, environmental, or other things that are converging through multiple pathways. It is important to think about being broad here and being able to tune down the inflammatory signal rather maybe than just targeting one specific thing. Third is safety and tolerability. This is a main limitation. Obviously, JAK inhibitors are some of our most effective therapies, particularly upadacitinib, most effective therapies for ulcerative colitis. But there's a black box warning, at least in the U.S., we don't use this as first-line therapy. So that remains very much an unmet need. Next slide, please. This is just bringing those concepts together. How do we think of a rationale for a multi-driver targeting therapy? And the idea here is to think of something that has a convergent signaling pathway, and that's the subject of today's discussion, particularly thinking about STAT3 as a target. And why should STAT3 then be part of this convergent signaling hub? Is it downstream of these signaling pathways and multiple signaling pathways that then allow contribution to these different pathophysiologic mechanisms that constitute this unmet need? We have these sort of laid out. If you think about it in terms of immune dysregulation, there are many different cytokines that are using this pathway. If you can target this pathway specifically, maybe you can block that overall inflammatory tone. Two, can you block specifically the effector cell differentiation? You have lymphocytes and other cells that now are being trained in this environment. Can that STAT3 inhibition now lead to a dampening of some of those lymphocytes? Third is this question of tissue remodeling. We think that part of it is cytokine activation, but part of it also, once disease gets going, you have this sort of chronicity of disease, and it also gets very much harder to treat. We know that from studies as well. You can track sort of disease duration or medication exposure. Those patients do much worse and much more difficult to treat in some of our studies. We think that there is this tissue remodeling, this tissue memory that is then imprinting this response. What is driving that? We think that cytokines are driving that, and whether or not this conversion hub, particularly STAT3, can impinge on that. Next slide, please. Okay. These are kinds of how we think about this. We have talked about these buckets, particularly starting in the middle with biologic- exposed or refractory ulcerative colitis. I think that this is the situation where JAK inhibitors are certainly something that many in the field are considering because they lead with efficacy. To some extent, they are a different mechanism of action. The question being here is whether or not, again, this convergent hub of signaling with the STAT3 can be more selective and more effective, really, in sort of integrating some of those different signals that we think about with respect to IL-23 signaling, with respect to IL-6 signaling, and some of the other inflammatory cytokines. On the first-line therapy, I think it is also an opportunity. We talked about how anti-integrin has sort of switched to IL-23 blockade as being one of the first-line therapies. I think what we think about in the field is having a room temperature stable medicine that exists in our cabinet that we can start the patients on without having to check for infectious risk factors or other things that has great safety, that we can initiate without having to write a prescription for prednisone. I think that unmet need exists as well, but I think the driver there is still to show efficacy. If we have something that does not have that efficacy, the utility of it as front line is still more mild. I think the third thing that we will sort of just touch on, I would say, is Crohn's disease. For many of these signaling pathways that we talk about, a lot of them are overlapping because a lot of the different cytokines that are active in the gut are shared between these different cell types. However, in Crohn's disease, the stakes are higher, particularly since there is transmural activation. We also think that some of these inflammatory macrophages, which really are the hubs that are integrating these cytokines, and particularly notable for STAT3 activation, can be the organizers of that transmural inflammation, lending to inflammatory fibroblasts and other types of immune cells, which are underlying the complications of Crohn's disease, namely fibrostenotic disease. I think the opportunity there, we haven't talked as much really about Crohn's disease, but the opportunity there is for fibrostenotic Crohn's, which obviously we currently do not have any medicines that address that. Okay, next slide. I think that might be it, and so I'll turn it back to you, Imran. Yeah. Dr. Longman, thank you. I want to pick up where you ended. There's real therapeutic progress in UC, and yet a ceiling of roughly 30% remission, secondary loss of response, and some 70% of patients are unmet. During my presentation, I'll make the case that the ceiling has a molecular explanation, that STAT3 sits at the center of it, and that TTI-109 gives us a differentiated way to test that hypothesis in patients. Let's step back and consider all the signaling inputs that Dr. Longman just mentioned that have been targeted individually over the years. Cytokines like IL-6, IL-23, IL-1 beta, TNF-α, growth factors, even non-receptor kinases. All of these converge on a single transcription factor, STAT3, which becomes phosphorylated or activated into pY-STAT3, homodimerizes, and moves into the nucleus. There it drives the transcriptional cascades of the three core programs of disease: immune dysregulation, inflammation, and proliferation. Now overlay today's therapies. Every approved advanced mechanism in UC intercepts one input into this network. But block any single upstream pathway, like TNF-α or IL-23, and because the cascades are redundant, the remaining pathways compensate, and STAT3 activation stays substantially intact. We believe this redundancy is a molecular explanation for therapeutic ceiling and the secondary loss of response Dr. Longman just described. It is not that current drugs miss their targets. It is that the disease does not depend on any single one of them. Our approach is to inhibit the node itself. Tvardi's oral small molecules non-covalently bind STAT3 and block its activation. A single target shuts down all the downstream mechanisms, regardless of which upstream cascade is signaling. And selectivity matters within STAT3 as well. We have published that in vitro, we have no impact on STAT3's mitochondrial function. More importantly, we have now demonstrated it clinically. Across more than 400 subjects treated with our inhibitors, we have not observed drug-related mitochondrial toxicities such as peripheral neuropathies and lactic acidosis seen with other STAT3 targeting agents. TTI-109 doesn't start from zero, and I want to spend a moment here because this slide is the basis of everything we do. Pre-clinically, across our model systems, STAT3 inhibitors did three things consistently. They engaged their target, they decreased inflammation, and they reversed proliferation. The question that matters for any platform is whether that biology translates to humans. With our first-generation molecule, TTI-101, it did. First, we hit the target. In our phase I oncology study, patients with paired biopsies showed a median 55% reduction in activated STAT3, 79% among patients who achieved stable disease, and 100% of the patients with elevated baseline activated STAT3 showed a decrease within approximately six weeks. Second, we decreased inflammation and fibrosis in patients. In the REVERT phase II study in idiopathic pulmonary fibrosis, pooled TTI-101 arms showed a more than fourfold difference versus placebo in the slope of IL-6, the key STAT3-mediated cytokine associated with inflammation. On fibrosis, TTI-101 treated patients demonstrated a decrease in fibrosis score from baseline at 12 weeks, a 7 percentage point difference versus placebo on the baseline weighted score. I want to underline this result. To our knowledge, no other IPF trial has demonstrated a decrease in fibrosis from baseline. Other agents have slowed or prevented worsening, but we are not aware of any that decreased it from baseline, and certainly not within 12 weeks. This recapitulates our preclinical work, the hallmarks of STAT3 biology, inflammation, and proliferative fibrosis decreased in patients. Third, safety. Across more than 300 subjects treated with TTI-101, we have not observed the mitochondrial toxicities reported with other STAT3 inhibitors, peripheral neuropathy and lactic acidosis, nor the signals associated with JAK inhibitors, major adverse cardiovascular events, malignancies, cytopenias. The most common adverse event has been diarrhea. That last observation was one of the motivations to develop a prodrug, which we termed TTI-109, which was designed to deliver and improve tolerability while preserving the mechanism of action of our STAT3 inhibitors. On the left, what TTI-101 established clinically, target engagement of activated STAT3, reduction in inflammatory cytokine IL-6, and reduction in fibrosis. TTI-109 was designed to build on that foundation, and it is worth explaining how. TTI-109 is a phosphate prodrug. At the doses we give, it is inert as it moves through the gut and is designed to convert to the active moiety TTI-101 only after it is absorbed, excuse me, cleaved by phosphatases that are abundant in the blood. That design achieves systemic exposure to the active drug while limiting exposure of the gut to lumen to it. In our phase I healthy volunteer study, TTI-109 delivered on that design. On pharmacokinetics, it converted rapidly to TTI-101 and achieved dose proportional exposures above the STAT3 IC50. On GI tolerability, it performed similarly to placebo and was substantially improved versus TTI-101. Third, the new data I want to spend the next several minutes on. It modulated the immune system measurably, reducing both cellular and humoral populations relevant to UC. Taken together, TTI-109 preserves the mechanism we established with TTI-101 while advancing how we deliver it and how patients tolerate it. Going into the study, 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 and cannot produce autoantibodies. If TTI-109 was engaging its target, these are precisely the populations that should change. That is exactly what we saw. In the multiple ascending dose cohorts, we ran flow cytometry on peripheral blood mononuclear cells and measured the percent change from baseline, normalizing each active dose to placebo across four dose levels. Across the active dose range, the doses achieving exposure above the STAT3 IC50, we observed downregulation across 16 cellular and humoral immune subsets recognized as pathologic markers of inflammatory and proliferative disease, with key markers reduced up to 60%. Sustained across the range, and as you will see, higher still in UC-relevant subpopulations. It is worth pausing on the consistency here. If this were random fluctuations, the probability that all 16 subsets would move in the same direction is less than one in 65,000, and we observe the same directional pattern at each of the three active dose levels. Of note, these are healthy volunteers in whom these populations sit at a homeostatic baseline. If TTI-109 can move them from a normal baseline, we see no reason why it would fail to move them in the disease state, where the same populations are pathologically expanded. The next three slides break these 16 subsets into three compartments that define UC immunopathology, the Th17 effectors that drive mucosal inflammation, the T follicular helper cells that license the B cell response, and the B cells that produce autoantibodies. Each one of these is a recognized axis of disease. TTI-109 moved all three. Start with Th17 biology, which Dr. Longman identified as central to UC pathogenesis. Core Th17 cells declined 54% for placebo. The CCR6- positive memory populations that home to the gut mucosa declined between 35% and 76%. Importantly, and interestingly, the pathogenic Th17 phenotypes, the population the literature most strongly associates with mucosal destruction and treatment-refractory UC, declined as much as 76%. Every row on this table is tied to published work cited here to mucosal inflammation in UC. This is broad suppression of the cellular arm. UC is not only a T cell disease, which brings me to the T follicular helper compartment. T follicular helper cells are a bridge between cellular and humoral immunity. They drive the B cell activation and autoantibody production increasingly implicated in UC. TTI-109 reduced T follicular helper cells 34%, CXCR5- positive CD4 T cells 38%, and central memory CXCR5 population that tracks with UC disease activity by 43%. The effect crosses from the T cell compartment into the memory that licenses B cell, and it carries to the B cells themselves. In the humoral compartment, TTI-109 reduced B cells by 20%, memory B cells by 46%, and class-switched memory B cells by 56%. It reduced IgG- positive switched memory B cells, the population that accumulates an inflamed colon and generates autoantibodies against the gut lining, by 71%. Taken together, these three compartments show a single oral agent reducing populations in both the areas of immune response that define UC pathology, cellular and humoral, in a placebo-normalized phase I setting. This is consistent with what inhibiting a convergent node would be expected to do. With that, let me turn to how these pathways operate in the disease itself. This slide organizes everything you are about to see. pY-STAT3, or activated STAT3, drives three interlocking mechanisms in ulcerative colitis. First, immune dysregulation, antigen-presenting cells, cytokine milieu driving pathogenic T cell responses, and autoantibody production. That chronic immune activation feeds a second mechanism, inflammation, endothelial activation, immune cell recruitment, barrier dysfunction, epithelial injury, and ulceration. Sustained injury drives a third, proliferation, myofibroblast activation, matrix production, and over time, the remodeling, fibrosis, and dysplasia risk of chronic disease. In each of the four upcoming slides, I will show you the same evidence pattern built in three parts. First, the human disease association with what the published literature tells us about how the mechanism behaves in UC patients and how it tracks with disease activity and severity. Next, the preclinical evidence, what our STAT3 inhibitors did in mechanistically distinct colitis models driven by different immune axes, so the effect is not an artifact of any single system. Finally, the clinical proof of concept, what we've observed in humans with our own molecules. Let's start with the target itself, activated STAT3. Disease association first in the left panel. Tissue pY-STAT3 with UC clinical activity. The more active the disease, the more activated STAT3 you find in the mucosa. It tracks with the endoscopic and histologic severity of inflammation, which tells us this is not a bystander marker, it moves with the disease itself. The more important point is the next one, and I want to spend a moment on it because this is the human validation of STAT3 as a target in ulcerative colitis, and it did not come from our program. It came from independent clinical studies of other mechanisms. In published studies of both JAK inhibition and IL-6 trans- signaling blockade with olamkicept, the patients whose tissue pY-STAT3 came down were the patients who responded. The patients whose tissue pY-STAT3 did not come down did not respond. The question these studies answer is not whether STAT3 is the right target in UC. The two different mechanisms arriving at STAT3 from two different directions both show the same thing. Knock down activated STAT3 in the colon, and the patients do better. In the middle panel is the preclinical evidence. In two mechanistic distinct colitis models, DSS, which is an innate immune-driven, and oxazolone, which is an adaptive and Th2 driven, our STAT3 inhibitors restored elevated activated STAT3 levels to baseline. In the right panel, the clinical proof of concept. The paired biopsy data from the phase I oncology study, a 55% median reduction in activated STAT3 and a decrease in every single patient who had activated STAT3 baseline within about six weeks. The target is validated in patients, and we have demonstrated we can engage it. Next, the first mechanism, immune dysregulation. The first mechanism, immune dysregulation, follows the same pattern. In the left panel, the disease association Th17 frequency rises with UC severity and correlates directly with Mayo Score. B cells and plasma cells heavily infiltrate the inflamed mucosa of UC patients. These are not incidental findings, the degree of Th17 plasma cell expansion tracks with disease severity. In the middle panels, preclinically in the DSS and TNBS models, driven by innate and adaptive immune accesses respectively, activated STAT3 inhibition restored Th17 cells to homeostatic levels. In the right panel, the healthy volunteer data I just walked you through that showed reductions across all three compartments, Th17, T follicular helper cells, and B cells. The same population the literature identifies as expanded in active UC populations are brought down in humans. Mechanism two, inflammation. In the left panel, IL-6 is the canonical STAT3 cytokine, and serum IL-6 is significantly associated with worsening UC disease activity. In the middle panel, preclinical colonic inflammation was significantly attenuated in both the DSS and TNBS models. In the right panel, clinically in the phase II IPF study, pooled TTI-101 patients showed a four-and-a-half-fold difference in the IL-6 slope versus placebo. IL-6 signals directly through STAT3, and inhibiting STAT3 reduced it in both settings. Mechanism three, proliferation and remodeling. In the left panel, structural changes is embedded in how UC severity is scored, and it is the biology that separates transient response from durable disease control. The middle panel, in my mind, is the most striking image in this presentation, and I would ask you to look at it closely. These are murine colons. Untreated DSS colitis in the middle, shortened, thickened, inflamed. Treatment with our STAT3 inhibitor on the right, and the tissue is essentially indistinguishable from the healthy control. Colon length and architecture are standard structural readouts in this model, and both preserved. This has been examined independently. In a third-party literature survey comparing agents in the same DSS colitis model, our STAT3 inhibitor outperformed the competitors evaluated, including approved tofacitinib and other STAT3 direct candidates across the efficacy measures assessed with a 90% recovery on colon length and colonic inflammation score. In the right panel, clinically at IPF at 12 weeks, pooled TTI-101 showed a 7 percentage point difference in baseline weighted fibrosis score versus placebo. So that is the target in all three mechanisms, each supported by disease literature, by mechanistically distinct preclinical models, and by clinical observations with our molecules. The next step is to test whether that translates into clinical benefit in UC patients, which brings me to our proposed study. The study is a randomized placebo-controlled proof- of- concept trial in moderate to severe ulcerative colitis, enrolling patients with inadequate response to prior advanced therapies, which, as Dr. Longman described, is where the unmet need concentrates. Five arms, placebo, two once- daily doses, and two twice- daily doses informed directly by the phase I PK/PD. 12 weeks of induction followed by 12 weeks of maintenance. The primary endpoint is safety. The key secondary endpoint is clinical remission at 12 weeks. The exploratory, excuse me, endpoints, serum biomarkers, tissue analysis, and genetic polymorphisms are how we build the response signature, which I will describe in a moment. We designed this study against the key challenges in UC that Dr. Longman highlighted. One, targeting STAT3 addresses persistent disease biology. Two, TTI-109 is a differentiated oral therapy with targeted tissue exposure. Three, STAT3 enables a precision medicine strategy. The next three slides we will take this one at a time. The first challenge, overcoming persistent disease biology. You've seen this convergent schematic where single pathway inhibition fails to suppress STAT3 due to redundant signaling cascades. Here is the evidence assembled against in one view. In murine UC models across all the immune accesses tested, our molecules reduced pathogenic Th17 cells, reduced colonic inflammatory scores, and preserved colon integrity. In humans, we have now moved all three arms of this biology with our molecules. Immune dysregulation, reductions across 16 STAT3-driven immune subsets in the TTI-109 study, the four-and-a-half-fold difference in IL-6 versus placebo with TTI-101, and proliferation, the decrease in fibrosis score from baseline at 12 weeks. Single pathway inhibition leaves these redundant networks intact. Targeting STAT3 addresses it as a point of convergence, and clinical remission at 12 weeks is the endpoint by which we will evaluate this approach. The second challenge is differentiation, and it has two parts, safety and exposure. On safety, JAK inhibitors carry black box warnings for major cardiovascular events, thrombosis, and malignancy, and S1P modulators require cardiac monitoring. On exposure and durability, there is a broader limitation across UC therapies. Agents that require loading or extended induction to reach therapeutic levels and loss of response over time. Against that backdrop, three points of differentiation. Safety. Our clinical database now spans more than 400 subjects treated with TTI-101 and TTI-109, with up to two years of exposure and without those class signals to date. Exposure. In UC models, TTI-109 showed greater than an eightfold target-dependent accumulation in colon tissue relative to plasma. The published experience with JAK inhibition and IL-6 trans- signaling blockade indicates that suppressing STAT3 in colon tissue, not in blood, is what tracks with response. Preferential accumulation at the site of disease is therefore a design feature we consider central rather than incidental. On the speed and durability of the biological effect, immune subsets move by day 21 into healthy volunteers. Fibrosis moved by week 12 in IPF. In a refractory oncology population, we observed 83% of the durable objective responses by week eight. Both properties matter here. Rapid onset supports a 12-week induction readout in our proposed study without the loading or extended induction other agents require. Durability speaks directly to secondary loss of response, which remains the principal limitation of current therapy. Third, the third challenge is precision medicine. UC drug development today largely enrolls broad, unselected populations, response remains unpredictable, and molecular profiling is itself an unmet need. The middle panel returns to the point I made earlier, because this is the foundation of this argument. Across independent studies of different mechanisms, reduction of activated STAT3 correlated with clinical response, and non-responders showed little or no reduction in activated STAT3. This is a consistent finding, and it raises a reasonable question. If the reduction of activated STAT3 is what distinguishes responders from non-responders, there is a case for inhibiting STAT3 directly rather than approaching it through one input in a redundant cascade. That is the hypothesis this program is built to test, and activated STAT3 gives us a measurable readout on whether we are achieving it in patients. Alongside that, two further elements. STAT3 polymorphisms have been associated with elevated UC risk, and the immune signatures I showed you today, pathogenic Th17, inflammatory macrophages, CD4 T follicular helper cells, are STAT3-driven and measurable. Combined with tissue pY-STAT3, these are components of a STAT3-mediated response signature. Our exploratory endpoints, the serum, tissue, and genetic analysis in the study are designed to assemble it with the goal of enriching future trials for patients most likely to benefit. Let me close by putting the whole program in one view. STAT3 is a highly validated convergent node in inflammatory and proliferative disease. The point at which the cytokine cascade is relevant to UC ulcerative colitis intersect, and the point at which independent clinical studies of other mechanisms indicate response is determined. We have translational proof of concept across that biology. Pre-clinically, in models driven by distinct immune accesses, our STAT3 inhibitors reduced activated STAT3, reduced pathogenic immune populations, attenuated colonic inflammation, and preserved colon integrity. Clinically, with TTI-101 and TTI-109, we engaged the target in patient biopsies, reduced IL-6, and observed a decrease in fibrosis score from baseline. TTI-109 has added phase I validation of its own. It converts rapidly with dose proportional exposure above the STAT3 IC50. It improved GI tolerability relative to TTI-101, and it reduced 16 STAT3-driven immune populations, spanning both cellular and humoral arms of the response. That is why ulcerative colitis is our lead indication. A single convergent node in place of a single upstream pathway, an oral therapy with preferential exposure in colon tissue, and a pharmacodynamic readout allows us to assess STAT3-mediated response within the trial itself. Finally, let me point you to the pipeline and near-term catalysts. In ulcerative colitis, we expect to initiate the TTI-109 study in 2027, subject to IND clearance and availability of additional funding. In HCC, we expect to report phase I-B/II top-line data for TTI-101 in the fourth quarter of this year. Two programs, two catalysts, both reading out the same target biology. I will leave you with this. STAT3 has been implicated in ulcerative colitis for two decades, and independent clinical studies indicate that its suppression in colon tissue is what separates responders from non-responders. What has been missing is an agent that inhibits it directly, that reaches the colon, and that has not shown the class safety signals associated with other oral agents available today. We believe TTI-109 is that agent, and the phase I data we reviewed today are the first human evidence that it behaves as it is designed. For an independent assessment of that evidence from a clinician who treats these patients and studies immunology, Dr. Longman, the floor is back to you. Great, thanks. Can you hear me? Yeah. Yeah, great. I don't know if there's a next slide, but I think the things that you covered that I really wanted to highlight that are most impactful for me, one is the data that you showed with respect to target engagement. I really like that and that clear evidence of this dose-dependent engagement, particularly in the peripheral blood, of these different cell types. I think that that's really meaningful. The second thing that is really impactful, I think, for me, is the evidence that you walked us through, showing that STAT3 is increased in inflammatory tissue, in particularly ulcerative colitis, right? Because one may wonder, well, why would you want to inhibit STAT3 everywhere? What is sort of the selectivity of being able to do this? The selectivity of being able to do this is driven by the inflammatory process, right? By having those inflammatory cells come into that site, that is giving you the selectivity of how your medicine is working. You can think about this in the same, for IL-23 inhibition, right? IL-23 can trigger IL-22 in some ways. IL-22 can be seen as something good in sort of restoring the epithelial barrier and in antimicrobial peptides. But it's really about titrating that response. I think that that inflammatory response, and as you've illustrated, the inflammatory response, which tracks with STAT3, makes it a clear target and a selective target. I think the data that you highlighted for us with respect to fibrosis is very convincing. You have clinical evidence to suggest that this acts in an anti-fibrotic mechanism that's really well advanced to many of the other medicines that we have currently that are being evaluated in this space. I think that that is meaningful to have that data already in a clinical context. I think that that's very helpful. Then finally, I'm really enthusiastic about the precision medicine approach that you just walked us through here. This is totally feasible in the sense of looking at STAT3 phosphorylation, ex vivo, as well as being able to genotype patients. We've seen it done in other trials. We've seen it done with some of the work that Scott Snapper has done out in Boston. This is entirely plausible. I think that many KOLs, many site investigators would be very enthusiastic about it. I think that that would also help with respect to recruitment and enthusiasm within the field to be able to test this mechanism. So those are the things, Imran, that have stuck with me. Yeah, appreciate it. I think from there, we'd like to open up with questions. I'll turn it back to the moderator to open up the phone lines. Great. Thank you, Imran and Dr. Longman. Please hold for a brief moment while we poll for questions. Our first question comes from Julian Harrison at BTIG. Please go ahead, Julian. Hi. Thank you for taking the questions and for hosting this very comprehensive event. First, a question for Dr. Longman. I am wondering if you could talk broadly about your expectation for enduring receptivity for novel and safe mechanisms of action in inflammatory bowel disease that can be orally administered. Maybe especially in consideration of recent success and assuming continued success of drugs like obefazimod and izokibep. Yeah. I think that the Abivax program is very exciting in the sense that it would be potentially an oral medicine that has a mechanism of action that appears to be orthogonal to some of the other mechanisms that we have. I think some of the maintenance data that we saw was very impressive. We are still lacking some of the data to understand the speed of this type of mechanism, how quickly it can act. I think that that still is an area that we need to clarify. But I think that, and we have touched on this topic. The need to be a little bit more comprehensive with respect to inhibiting these cytokine mechanisms, particularly in refractory patients, remains an unmet need. Just like with this microRNA inducer, STAT3 also reflects a more broad potentially approach. The microRNA approach, though, as you know, we do not fully understand exactly how that mechanism is working. Now with respect to IL-23 oral peptides, in that situation, the expectation is for them to perform as well or better than the injectable, because it is not my clinical experience that patients want to trade a less effective oral for an injectable. Furthermore, I would anticipate that an IL-23 oral inhibitor would also have the same screening recommendations and immunosuppressive considerations that we would think of for the IL-23. So in that situation, I think the real benefit that we are seeing from some of those medicines is having a room temperature stable medicine that exists in the cabinet that you could just start your patient on and trying to capture that quickly. But at the end of the day, in my experience, efficacy is really the driver. Some of the leading efficacy that we've seen for ulcerative colitis still rests with the JAK inhibitors, but the JAK inhibitors have a black box, so they are a second-line therapy. Thinking about something that has that level of efficacy and potentially even has efficacy in a JAK refractory patient population would really be quite meaningful, not just because of the oral administration. Excellent. That's very helpful, Dr. Longman. Then two follow-ups, if I may, both for you and Imran. I'm curious what you both look for in an ulcerative colitis study to maybe build your confidence in the translatability to activity in Crohn's and perhaps fibrostenotic Crohn's as well. Then second, I'm wondering how you think about the combination potential of TTI-109, given it's been very persuasively established STAT3 is a central node of inflammation propagation. Are there maybe any established mechanisms out there that maybe have the highest odds for additive efficacy with TTI-109, taking a long-term view there? Imran, do you want me to start? I can— Are you good? Yeah, I'll go ahead. I'll start. Yeah. I think, on your second question, let's prove the proof of concept first. Let's demonstrate that STAT3 is what we think it is, and we can go from there. But there is a multitude of options that we can combine with eventually. But, at this point, what will be really interesting is that, hey, we'll get clinical remission rates, but we'll also have these biopsies. At 12 weeks, you're getting pre-treatment at zero weeks, and then 12 weeks, and then at 24 weeks, you're getting biopsies. So you'll be able to track that. So I'd rather not postulate, I'd rather let the data lead us, because I think we will have that tissue to help inform that decision. So I think that's to your second question. Sorry, Julian, what was your first question? I was so focused on the second one. Yeah, sure. So my first question was, as you eventually collect efficacy data and also— In Crohn's. Yeah. —what translatability to Crohn's and FSCD? Yeah. No, I think, in some ways it's really interesting. It's almost the perfect conduit, right? There's substantial information out there and evidence that this would work as well in Crohn's as it would in ulcerative colitis. The reason we built the trial this way is partly practical, and that is that in the case if we get to biologically exposed patients in UC, and we see an efficacy and safety threshold that we think is dominant, then that allows us to actually go in both directions. It allows us to move forward into the naïve populations, and then move downstream, as it were, into Crohn's. I think in Crohn's, particularly fibrostenotic Crohn's, for example, is very intriguing. Right? Because you're now looking at mechanisms that are much more aggressive, much more chronic, where STAT3 actually is even further activated. So there is very good rationale. From the perspective of a company trying to execute and get data, and then build from there, this platform in biologically exposed UC patients allows us to get that initial proof of concept data and then expand. Do that in a timeframe where within a year or so we have that data and we can then move to other trials beyond this proof of concept. So it's more of it's execution, rather than science per se. Make sense, Julian? Very helpful. Thank you. Thanks for the questions, Julian. Our next question comes from Jay Olson at Oppenheimer. Please go ahead, Jay. Hey, thank you for providing this educational update, and thanks for taking our questions. Since one of the historical challenges in treating ulcerative colitis has been a disconnect that sometimes exists between symptomatic improvement and mucosal healing, would it be reasonable for us to think that STAT3 inhibition with TTI-109 has potential to impact endoscopic outcomes, tissue healing and fibrosis to a significantly greater extent than the currently approved agents? Separately, with regards to Crohn's disease, would it also be possible for STAT3 inhibition to achieve disease-modifying benefits in Crohn's disease as well? Thank you. Randy, you want to try that? I will add anything. Yeah, sure. Great question. 100%. The endoscopic, and sometimes histologic outcomes are the strongest data that we have for clinical studies. That certainly will, is my anticipation, that certainly will be part of the week 12 induction study that Imran was highlighting. That would be my impression of how that would be approached. Yes, that's exactly what I think this company is driving at, to be able to evaluate the possibility that true endoscopic healing, which would be reflected also in PROs, I would presume, of stool frequency and rectal bleeding. Those are the classic ones. I will also highlight, I think this goes to the former person's question, too. One of the things that we think about with respect to inflammatory bowel disease is getting medicine in the gut, and we generally think that more medicine is better. We see that frequently. If you compare IBD to some of the [rheum] trials, frequently our doses are higher. One of the things that I like from the data that Imran just presented, is the fact that you see, even at these lower doses, very effective inhibition of some of these cellular populations. That encourages my confidence, that as some of these inflammatory pathways get amped up in an inflammatory cohort, that you will still be in the therapeutic range. Now similarly, with respect to your question for Crohn's disease, that is exactly the question. Do we get deep enough tissue penetration to be able to assess the fact that STAT3 inhibition or whatever your target for Crohn's disease is having that effect. I think that again, the pharmacokinetics give me confidence that this company will be able to evaluate that impact that it could have in Crohn's disease as well. Only thing I would add on top of that, the proof will be in the pudding, but I think what gives us some confidence is that we saw changes in fibrosis, in the IPF patient population, where we had not seen in any other trial that we've seen reported the changes from baseline in fibrosis. Potential disease modification was occurring there. We would be more than pleased to replicate that in the ulcerative colitis population. Super helpful. Thanks again for doing this. Yeah. Pleasure. Thanks, Jay. Yes, thanks for the questions, Jay. Our next question comes from Yasmeen Rahimi at Piper Sandler. Please go ahead, Yas. Hi, team. Thank you so much for the excellent presentation and the color. I guess the questions I have is, given this precision medicine approach for enriched patients who have a p-STAT signaling defect, would you consider incorporating an enrichment strategy for enrolling patients with such a biomarker ahead of time, even if it's a small subset? That way, we can actually learn more. Then two, help us understand what more needs to be done to explore. I don't think on the slide you disclosed the doses, so how do you think about the dose ranges you would like to pursue in your POC study? Also, I know the study is kicking off in 2027, but to the extent you've done your homework on the length it could take for enrollment and top-line data, that would be really helpful. Sorry, lots of execution-related questions. I love it, Yas. I appreciate that. I think the doses will be driven by a few different measures. One that is PK and PD. Actually, in our previous slides that are on our website, we've actually disclosed what the exposures we've seen are. Ultimately, the trial is designed not only from perspective of can we get there with BID dosing, but can we get there with QD dosing? Because of the shifts, not only from an exposure perspective, but also of the shifts from a dynamic perspective, that we were able to really see changes, and measurable changes, within 21 days. I think the time to identify that is all now. From our perspective, we think that this can happen rapidly. We believe that we can get this trial started in 2027 and potentially have data by mid 2028. From that perspective, if we were to run this trial. The trial size would be what we've seen. We'd obviously have to work with the agencies to confirm, but this would be a proof- of- concept trial in the same size that we've seen with other first-in-UC type patients. So, once that is agreed to with the agencies, we'll be happy to share all that information. But we feel that everything that precedes us sets us up in a really nice pathway from a regulatory perspective to get this trial complete, achieve the goals we'd like to do, and in a relatively short timeframe. Thank you. Thanks, Yas. Yes. Thanks for the questions, Yas. Our next question comes from Nick Econom at Cantor Fitzgerald. Please go ahead, Nick. Hi, this is Nick on for Steve. Thank you for the question. We just had a mechanistic question from your early colitis work with TTI-101. It seems when you knock out the STAT3β isoform, colitis becomes exacerbated. But when you dose TTI-101, which hits both isoforms, it's protective of colitis. How do you reconcile those findings? Do we know if UC patients have a different expression profile of the alpha versus the beta STAT3 isoforms? Yeah, I think that goes to the point. The whole point is if you knock out STAT3 completely, it causes issues. That's where others have faced and met challenges in the past. That is that by eliminating the protein, this is where you see many issues. But in this scenario, what our drug does is simply inhibits its activation, and the inhibition of the activation of this protein from inducing these downstream changes. So it's actually mechanistically perfectly tied from this perspective. It's not affecting the protein, it's simply affecting its activation. That's where we believe others have failed in this space. I think, actually, our own paper goes on, and I know the paper you're mentioning goes on to describe why that situation occurs and why we think pharmacological inhibition through non-covalent inhibition of activation of phosphorylated STAT3 is the optimal route. That's really proved out over time as well, when we've looked at our data relative to others. Thank you. Yeah. Randy, you want to say something? Sorry. You were nodding. Okay. All right, forget it. No, that's all you. Okay. I thought so. All right. Next question. Awesome. Yes. Our next question comes from Ryan Deschner at Raymond James. Please go ahead, Ryan. Thank you. Maybe first one for Dr. Longman. Which single aspect of the STAT3 inhibition mechanism seen in Tvardi's preclinical and human patient datasets gets you the most excited about the prospects of using TTI-109 in UC? Fibrosis biomarkers, tissue-targeted exposure, cellular reductions, Th17? Just curious on that, and then I have a follow-up. Yeah, it's hard to disentangle them a bit. But obviously, for inflammatory bowel disease, tissue is the issue, right? And so being able to get into the gut is sort of the thing that we're trying to do here. Right? And so I think the evidence supporting the fact that STAT3 is increased in those areas, and the fact that there's target-specific engagement of that in the dose range that is being looked at, I think that is the essence of my excitement, with the other things on the periphery also making me excited. Got it. And then, also in your perspective, I guess at a minimum, what would a new entrant like a STAT3 inhibitor need to show to be a viable drug candidate that would find utilization in your current UC treatment paradigm? I think those things are really driven by safety and efficacy. You want something that is safe, that is not going to have the class black box that JAK inhibitors have, that you can be able to use first line. Then, there are certain benchmarks by which we look at induction studies to be able to say something is meaningful. Obviously, to have it in the range of a leading medicine, which would be sort of where the TL1As and the upadacitinib sit in some of the earlier studies, I think that would be exciting, greater than 20% placebo adjusted for remission rates after induction. But also with respect to some of these other metrics, that could also make it exciting. I think, beating the benchmark with respect to efficacy would be great. But then other things depend on that as well. It is helpful. Thank you. Thank you for the questions, Ryan. Randy, have you trademarked "Tissue is the issue"? Because I am going to use that on a go-forward basis. Even my CFO just sent me a text message and said he liked that, too. Just wondering, is that trademarked, or can I use that on a go-forward basis? Yeah, you can use that. All right. Any more questions, Tara, before we wrap up? Yes, we have a few more questions. All right, great. in the queue. Our next question comes from Avni. Our next question comes from Avni Bhalgat at Jones Trading. Please go ahead, Avni. Avni, you might be on mute. Hey, can you hear me now? Yes. Yes. Sorry about that. Thank you guys again for the presentation. This is Avni on for Debanjana. The first question that we have, I guess, piggybacks off of Nick's question to Dr. Longman. I know you touched upon this a little bit in the presentation about where in the paradigm a STAT3 oral would fit in, but can you add a little bit more color on where you think that would go if the efficacy hits that benchmark that you just talked about, and let's say the safety is clean, versus, let's say, if it hits that efficacy and there are slight safety issues? The hope would be the unmet need is for something that has first-line safety with the efficacy benchmark that RINVOQ currently has in this space. If we had that magic medicine, that would really take the place of what's emerging for IL-23 inhibitors, whether or not they're injectables or potentially oral or whatever. As physicians, as healthcare providers, we're looking for something that would be able to take that space. Particularly take that space with respect to something that you have room temperature stable, ready to go to the patient. Also, one of the things that's notable, obviously, about RINVOQ, upadacitinib, is the speed, is our perception, at least, of the speed with which it happens, and with which it acts. Both for vedolizumab and to a certain extent, IL-23 blockade as well, we do not necessarily observe the same type of onset that we see. I think the hope would be is that if you had something like a STAT3 inhibition that had no safety signals, that did not have the JAK inhibition box label, but had the same qualities of speed with respect to inhibition of the inflammatory circuit, that would be really impactful. That would position it in that first-line type therapy, but also in second line. Maybe even before going to a JAK inhibitor, for patients who have other reasons that they cannot take a JAK inhibitor, or older patients or other things. Thank you. Just a quick follow-up. Are there any specific prior therapies or mechanisms of failure, since I know that is one of your key inclusion criteria, where you believe that TTI-109 may have a greater likelihood of success? For example, would you expect patients that failed TNF or IL-23 or JAKs to respond better or differently to the STAT3 inhibition? Will that data also be captured in the trial in terms of what are the previous therapies that patients have been on? I will answer and then Randy, if you have anything to add, please do. I think what Randy said early on was very interesting, and that is that he was talking about people who failed TNF-α inhibition are seeing these other pathways, and these are cytokines that are driving this disease, and they, we know, function through STAT3. That is, I think, very encouraging. I think there has not been, and Randy and I have talked about this, I have talked to other KOLs about this as well, that we have not done what we have done in other diseases like oncology. We have not gone through and said, "Hey, okay, here is a resistance mechanism. This is how it is working." We do not know that as well. That is coming, and that is coming over time. What we will use this trial to do is also advance that thought, and part of the trial will be to say, okay, for the patients who had this, like say TNF-α, and then being able to track with not only remission, but also looking at PD, and not only STAT3, but also the other potential cytokines that are being upregulated will be very, very intriguing. I think it is hard to predict, but there certainly is a growing body of evidence that whether it be IL-23, whether it be TNF-α, that there are other redundant mechanisms like that first slide we showed, at the very beginning of this talk showed, that are causing this pathway escape, but they all seem to still coalesce on STAT3. It will be part of our analysis, and one that we're incredibly intrigued by, but we don't understand it in the same way that we understand oncology at this point. Like we understand why RAS inhibitors are escaping therapy yet. That's to come, and I think that's something that's exciting that the field will be able to eventually understand. Randy, any thoughts? Yeah, no, I agree with that. I think it's, on the one hand, it could be mechanistic, but exactly as you said, it just can be pharmacokinetic. If you're getting a more effective drug in that space with a higher concentration, we've seen that time and time again, with respect to some of the dosing of our medicines. I think that that's a really good point. No, and that reminds me. Yeah, thanks. If you look at the data for tofacitinib and you look at the data for olamkicept, two different mechanisms, JAK inhibition and IL-6 trans- signaling. They both, when they saw STAT3 go down, it occurred, but they used it as a marker of how much drug can we get in. When they didn't get high enough exposure of their drug, they couldn't cause STAT3 to go down because they're part of a redundant cascade. I think hitting the target that we know seemingly correlates with progression and response, is I think a different path than we've had previously, when we've only looked at single cascades. Thank you. Yeah. Thanks, Avni. Yes. Thanks for the questions, Avni. Imran, that was actually the last question, so I will turn it back to you for closing remarks. Yeah. Let me say a few words of thanks. Dr. Longman, thank you. Your perspective is what makes sessions like this worth an hour and 15 minutes of everyone's time, and we are grateful you gave us yours. To everyone on this call, thank you for your time this morning. If you have questions we did not get to, please reach out to us directly and we will follow up. I will add something personal. This presentation mattered to me more than most. I was there at the genesis of TTI-109 when the molecule was being designed, and I have been part of every step from that point to the data we shared with you this morning. None of it started with me, however. It was built on the seminal work of our founders, who identified STAT3 as a target long before the field came around to it, and carried forward by a team of people whose names were not on this call, the employees who ran this study, the investigators and patients who participated in them, and the shareholders who have backed this program. I represent all of them today. I should mention one more thing. The stakes this morning were higher than usual. My dad was listening in. Thank you all.