Tvardi Therapeutics, Inc. (TVRD) Earnings Call Transcript & Summary

Good morning, and welcome to the Tvardi Therapeutics KOL webinar on the potential of TTI-109 in ulcerative colitis. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the company any 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 in the company press release will contain forward-looking looking statements. including statements concerning the anticipated benefits of Tvardi's product candidates, the potential 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 in 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 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, August 19, 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 4 parts: Dr. Langman will open with the evolving ulcerative colitis treatment landscape in 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 and 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 a Director of the [indiscernible] Center for Inflammatory Bowel Disease and Professor of Medicine at the Weill Cornell Medicine. He is a gastroenterologist and [indiscernible] 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, a 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.

Super. Can you hear me okay?

Yes.

Great. Okay. Good morning. Just as Imran said, I'm the Director of the IBD center here at Weill Cornell 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 kind of quickly. But it is a chronic intestinal inflammation. The pathogenesis as we'll sort of 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 sort of the basis of our metrics for many of these clinical trials. The diagnosis is based on colonoscopy in biopsy. Here, you can see pictures of different stages of disease, and these are different endoscopic scoring systems. And these are what we find to be really the most valid clinical metrics as outputs, right? We know that the PRO2 store frequency, rectal bleeding is very good. [indiscernible] as a biomarker is also very good. But really having 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're really talking about a span of biologics, and we'll talk about those in sort of the therapeutic need. End-stage disease are very severe disease can be treated with colectomy. Next slide, please. Okay. So this is just a high-level slide sort of highlighting the multi-layers of inflammatory bowel disease, pathophysiology. Inflammatory -- ulcerative colitis in particular, is an ulcerative disease. And so this is an alteration of the mucosal layer. And although it could start with that, and obviously, that is the diagnostic criteria that we're looking for in contrast to Crohn's disease, which would be a transmural inflammation, there is inside out signaling. And 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 results in inside-out inflammation resulting in alteration. Ultimately, this leads to chronic mucosal inflammation, which is the thing that we're trying to break, right? We're trying to figure out a medicine here that's going to allow us to break the cycle and to prevent recurrence of disease and allow for maintenance of remission. As we've touched on, disease phenotype is important to think about as we characterize ulcerative colitis. So we talk about different types of patients, patients who can have a single flare and then go into remission. Some that have, sort of, this chronic relapsing and some are very acute and get very sick right away. Immune dysregulation is the different types of immune cells that could be contributing, and we'll 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 the genetic and environmental susceptibility as well. Next slide. Okay. So then -- so what is the treatment paradigm as of today? So once we confirm ulcerative colitis, patients are stratified into mild to moderate or moderate to severe more on the severe side. And 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're talking about advanced therapies. And as of now, all of those advanced therapies, including steroids, which we're trying to minimize because that is the 1 medicine that really has the highest risks in patients with ulcerative colitis and IBD are immunosuppressive therapies. So these are all TNF alpha inhibitors, anti-integrins, IL-23. These are all medicines for which we have to check for hepatitis, exposure for tuberculosis and [indiscernible] patients own different risks of reactivation of different infections. That's for first-line therapy. So first-line therapy for many years was dominated, I would say, particularly in our practice by Alpha-4, beta-7 blockade. We've seen a shift in that practice, particularly to IL-23 inhibitors as first-line therapies, kind of, moved away from TNF alpha 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. Okay. This is just, sort of, a list of that in 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. So 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 alpha 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 [indiscernible]. But I would say that, that's more in sort of the mild, mild to moderate sort of category, particularly for first line. Next slide, please. Okay. So this is, sort of, just visually reflecting the unmet 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 3 things that are highlighted here, sort of, reflect that: one, secondary loss of response. So this is the situation where you get antidrug antibodies. The mechanism shifts, right? We have data suggesting that people who are treated with TNF alpha may 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. And so 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 morning, at least in the United States, we don't use this as first-line therapy. So that remains a very much an unmet need. Next slide. Okay. And so this is, sort of, just bringing those concepts together, right? 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 the signaling pathways and multiple signaling pathways that then allow contribution to these different pathophysiologic mechanisms that constitute this unmet need. And we have these, sort of, laid out, right? If you think about it in terms of immune dysregulation, right, there's many different cytokines that are using this pathway. And so if you can target this pathway specifically, maybe you can block that overall inflammatory tone. Two, can you block specifically the effector cell differentiation, right? You have lymphocytes and other cells that are being trained in this environment, can that STAT3 inhibition now lead to a dampening of some of those lymphocytes. And third is this question of tissue remodeling, right? We think that of disease, and it also gets very much harder to treat. And we know that from studies as well, right? 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. And so we think that there's this tissue remodeling, this tissue memory that is then in printing this response. What is driving that? We think that cytokines are driving that and whether or not this convergent hub, particularly STAT3, can impinge on that. Next slide, please. Okay. So these are kinds of how we think about this. We've 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. And to some extent, there 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 and sort of integrating some of these 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's also an opportunity, right? 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. And so I think that unmet need exists as well. But I think the driver there is still to show efficacy, right? I mean if we have something that doesn't have that efficacy, the utility of it is front line is still more mild. And I think the third thing that will, sort of -- just, sort of, touch on, I would say, is Crohn's disease. And 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's 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. It can be the organizers of that transmural inflammation lending to inflammatory fibroblast and other types of immune cells which are underlying the complications of Crohn's disease, namely fibrostynotic disease. And so I think the opportunity there, we haven't talked as much really about Crohn's disease, but the opportunity there is for fibrostynotic 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.

Yes. Dr. Longman. 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 puts that Dr. Longman just mentioned, that have been targeted individually over the years, cytokines like IL-6, IL-23, IL-1beta, TNF-alpha, growth factors, even non-receptor kinasis. All of these convert on a single transcription factor, STAT3, which becomes phosphor-related or activated into PY STAT3, homodimerizes and moves into the nucleus. There, it drives the transcriptional cascades of the 3 core programs of disease, immune dysregulation, inflammation and proliferation. Now overlay [ today's therapists ]. Every approved advanced mechanism in UC intercepts 1 input into this network, but block any single upstream packet like TNF alpha or IL-23 and because the cascades are redundant, the remaining pathways compensate and STAT3 activation stay 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 to inhibit is to inhibit the node itself. Tvardi's oral small molecules non-covalently binds STAT3 in block its activation. So a single target shut down, all the downstream mechanisms regardless of which upstream cascade is signaled and selectivity matters within STAT3 as well. We have published that in vitro. We have no impact on STAT 3's moderate control 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. preclinically across our model systems, staffing inhibitors to 3 things consistently, we engage their target that 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-109, it did. First, we hit the target. In our Phase I oncology study, patients with paired biopsy showed a median 55% reduction in activated STAT3, 79% among patients who achieved stable disease and 100 patients of the patients with elevated baseline activity stock showed a decrease within approximately 6 weeks. Second, we decreased inflammation and fibrosis in patients. In the REVERT Phase II study in idiopathic pulmonary fibrosis, pool TTI-109 arms showed a more than fourfold difference versus placebo in the slope of IL-6. The key STAT3 mediate cytokine associated with inflammation and 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 decrease 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 101, we have not observed the mitochondria toxicities reported with other STAT3 inhibitors, peripheral neuropathy and lactic acidosis nor are the signals associated with [indiscernible] inhibitors, major adverse cardiovascular events, malignancies, cytopenias. The most common adverse event has been diarrhea. And that last observation was one of the motivations to develop a prodrug, which we term TTI-109, which was designed to deliver an improved tolerability by preserving the mechanism of action of our STAT3 inhibitors. So on the left, what TTI-101 established clinically, target engagement of activated STAT3, reduction in inflammatory cytokine IL-6 and reduction of 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 it is designed to convert to the active [indiscernible] TTI-101 only after it is observed -- absorbed, excuse me, cleaved by phosphatases that are 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 pharmakinetics, it converted rapidly to 101 and achieved dose proportional exposures above the STAT3 IC50. On GI tolerability, it performed similarly to placebo and was substantially improved versus 101. And 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 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 NP cell function. We know this from genetic knockout studies, where T cell and B cell specific STAT3 knockouts are Th17-deficient and cannot produce autoantibodies. So if TTI-109 was engaging its target, these are precisely the populations that should change and that is exactly what we saw. In the multiple ascending dose cohorts, we ran flow cytometry on peripheral blood mononuclear cells and measure the percent change for baseline normalizing each active dose to placebo across 4 dose levels. Across the active dose range, i.e., the doses achieving exposure above the state IC50, we observed down regulation across 16 cellular in humoral immune subsets -- immune subsets, excuse me, recognized as pathologic markers of inflammatory and prolific disease, with key markers reduce up to 60%, sustained across the range. And as you will see, higher still in UC relevance populations. It is worth pausing on the consistency here. If these were random fluctuations, the probability that all 16 subsets would move in the same direction is less than 1 in 65,000. And we observed the same directional pattern at each of the 3 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 we failed to move them in the disease state where the same populations are pathologically expanded. The next 3 slides break these 16 subsets into 3 compartments that define UC immunopathology, the Th17 effectors that drive mucosa inflammation, the T follicular HEPAcells that license the B cell response and the B cells that produce autoantibodies. Each one of these is a recognized access 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 decline between 35% and 76%. And 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 information in UC. This is a broad expression of the cellular arm. But 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 herbicels 34%, CXCR5 positive CD4 T-cells, 38% and central memory CXCR5 population that tracks with the UC disease activity by 43%. So the effect across crosses from the T-cell compartment into the memory that licenses we sell and it carries the B cells themselves. In the humoral compartment, TTI-109 reduced B cells by 20%, memory B cells by 46% and class switch memory B cells by 56%. And it reduced IgG positive switch memory B cell, the population that accumulates in inflamed colon and generates auto antibodies against the gut lining by 71%. Taken together, these 3 compartments show a single oral agent reducing populations of 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're about to see. PY Sator activated state drives 3 interlocking mechanisms in ulcerative colitis? First, immune dysregulation, antigen-presenting cells, cytokine driving pathogenic T-cell responses and autoantibody production. That chronic immune activation feeds a second mechanism inflammation, endothelial activation, immune cell recruitment, [indiscernible] dysfunction, epithelia injury and alteration and 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 4 upcoming slides, I will show you the same evidence pattern built in 3 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 meters did and mechanistically distinct colitis models, models driven by different immune accesses. So the effect is not an artifact of any single system, and finally, the clinical proof of concept, what we've observed in humans with our own molecules. Let's start with the targeted self-activated STAT3. Disease Association first in the left panel, tissue PY STAT3 with UC clinical activity. the more active disease, the more activity sector find in mucosa, and it tracks with the endoscopic and histologic severity of inflammation, which tells us this is not a bi-standard marker, it moves with the disease itself. But the most important -- or more important point is the next one, and I want to spend a moment on it because this is the human validation of STAT3 is a target in ulcerative colitis and it did not come from our program. It came for independent clinical studies of other mechanisms in published studies of both JAK inhibition and IL-6 trans-signaling blockade with on [indiscernible] 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. So the question of these studies answer is not whether STAT3 is the right target in UC. The 2 different mechanisms arriving at STAT3 from 2 different doctors both show the same thing: knockdown activated STAT3 in the colon and the patients do better. In the middle panels, the preclinical evidence. In 2 mechanistic distinct colitis models, DSS, which is an innate immune driven and exasolene, which is an adaptive and Th2-driven ARSAT inhibitors restored, elevated, activated STAT3 levels to baseline. And 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 activate had activated STAT3 baseline within about 6 weeks. So the target is validated in patients, and we have demonstrated we can engage it. Next, the first mechanism, immune dysregulation. The first mechanism of 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 and B cells and plasma cells heavily infiltrate the inflame musoca 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. And in the right panel, the healthy volunteer data I just walked you through that showed reductions across all 3 compartments, Th17, T follicular hepa cells and B cells. So the same population that literally identifies as expanded and active UC populations are brought down in humans. Mechanism two, inflammation. In the left panel, IL-6 is a canonical STAT3 cytokine and serum IL-6 is significantly associated with worsening disease activity. In the middle panel, preclinical colonic inflammation was significantly attenuated in both at DSS and TMBS malls. And in the right panel, clinically in the Phase II IPF study, pooled TTI-101 patients showed a 4.5-fold difference in the IL-6 slope versus placebo. IL-6 signals directly through STAT3 and inhibiting STAT3 reduced it in both settings. Mechanism 3, proliferation and remodeling. In the left panel, structural changes is embedded in how you see 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 marine colons, untreated DSS colitis in the middle, shorten, thickened inflated, treatment with STAT-3 inhibitor on the right and the tissue is essentially indistinguishable from the health and control. [indiscernible] length can architecture or standard structural readouts in this model and both preserved. And this has been examined independently, and a third-party literature survey comparing agents in the same DSS colitis model, our STAT3 inhibitor outperformed the competitors evaluated, including approved tevatinib and other STAT3 direct candidates across the efficacy measures assessed with a 90% recovery on colon length and colonic inflammation score. And in the right panel, clinically at IPF for 12 weeks, pulled TTI-101 to a 7 percentage point difference in baseline weighted fibrosis score versus placebo. So that is the target in all 3 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 clinics, enrolling patients with inadequate response to prior advanced therapies, which as Dr. Longman described, is where the unmet need concentrates, 5 arms, placebo, 2 once daily doses and 2 twice daily doses informed directly by the Phase I, PK and 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 and the clinical -- and 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, 109 is a differentiated oral therapy with targeted tissue exposure; and three, STAT3 enables a precision medicine strategy. The next 3 slides we will take this one at a time. The first challenge overcoming persistent disease biology. You've seen this convergence schematic where a single pathway inhibition fails to suppress STAT3 due to redundant signaling cascade. Here is the evidence assembled against in 1 view. In marine UC models across all the immune axises tested molecules reduce pathogenic Th17 cells, reduced colonic inflammatory scores and preserved colon integrity. And in humans, we have now moved all 3 arms of this biology with our molecules. Immune dysregulation, reductions across 16 STAT3 driven immune subsets in the 109 study, the 4.5-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 at as point of conversion and clinical remission at 12 weeks at the endpoint by which we will evaluate this approach. Next, the second challenge is differentiation. And it has 2 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 therapies, agents that require loading or extended deduction to reach therapeutic levels and loss of response over time. Against that backdrop, 3 points of differentiation, safety. Our clinical database now stands more than 400 subjects treated with 101 and 109 with up to 2 years of exposure and without those class signals to date. Exposure. In UC models, TTI-109 showed growth within an 8-fold target-dependent accumulation in colon tissue relative to plasma. This -- 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. And on the speed and durability of the biological effect, immune subsets moved by day 21 into healthy volunteers. Fibrosis moved by week 12 in IPF. And in a refractory oncology population, we observed 83% of the durable objective responses by week 8. Both properties matter here. Rapid onset supports a 12-week induction readout in our proposed study without the loading or extended induction other ages require. And 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 nonresponders showed little or no reduction in activated STAT3. This is a consistent finding -- consistent finding, and it raises a reasonable question. if the reduction of activated STAT3 is what distinguishes responders from nonresponders, there is a case for inhibiting STAT3 directly rather than approaching it through 1 input in a redundant cascade. That is the hypothesis. This program is built to test and activated STAT3 gives us a measurable readout and whether we are achieving it in patients. Alongside that, 2 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 [indiscernible] 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 cytokines which cytokine assay 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 preclinically and models driven by distinct immune accesses our STAT3 inhibitor reduced activated STAT3, reduced pathogenic immune populations, attenuated colonic inflammation and preserve colon integrity. Clinically, with 101 and 109, we engaged the target in patient biopsies, reduced IL-6 and observe a decrease of fibrosis score from baseline. TTI-109 has added Phase I validation of its own. It converts rapidly with dose proportional exposure above the sector IC50. It improved GI tolerability relative to 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 a single upstream pathway in 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 109 study in 2027, subject to IND clearance and availability of additional funding. In HCC, we expect to report [ Phase 1B II ] top line data for 101 in the fourth quarter this year, 2 programs, 2 catalysts, both reading out the same target biology. I will leave you with this. STAT3 has been implicated in ulcerative colitis for 2 decades. And independent clinical studies indicate that its suppression and colon tissue is what separates responders from nonresponders. 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 the overall agents available today. We believe 109 is that agent, and the Phase I data we review 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.

Yes, great. So I don't know if there's a next slide, but things of -- 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 in that clear evidence of this dose-dependent engagement, particularly in 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 and 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. And the selectivity of being able to do this is driven by the inflammatory process, right? And so by having those inflammatory cells come into that site, that is giving you the selectivity of how your medicine is working. And so 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, sort of, titrating that response. And I think that, that inflammatory response, and as you've illustrated that 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. And so I think that, that is meaningful to have that data already in a clinical context. I think that's very helpful. And 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. And so this is entirely plausible. I think that many KOLs, many investigators would be very enthusiastic about it. And so 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.

Yes, appreciate it. So I think from there, we'd like to open it up for questions and I'll turn it back to the moderator to open up the phone lines.

[Operator Instructions] Our first question comes from Julian Harrison of BTIG.

Thank you for hosting this very comprehensive event. First, a question for Dr. Longman. I'm 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 obafosamid and icotrokinra?

Yes. So I mean, I think that the [indiscernible] 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 the -- some of the maintenance data that we saw was very impressive. We're still lacking some of the data to understand the speed of this type of mechanism, right, how quickly it can act. And so I think that, that still is an area that we need to clarify. But I think that -- and we've touched on this topic, right, the need to be a little bit more comprehensive with respect to inhibiting these cytokine mechanism, particularly in refractory patients remains an unmet need. And so just like with this microRNA inducer, STAT3 also recommend -- reflects a more broad potentially approach. The microRNA approach, though, as you know, I mean it's still -- we don't fully understand exactly how that mechanism is working. Now with respect to IL-23 oral peptides, I mean, in that situation, the expectation is for them to perform as well or better than the injectable because it's not my clinical experience that patients want to trade in oral, 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're 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, right? And so 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. And so 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. And then two follow-ups, if I may, both for you and Imran. I'm curious what you both look for an ulcerative colitis study to maybe build your confidence in the translatability to activity in Crohn's and perhaps fibrostenotic Crohn's as well. And 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. Or 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?

Do you want to ...

Yes, I'll go ahead. I'll start. I think on your second question, let's prove the proof of concept first, right? Let's demonstrate that STAT3 is what we think it is, and we can go from there. But there as a multitude of options that we can combine with eventually. But at this point, our -- what will be really interesting is that, hey, we'll get clinical revision rates, but we'll also have these biopsies, right? At 12 weeks, you're getting pretreatment at 2 weeks and then 12 weeks and then 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 those -- that tissue to help inform that decision. So I think that's to the first -- to your second question -- sorry, Julian, what was your first question? I was so focused on the second.

Yes, sure. So my first question was, as you eventually collect of data in line we have translatability to Crohn's and FSC.

Yes. I don't know. I think in some ways, it's really interesting. It's almost a perfect conduit, right? If you can be -- and this is we -- there's substantial information out there and evidence that this would work as well in Crohn's as it would in ulcerative colitis. But 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 is, we think, is dominant. Then that allows us to actually go in both directions. It allows us to move forward into the naive population and then move downstream as it were into Crohn's and I think in Crohn's, particularly in fibrostenotic Crohn's, for example, is very intriguing, right, because you're -- now you're looking at mechanisms that are much more aggressive, much more chronic for STAT3 actually even further activated. And so there is very good rationale. But from the perspective of 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 and do that in a time frame where within a year or so, we have that data, and we can then move to other trials beyond this proof of concepts. And so that was the -- it's more of a -- it's execution rather than science per se.

Our next question comes from Jay Olson at Oppenheimer.

Thank you for providing this educational update. 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? And then 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.

Randy, do you want to draw it? And then I'll add anything?

Yes, sure. Great question. 100%, the endoscopic and sometimes histologic outcomes are the strongest data that we have for clinical studies. And that certainly will is my anticipation that certainly will be part of the induction study that Imran was highlighting. That would be my impression of how that would be approached. And yes, I mean that's exactly what I think this company is driving that to be able to evaluate the possibility that true endoscopic healing would be reflected also in PROs, I would presume of stool frequency and rectal bleeding. So those are the classic ones. I will also highlight, and I think this goes to the former person's question to 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 room trials. Frequently our doses are higher and so we always think more medicine, the better. And so 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. And so 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. And 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. And 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.

The only thing I would add on top of that, and 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, right, where we had not seen in any other trial that we've seen reported that changes from baseline in fibrosis. So potential disease modification was occurring there. And so we would be more than pleased to replicate that in the ulcerative colitis population.

Our next question comes from Yasmeen Rahimi at Piper Sandler.

Thank you so much for the excellent presentation and the color. I guess the questions I have is given this precision medicine approach for [indiscernible] patients who have a p-STAT signaling defect that would you consider incorporating an enrichment strategy for enrolling patients with such a biomarker ahead of time even if it's a small subset, we can actually learn more? And then two, help us understand sort of what work needs to be done to explore like I don't think on the slide you disclosed the doses. So like how do you think about the dose ranges you would like to pursue in your POC study and also sort of -- I know the study is kicking off in 2027. But to the extent you've done your homework on sort of the length it could take for enrollment and top line data, that would be really helpful. Sorry, lots of execution related questions.