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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 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 company 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 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 has filed with the Securities and Exchange Commission, including its most recent annual report on Form 10-K for the year ending December 31, 2025, and subsequent filings with the SEC. This conference call contains time-sensitive information that represents management's judgment and intention and is accurate only as of today, 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. 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 a Director of the Joel Roberts Center for Inflammatory Bowel Disease and Professor of Medicine at the 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 into 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.

Super. Good morning. 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. 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 and 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 stool frequency and rectal bleeding is very good. Fecal calprotectin 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-ASA 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 and 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 multilayers of inflammatory bowel disease pathophysiology. Inflammatory -- ulcerative colitis, in particular, is an ulcerative disease. And so this is an ulceration 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 result in inside out inflammation resulting in ulceration. 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 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'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 nonimmunosuppressive 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 one 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-integrin, 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'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 a 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 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. 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 CNF-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 Velsipity, 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 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 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 Baricitinib, most effective therapies for ulcerative colitis, but there's a black box warning at least in the United States, we don't use this as first-line therapy. So that remains very much an unmet need. Next slide, please. 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 these 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 now 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 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. 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 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 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, they're 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'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 as frontline 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 talked 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 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 fibrostenotic 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 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.

Yes. 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 alpha, growth factors, even nonreceptor kinases. All of these converge in 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 3 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 alpha 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 to inhibit is to inhibit the node itself. Tvardi's oral small molecules noncovalently bind STAT3 and block its activation. So 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 0. And I want to spend a moment here because this slide is the basis of everything we do. Preclinically across our model systems, STAT3 inhibitors did 3 things consistently. They engage 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 patients with elevated baseline activated STAT3 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, 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. 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 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 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. And 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. So 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 it is designed to convert to the active moiety, TTI-101, only after it is absorbed, cleaved by phosphatases that are abundant in the blood.

That design achieved systemic exposure to the active drug by limiting exposure of the gut lumen to it. In our Phase I healthy volunteer study, TTI-109 delivered on that design. On pharmacokinetics, 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 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. 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 from baseline, normalizing each active dose to placebo across 4 dose levels. Across the active dose range, i.e., 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 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 it would fail 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 mucosal inflammation, the T follicular hypo 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 3.

Start with Th17 biology, which Dr. Longman identified as central to UC pathogenesis. Core Th17 cells declined 54% versus placebo. The CCR6 positive memory populations that home to the gut mucosa declined 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 inflammation in UC. This is a broad suppression 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 helper cells 34%; CXCR5 positive CD4 T cells 38% and central memory CXCR5 population that tracks with UC disease activity by 43%. So the effect crosses from the T cell compartment into the memory that licenses B cell, 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 switched memory B cells, a population that accumulates and inflamed colon and generates autoantibodies against the gut mining by 71%. Taken together, these 3 compartments show a single oral agent reducing population 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're about to see. pY-STAT3 or activated STAT3 drives 3 interlocking mechanisms of ulcerative colitis. First, immune dysregulation, antigen-presenting cells, cytokine milieu driving pathogenic T cell responses and autoantibody production. That chronic immune activation feeds the second mechanism, inflammation, endothelial activation, immune cell recruitment, barrier dysfunction, epithelial injury and ulceration and sustained injury drives the 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 inhibitors did in 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 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 activity STAT3 you find in the mucosa. And 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. 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 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. So the question these studies answer is not whether STAT3 is the right target in UC. The 2 different mechanisms arriving at STAT3 from 2 different directions both show the same thing, knockdown, activated STAT3 in the colon and the patients do better. In the middle panel, the preclinical evidence. In 2 mechanistic distinct colitis models, DSS, which is an innate immune-driven and oxacillin, which is an adaptive and Th2-driven, our STAT3 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 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, 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 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. And in the right panel, the healthy volunteer data I just walked you through that showed reductions across all 3 compartments, Th17, T follicular helper cells and B cells. So the same population that literature identifies as expanded in active UC populations are brought down in humans.

Mechanism 2, inflammation. In the last panel, IL-6 is a 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. 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 reduces 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 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 reserved. And this has been examined independently. In a third-party literature survey comparing agents in the same DSS colitis model, our STAT3 inhibitor outperformed the comparators 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. And in the right final 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 a 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 colitis, 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 exploratory 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 convergent schematic where single pathway inhibition failed to suppress STAT3 due to redundant signaling cascade. Here is the evidence assembled against in one view. In murine UC models across all the immune accesses tested, our molecules reduce pathogenic Th17 cells, reduce colonic inflammatory scores and preserve 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 it at a point of conversion and clinical remission at 12 weeks is 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 [UCU therapies], agents that require loading or extended induction 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 greater than an eightfold 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 in the 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 agents 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, 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 one 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 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 cytokine cascades -- which the cytokine cascade is relevant to UC ulcerative colitis intercept and the point at which independent clinical studies of other mechanisms indicate responses determined.

We have translational proof of concept across that biology. Preclinically in models driven by distinct immune accesses, our STAT3 inhibitors reduced activated STAT3, reduced pathogenic immune populations, attenuated colonic inflammation and preserved clone integrity. Clinically, with 101 and 109, we engaged the target in patient biopsies, reduced IL-6 and observed a decrease of fibrosis score from baseline. TTI-109 is added Phase I validation of its own. It converts rapidly with dose proportional exposure above the STAT3 IC50. It improved GI tolerability relative to 101 and introduced 16 STAT3-driven immune populations spanning both cellular and humoral arms of 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 109 study in 2027, subject to IND clearance and availability of additional funding. In HCC, we expect to report Phase Ib/II top line data for 101 in the fourth quarter of 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 in cone tissue is what separates responders from nonresponders. What has been missing is an agent that inhibits it directly, that reaches the cone and that has not shown the class safety signals associated with other oral agents available today. We believe 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.

Can you hear me?

Yes.

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

Great. Thank you, Imran and Dr. Longman. So please hold for a brief moment while we pull for questions. Our first question comes from Julian Harrison of BTIG.

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 could be orally administered, maybe especially in consideration of recent success and assuming continued success of drugs like obefazimod and Icotrokinra.

Yes. So I mean, 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 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 mechanisms, particularly in refractory patients remains an unmet need.

And so just like with this microRNA inducer, STAT3 also 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 I -- it's not my clinical experience that patients want to trade an 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 2 follow-ups, if I may, both for you and Imran. I'm curious what you both look for in 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 PTI-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 PTI-109 taking a long-term view there?

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's 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 remission rates, but we'll also have these biopsies, right? At 12 weeks, you're getting pretreatment at 0 weeks and then 12 weeks 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 one.

Yes, sure. So my first question was as you eventually collect efficacy data -- translatability to Crohn's and FSCD?

Yes. No, no. 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 populations and then move downstream as it were into Crohn's. And I think in Crohn's, particularly fibrostenosis in 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 with STAT3 actually is even further activated.

And so there is very good rationale. But 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 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 concept. So that was a -- it's more of a -- it's execution rather than science per se. Makes sense, Julian?

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 try that 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 week 12 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 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. So those are the classic ones. I will also highlight, and 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 medicines 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.

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 the 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.

I guess the questions I have is given this precision medicine approach for enrich patients who have a pSTAT 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 that 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.

I love it. Yes. I appreciate that. I think the doses are -- will be driven by a few different measures, one that is PK and PD, right? And we -- and actually, in our previous slides that are on our website, we've actually disclosed what the exposures we've seen are. And ultimately, the trial is designed not only from a perspective of can we go BID dosing, but can we get the QD dosing because of the shifts not only from an exposure perspective, but also shifts from pharmacodynamic perspective that we were able to really see changes and measurable changes within 21 days. And so I think the time to identify that is all now.

And from our perspective, we think that this can happen rapidly. We believe that we can get the trial started in 2027 and potentially have data by mid-'28 from that perspective if we were to run this trial. And the trial size would be what we've seen. We'd actually have to get -- we 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 perceived us set us up as a really nice pathway from a regulatory perspective to get this trial complete and get the -- achieve the goals we'd like to do and in a relatively short time frame.

Our next question comes from Nick Econom at Cantor Fitzgerald.

This is Nick, on for Steve. We just had a mechanistic question from your early colitis work with TTI-101. It seems when you knock out the STAT3 beta isoform colitis becomes exacerbated. But when you dose 101, which hits both isoforms, it's protective of colitis. How do you reconcile those findings? And do we know if you see patients have a different expression profile of the alpha versus beta STAT3 isoforms?

Yes. I think that goes to the point, right? That it's -- the whole point is if you knock out STAT3 completely, it causes issues, right? And that was the whole -- and that's where others have faced challenges in the past. And that is, is that by eliminating the protein, this is where you see many, many issues. But in this scenario, what our drug does is simply inhibits 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. And that's where we believe others have failed in this space. And I think actually our own paper goes on and another paper you're mentioning goes on to describe why that situation occurs and why we think pharmacological inhibition through noncovalent inhibition of activation of phosphorylated STAT3 is the optimal route. And that's really proved out over time as well when we looked at our data relative to others.

Randy, do you want to say something? Sorry, you were nodding.

Yes. Our next question comes from Ryan Deschner at Raymond James.

Maybe first one for Dr. Longman. Which single aspect of the STAT3 inhibition mechanism seen in Tvardi's preclinical and human patient data sets 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.

Yes. I mean 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 has been looked at. I think that is the essence of my excitement with the other things on the periphery being also excited -- 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?

So I think those things are really driven by safety and efficacy, right? You want something that's safe, that's not going to have the class black box that JAK inhibitors have that you can be able to use first line. And 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 sort of a leading medicine, which would be sort of where the TL1As and Upadacitinib sit in some of the earlier studies, I think that would be exciting, greater than 20% placebo adjusted for remission rate after induction. But also with respect to some of these other metrics that could also make it exciting. So I think beating the benchmark with respect to efficacy would be great. But then other things depend on that as well.

Thank you for the questions, Ryan.

Randy, have you trademarked tissue is the issue because I'm going to use that on a go-forward basis. Even my CFO just sent me a text message and said he liked that, too. So just wondering is that trademark or can I use that on a go-forward basis?

Yes, you can use that.

All right. All right. All right. Any more questions, Tara, before we wrap up?

Yes. We have a few more questions in the queue. So our next question comes from -- our next question comes from Avni Bhalgat at Jones Trading.

Can you hear me now?

Yes.

Okay. Sorry about that. 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.

We're -- 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. And so if we had that magic medicine, that would really take the place of what's emerging sort of for IL-23 inhibitors, whether or not they're injectables or potentially oral or whatever, we're looking for something as physicians, as health care providers, we're looking for something that would be able to take that space and particularly take that space with respect to something that you have room temperature stable, ready to go to the patient. And 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 vedolizumab and to a certain extent, IL-23 blockade as well, we don't necessarily observe the same type of onset that we see.

And so 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. And so that would position it in that first-line type therapy, but also in second line and maybe even before going to a JAK inhibitor for patients who have other reasons that they can't take a JAK inhibitor or older patients or other things.

And then just a quick follow-up. So are there any specific prior therapies or mechanisms of failure since I know that's one of your key inclusion criteria where you believe that TTI-109 may have a greater likelihood of success. So for example, would you expect patients that failed TNF or IL-23 or JAK to respond better or differently to the STAT3 inhibition? And then will that data also be captured in the trial in terms of what are the previous therapies that patients have been on?

I'll 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, is that he was talking about people who failed TNF alpha inhibition are seeing these other pathways. And these are cytokines that are driving this disease and say, we know function through STAT3. So that is, I think, very encouraging. I think there hasn't been -- and Randy and I have talked about this, I talked to other KOLs about this as well, we haven't done what we've done in other diseases like oncology. We haven't gone through and said, okay, here's the resistance mechanism. This is how it's working, right? We don't know that as well. And that's coming, and that's 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 patients who had this like say TNF alpha 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. And so I think it is -- it's hard to predict, but there certainly is a growing body of evidence that whether it be IL-23, whether it be TNF alpha, that there are other redundant mechanisms like that first slide we showed at the very beginning of this talk show that are causing this pathway escape, but they all seem to still coalesce on STAT3. So 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. And I think -- but 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?

Yes. No, I agree with that. I mean I think it's -- on the one hand, it could be mechanistic, but exactly as you said, it just can be pharmacokinetic. And 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. So I think that that's a really good point.

No. And that reminds me, yes, thanks. If you look at the data for tofacitinib and you look at the data for [indiscernible], 2 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 like how much drug can we get in. And when they didn't get high enough exposure of the drug -- of their drug, they couldn't cause STAT3 to go down because they're part of a redundant cascade. And so I think hitting the target that we know is seemingly correlates with progression and response is, I think, a different path than we've had previously when we've only looked at single cascade.

Imran, that was actually the last question. So I'll turn it back to you for closing remarks.

Yes. Let me say a few words of things. Dr. Longman, thank you. Your perspective is what makes sessions like this worth an hour and 15 minutes of everyone's time, and we're grateful you gave us yours. And 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 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 the study, the investigators and patients who participated in them and the shareholders who have backed this program. I represent all of them today. And I should mention one more thing. The stakes this morning were higher than usual. My dad was listening in. Thank you all.

Good morning, and welcome to the Tvardi Therapeutics Investor Webcast. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be available on the company website following the conclusion of the event.

I will now turn the call over to P.J. Kelleher of LifeSci Advisors. Please go ahead, P.J.

Thank you, Wilson, and good morning, everyone. Earlier today, Tvardi Therapeutics issued a press release announcing data from its Phase II heels of its next-generation STAT3 inhibitor TTI-109. A copy of this press release is available on Tovardi's website at tovarditherapeutics.com. Joining me on today's call is Imran Alibhai, Chief Executive Officer of Tvardi Therapeutics. Before I turn the call over to Imran, I would like to remind everyone that this discussion in the accompanying press release will contain forward-looking statements, including statements concerning the anticipated benefits of Tivarti's product candidates, the potential benefits of TI. -- as compared to TTI-101, Tavares ongoing and planned future clinical trials and anticipated timing of reporting data from such trials.

Potential indications for its product candidates, Tovardi'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 Devardi'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 to already has filed with the Securities and Exchange Commission. including its most recent annual report on Form 10-K for the year ending December 31, 2025, in subsequent filings with the SEC.

This conference call contains time-sensitive information that represents management's judgment and intention and is accurate only as of today, July vary undertakes no obligation to update or revise any forward-looking statements, except as required by law. I will now turn the call over to Imran Alibhai, Chief Executive Officer of Tvardi Therapeutics. Imran?

Thank you, [indiscernible], and thank you for everyone for joining this call this morning as we review new and exciting data from our TT development program. Ben, I'd like to point out that the slides that accompany this call are available on our site with an appendix that includes additional materials, including more in-depth data from our preclinical program in model systems that are the backbone of our translational program as well as the data we presented earlier this year from our Phase II IPF study, which we will highlight today. That brings us to step, which is what we are focused on. Satis an incredibly a validated convergent node, if you drop it into PubMed, only 45,000 papers describe its role as a central mediator inflammatory inflatory and proliferative disease.

What we have demonstrated over time is that preclinically, we can downregulate activated STAT3, which then leads to down-regulation of immune disregulation, inflammation and proliferation. We can now show you that we've confirmed these findings in patients in that week show target engagement, downregulation of the cellular and humoral responses as well as actual validation of decreases in inflation. That brings us to 109. This is our next-generation STAT3 inhibitor, which is a phosphate prodrug of a first-generation molecule. Today, we will idostrate that TTI109 met the design objectives that in that rapidly converts with predictable dose proportional PK and has improved GI tolerability to our first-generation molecule. Beyond this, we will mechanistic pharmacodynamic data of reductions in disease-associated immune populations, specifically T cells and B cells.

Seeing this kind of pharmacodynamic data signal in healthy volunteers, we believe portends well for patients with chronic and inflammatory diseases in the dermatologic GI space, that exhibit State driven immune to circulation, inflammation and proliferative tissue modeling. If you take a step back and think about all the signaling pathways that have been individually targeted in the past, which code growth factors, cytokines, even non-tire smotherinses, all of these convergence step, and induce the protein to become phosphorylated, it then homodimerizes, moves into the nucleus where it drives the transcriptional cascades of immune disregulation, inflammation and proliferation. -- the common hammers we see in dermatologic and GI indications. What we've developed at Divardi, our noncovalent oral small molecule inhibitors that simply inhibits state's ability to become phosphorylated.

This prevents homodimerization, it's moving into the nucleus and the transcriptional cascades we associate with disease. What we do not do and what we have published on the bottom left and have demonstrated now in patients has had any impact on STAT3 in the mitochondria. This has been an issue previously for other molecules in the space and from our perspective, not only do we have the in vitro data that suggests that Step 3 is not affected. Now we don't affect motochondostat function. We now have 400 patients worth of data across our 2 molecules that demonstrate we have seen 1 example of a drug-related mitochondrial toxicity. The reason all this is so important is really here in the middle of the page. And then that is that STAT3 has a dual mechanism Intrinsically, we know that STAT3 activation drives the inflammation and proliferation we see in the cellular compartment.

But extrinsically and maybe equally important, we know that STAT3 activation also drives immune disregulation. What we have demonstrated in vivo, in vitro and now clinically is that intrinsically in the cell compartment, we can downregulate the inflammatory and proliferative cascades and simultaneously may control you extrinsically in the immune department that we can restore humoral and cellular immune deep. The basis of our program is on our first-generation molecule, TTI101, which is the clinical foundation for the development of TTI.

Our first in human study was actually an oncology study in which we demonstrated PK, PD, tolerability and activity. And shown here is that pharmacodynamic effect and that is that we were able to take biopsies for patients pretreatment and on treatment, and we were able to demonstrate that in every patient, we saw a decrease in activated STAT3. The overall decrease was 55% and in patients with clinical benefit, it was almost 80%. And then earlier this year, we presented data from the IPF study called RVI. Trial, which was a Phase II study, in which we demonstrated that in patients treated with TTI-101, we could decrease 1 of the hallmarks of inflammation in fibrosis, and that is -- what you see on the top of this panel is that patients treated with TTI-101 had a great for difference in the slope of the line versus patients on placebo or i6.

But the thing that was really encouraging to us is potentially early signs of disease modification in these patient populations. In that, in the bottom of the panel, you can see a difference in fibrosis. We measured by CT fibrosis pretreatment and posttreatment. And what you see is a 7% difference in weighted fibrosis score, an actual decrease in fibrosis, we are unaware of any other trial, whether they be a 12 trial like this or a 52-week trial has actually shown a decrease in fibrosis relative to the starting point of the patient population. And then finally, from an overall safety profile, we've tested TTI101 our first-generation molecule across 300 subjects. And we've demonstrated -- we do not see any of the moderate chondrotoxicity observed with other cat inhibitors like prophanopathy and lactic acidosis.

And commonly, we are compared to JAK inhibitors. But Similarly, we do not see the safety signals that we see with [indiscernible]. We don't see serious infections. We don't see major cornivascular events or malignancies. These are all black box warnings, nor do we even see the cytopenias. The most commonly reported adverse event with TTI101 has been diarrhea. So based on this foundation, we wanted to basically maintain this mechanism of action and observed clinical activity of 101. But we want to improve its drug delivery and diminishes GI exposure. And so we built TT100 on the left-hand side, T10 is the phosphate prodrug of TTA101. And interestingly, 109 it is like 101 delivered orally and once it passes through the gut is designed to convert to the active moiety in the blood because of all the phosphatases we have in our blood.

And so what that allows us to do is generate a very soluble molecule that's easily formulated, but two, because it has no activity, we're diminishing any of the GI exposure of the active Montan the guy. What we have demonstrated in our GLP results, IND-enabling Jigar results is that like 101, there were no tox mining on. Two, for the prodrug, we show that at equal -- or near equivalent doses of 109 and 101, we had equivalent exposures. And then finally, what we needed to show for this prodrug to be where we expect it to be is that 109 had to rapidly convert to the active Mode-101. And that's exactly what we see. See in the bottom right-hand corner, what you're looking at is the highest dose we tested in a GLP primate study.

And what you can see, within 2 hours, 109, which is an orange has now rapidly converted and the vast majority of it is converted into TTL101. To that end, we wanted to replicate these findings in humid banks. And so what we did is we ran a 3-part study. Part A was a sad portion of the study. In this portion of the study, we wanted to demonstrate that like in rats and monkeys, 109 rapidly converted 101. Part B was a pioequivalence crossover study in which we gave patients 101 or 19 to start, wash them out and then gave them the alternative molecule. And we wanted to show that equivalent doses of the molecules gave equivalent exposures, again, like what we had shown in rats and monkeys.

Finally, Part C was 3 arms combined. In that, we looked at placebo, TTL109 and TTA101 at the recommended Phase II dose. What this allowed us to do was look at steady-state exposures, safety and tolerability and really then demonstrate pharmacodynamics of 109. So first, from the SAD portion of the study, here on the left-hand side is the data I just showed you. This is the primate study. we saw that 109 rapidly convert to 101. Here is the human data. And what you can see, again, very similar to the animal data is that 109 in human being rapidly converts to 101. And again, at 2 hours, greater than 95% of 109 is converted to 101.

The next part of the study was giving near equivalent doses of 109 having a washout period in the gaming or reversing the order and demonstrating equivalent exposure. And that's exactly what we saw when we gave equimolar dosing confirmed equivalent exposure of the active LoDo 101 versus 109. And then the final part of the study was really understanding the exposures. And in the SAD portion of the study, which you can see is the higher the dose of 109 we gave the higher the dose of 101 we got. And at all the active doses, we were well above the IC50. This compares favorably to what we saw at steady state in the MAD portion of the study, which you can see that in green and purple, the same dose, we can see similar pharmacokinetic profiles of day 1 and day 21.

We see a predictable dose proportional PK increase at steady state and what's interesting is those exposures are all above the STAT3 IC50. So the next part of the site after we've now checked the boxes for exposure was to really demonstrate a differentiation in a healthy volunteer of the -- from a safety perspective. And so what you can see is the overall profile for these 3 molecules for placebo, for TTI-109 at different doses, and then a head-to-head comparison of 109 to 101. And what you can see, the overall, the safety profile appears favorable.

The incidences of TAEs are broadly similar across the groups from placebo to 109 to the recommended Phase II dose of 101. Interestingly, we did see a near molar equivalence of 109 and 101 and potentially improved profile 109. Important to note that the second dose level 101, we observed 1 subject who discontinued due to an episode of isolated transaminitis; however, it's unlikely related to TTI 109 as the lab values begin to improve while she was on treatment and prior to treatment discontinuation. In addition, we saw no changes in bilirubin so there was no indication of dili.

It was theorized that an alternative etiology for this could have been a passing of a gallstone as its shared much of the same symptomology. Importantly, the study demonstrated no SAEs no dose-dependent pattern in adverse events and no clinically relevant changes in vital science or ECGs. As detailed in the prior slide, we built TTI 109 to approve on the GI tolerability of 101. This slide highlights that improved tolerability. Overall, the TEA rates were similar, but we absorbed an important distinction between 109 and 101. When diving deeper into the characteristics of diarrhea, -- the duration of diarrhea for TTI-109 was comparable to placebo. It was transient and resolved without treatment, very placebo-like in contrast to T-11 at the recommended Phase II dose of TTL-101 wheat versus TD-019, you can see quite a contrast.

TTI109 had a duration last simple actually, and much less than what we see with TTI101. And interestingly, we had 3 patients exhibit diarrhea and 1 patient had a grade 1 in the 101 arm that actually led to discontinuation. So from our perspective, not only have we shown you from a kinetic perspective, we had achieved our goals, but also this data demonstrates to us that we have achieved our goals in improving the GI tolerability with 109 that had placebo-like activity. So the final part of the study was really -- was really understanding pharmakinetics. We had a specific hypothesis rooted in biology. State 3 is essential for Th17 and B-cell function. We know there's some genetic knockout studies where T cell and B cell specific state knockout mice are Th17 deficient or can't produce autoantibodies, respectively.

And what we have demonstrated previously, and this is a study done years ago. When you give TTI-101 to a healthy -- what you can see is a 50% reduction in Th17 cells, both in the blood and the spleen, which portends quite well for disease mice. And that when -- again, we know in diseases like -- in [indiscernible], these animals upregulate IL-17. And what you can see is that when we therapeutically treat with our molecule, we can reduce these IL-17 producing cells back to near baseline. So our expectation going into this healthy volunteer study was, can we see the same thing, can we demonstrate in a healthy volunteer a decrease in these immune populations and not only can we see in maybe Th17 cells, can we also see it in other immune cell populations that we know that are related to STAT3. That's exactly what we saw.

At the active doses, which are the 250-milligram and up doses, these were the doses as you recollect from the previous slides that were above the [indiscernible], we saw reductions in TH17 cells reductions in T follicular helper cells and in B cells. Now not only did we show it for simplicity, we were just showing these 3 cell types in the core cell types. But actually, we can show you and demonstrated that we saw reductions across 16 cellular in humoral immune subsets recognized as pathologic markers of inflammatory and proliferative dermatologic in GI diseases, all of which were sustained over the active dose range. So from our perspective, what we had demonstrated in a healthy population, is down regulation of cellular and human lumen populations, which portends really well for disease populations. And so the take home from our perspective, as we think about all of the clinical data that we have generated across 101 and 109 is this.

With 101, me, we've shown target engagement. We've seen decreases in disease populations of inflammation and proliferation. And now the 109 clinical observations build on this. In that, in the PK portion of the study, we showed rapid conversion with dose proportional exposures above the STAT3 IC50. Beyond that, from a GI tolerability perspective, we saw that 109 was similar to placebo in incidence and duration of diarrhea and improved versus DTA101.

And finally, what we were actually exceeded our own expectations is that in a healthy volunteer, we were able to show decreases in cellular and [indiscernible] disease-related immune population, which portends well for variety of STAT3 driven dermatologic and gastrointestinal indications. So over the next 4 slides, I will walk you through why we think these 2 therapeutic areas are key and could be well interrogated by 101 -- 109 excuse me. And that is that both these indications are driven by STAT3. And in these indications, we see immune disregulation. We see inflammation and we see proliferation, all STAT3 driven.

And so across -- you'll see this common theme across the next 4 slides. -- is that we'll walk you through both the dermatologic space and gastrointestinal space, preclinical data and then how that preclinical data has translated into clinical data and why this, we think portends well for disease population. So first, let's look at activated sector. And so there are 2 models that we've interrogated in the dermatologic space and 1 is a chemically induced inflammatory skin model in which the animals are delivered bleomycin, and we see inflammatory increase in proliferation in these models.

Second, we have a genetically induced on as a Tyskino1 model, and this is a growth factor dependent increase in inflammation and fibrosis. And what you can see is that when we therapeutically treat with our molecules, we retain -- return excuse me, activated Step 3 back to baseline levels. Similarly, when we go to GI models, whether they be models that are focused on the innate immune access or the adaptive immune access, we see the exact same phenotype. That translates to what we've seen clinically.

Again, in our oncology study, we saw reductions with cleared biopsies of activated STAT3. Now when we look at immune disregulation, across the -- across the dermatologic and GI space, we see increases in cellular responses. For example, in the dermatologic space, whether it be [indiscernible], systemic therasclerosis or stereoderma or even dermatomyositis, we see inductions of pathogenic Th17 cells. Similarly, when you go to the GI space, when you look at either UC patients or Crohn's disease patients, we see induction of TH17 cells. And then when we go to these models, and we look at TH17, we can see that all of these models like in humans, we see an induction of the Th17 response. And in the presence of our molecule, we can therapeutically return the IL-17 producing cells back to baseline.

And our conversion clinically is that we've showed you in a healthy population. We can actually down-regulate this not only TH17 response, but even the humoral response in a healthy population, which portends well for disease population. Now when looking at inflammation, that hallmark, the second hallmark of dermatologic disease. You can see across the chemically induced model and the genetically induced model, we return inflammation, looking at IL-6 back to near baseline levels. Similarly, the way we measure inflammation in an animal in the GI models is to look at colonic inflammatory scores.

And again, you see reductions with therapeutic treatment back to baseline levels. And that ties with what we've seen clinically in our IPF study where we actually showed reductions in IL-6, which is the key cytokine involved not only in inflammation, but later-stage proliferation. And then the final commentary here is on proliferation and that in both of these models, and I don't show all the data, it's in the back of this deck, you can see that when we therapeutically treat, we cannot only show reversals of this proliferative or fibrotic step, but we can also show you that we downregulate all of the indices related to this inflammatory profibrotic transcripts and this includes everything from CTG up to TGF beta to fibronectin [indiscernible] across the board, not only are we seeing reductions in the fibrosis, but we're seeing those in the markets that we associate with these populations.

Similarly, when we look at GI models, we see the same thing. -- with therapeutic treatment, we can see we -- and this is an example from the innate immune axis that we can actually retain colon length and morphology in these animals. And again, the final step of this is that we see we can reduce fibrosis in a human. That's how we've translated that in -- from our IPF study. So to wrap up here, I think what we've learned from our perspective is that we know STAT3 as a transcription factor is genetically validated. And what we've demonstrated preclinically as we can down regulate this in both the inflammatory and proliferative spaces in both the dermatologic and GI space.

And we've confirmed that not only in a healthy volunteer, but also in disease populations. And we believe 109 is now well suited to interrogate these populations where we know they're stat to be driven. And those -- that drives both the cellular humoral immune response, inflammation and proliferative tissue remodeling. And so -- that leads us to my last slide, and that is that today, we've reported out our top of the data. We anticipate incumbent on filing our INDs and funding for these indications. We can initiate these studies in the first half of 2027. And depending on the size and scope of the data, we expect to be able to quickly wrap these studies and provide proof of further validate and drive more proof of concept for our data so that we can eventually move to confirmatory spaces.

And also at the end of the year, in the second half of this year, we will also provide the top line data from our initial oncology study in HCC, which will report across lines. And so we believe we've developed a diversified pipeline with multiple data catalysts, which we can drive long-term value for our investors. So with that, I thank you for all of your time, and I'll open the door for questions from the audience.

[Operator Instructions] So our first question comes from Yasmeen Rahimi with Piper Sandler.

Okay. Wonderful. Sorry for the Manan. -- collapsing on the data, and thank you for really connecting the data, the product profile and also the opportunity of expansion in dermatology and gastroenterology. I think my question for you is just sort of maybe a little bit more granular in terms of how soon can you get the IND filed. Dermatology and gastroenterologists quite wide spaces? And at what point will you be in a position to kind of fine-tune as you think about which indications you're interested in pursuing?

And then also a reminder, like if you do move forward to a Phase II study, with these, given your tax coverage, I'm assuming you could rapidly expedite going into a Phase IIb study or Phase IIa. So you could just crispen out a little bit the way you envision the next step. That would be really helpful. Sorry, there will be many multipart costs.

No, no, no. These are all great questions. And so from our perspective, now that we have -- we've completed the 9-month monkey tox studies 109. We are -- anticipate that there are no other preclinical experiments to do here. We've now wrapped up with Phase I. We'll have the complete study report within the next few months. And then that allows us to rapidly move into D.

And we -- we believe we can file an IND for a Phase II program in 1 or both of these spaces by the end of the year. And so we could get, as I mentioned, a study advanced or initiated in the first half of the year. Now for a lead indication, there beyond the therapeutic areas is that selection remains ongoing. And it's really informed by kind of a number of important inputs and those include our Board the KOLs, our external consultants and importantly, our investors and the broader competitive landscape. We expect to announce the indication once we have completed that alignment process, and have the appropriate funding in place to support this future development.

Our priority is to select an indication where we know there's an unmet need. The competitive environment is there and we have a capital efficient clinical trial design that allows us to create meaningful value for patients and shareholders. And I think we actually identified some of those indications in this [indiscernible] in the dermatologic space and you could pick very small indications where we've seen like dermatomyositis, right? Two very large indications like hydride anticipative, all of which share the clinical features of STAT3 driven disease, which then meets information and proliferation in the modulation.

Similarly, in the GI space where you could pick very small indications or smaller indication small things like fibrosis in crude disease all the way to front-line alter colitis. And what we think is interesting across these spaces is that when you think about all of the drugs that we've that are approved even in these spaces. They hit singular pathways. And where STAT3 is multimodal, we think we'll be able to hit all of these consecutively. So I think -- once we have alignment and support and the funding in place, we think we can rapidly move into these Phase II studies. Is that fair?

Yes. Yes. That's very helpful.

Our next question comes from Steve Seedhouse with Cantor.

Yes. Thanks. Thanks for hosting the call and for the update. I wanted to just first ask if you could clarify like how -- and maybe signal to the market, like how much money do you think you'd need to raise to get to some sort of signing data in 1 or more of these candidate indications. And in different financing scenarios, like are you sort of ideally hoping for a parallel track development in a couple of these? Or are you really going to narrow it down to 1 and update the market at some point before the study initiation.

Yes, absolutely. So let me ask it all depends on the studies, right? And so we could -- because of the parallel nature of both of these therapeutic areas, we think that we could absolutely run these apparel. -- and we have the resources to do so. And I think the funding would be important. I think when we look at these trial designs that if you ran them in parallel, the run Phase II studies that it could be $100 million, but we could also run that or half that cost for 1 indication for smaller trials.

And so it really depends on having alignment from investors to the indication or indications that would allow us to move forward across the board so that we could put this data out there, have the ability for people to digest the data and then work on developing indication-specific protocols that will allow us to rapidly enter trials within a short time frame, get interim proof-of-concept data, and then beyond that have clinical evidence of that so that we could rapidly move it to confirmatory trials. Is that fair?

Yes. And just want to also follow up on the grade 3 transaminitis case. So just -- I think you mentioned maybe an alternative hypothesis or a hypothesis for what happened was this patient might have had a gallstone. Was that a formal diagnosis? Or is that just a hypothesis at this point?

It's not real -- yes, no, no. Yes. So I think important to note is that while the patient was on treatment, we saw an increase in her transaminases, but then a decrease while she's still on treatment. And so it is very -- we believe it's very unlikely that it was drug related. And again, there was no change in billing. It wasn't a formal diagnosis, but it did share some of those from some of the same symptomology from that perspective. And so that's why we think this is not related to our compounds.

Our next question comes from Julian Harrison with BTIG.

Okay. Great. Congrats on this update. First, on phosphorylated Step 3, sorry if I missed it, but just wondering how that compares between 100 and 101 on -- and then second, I'm wondering if you could talk more about your decision not to revisit IPF considering just how much the GI tolerability seems improved with 109 versus 101?

Yes. So it's no different. And sorry, it wasn't made clear. So 109 is the prodrug of 101. And the purpose of 109 is to basically -- it is -- 109 is inter. And so once it passes through the gut and into the bloodstream, it converts into the active 101. And we know when we have data that's demonstrated that how 101 works and 101 works by non-covenant binding at and then preventing that phosphor relation step that causes homodimerization, and its movement is the nucleus.

So empirically, once is converted to 101, which we demonstrated that, that seems to be occurring quite rapidly. There is no difference on how the -- this prevention of phosphorylation or is occurring. So does that make sense, Julien?

5 Yes, it does.

No. And look, on the IPF, I think -- from our perspective, the IPF study provided important clinical proof of mechanism for STAT3 inhibition, right? And what we've been able to show, as you mentioned, is decreases in the population and step 3. But -- that said, when we look at the IPF trials. These trials are longer trough. And we know that the validated mechanism -- the validated FDA endpoint in IPF is now forced motor capacity. And that even in itself has a tremendous amount of variability. And so it's clear that these studies need to be really 6 months or potentially even a year. And so -- and then also you have to take into account that we have new drugs that are now available in the space beyond what we had with EsperNovev now we have the PDE4 inhibitor and then and potentially inhaled treprostinil.

And so that landscape has changed dramatically in the last year or 2, which is great for patients. Now I don't -- we don't believe that these mechanisms or disease monitoring, but they are -- they have changed FVC values. And so running a trial like that in the U.S. or even ex U.S. is -- will take a lot of time. and to be quite costly because we would have to fund the background in these indications in ex U.S. studies, where here in the United States, that's paid for because of interest. But ex U.S., you fund all of the components of these indications. And so -- and the final component of this is that with GI studies in derm studies, we are allowed to -- we take biopsies quite common and so that allows us to have interim data to provide that initial step that allows us to show, hey, we're hitting these kinoonical cascades by looking at activated STAT3 and looking at inflammatory and fibrotic markers in the skin and in the GI, whereas you can't do that in IPF.

So I think for all those reasons, it's something that we would happily revisit and some of the indications in these spaces have ILD components. But I think in this time, where we want to be capital efficient and move quickly, improve this proof of move to mechanism to profitable is really to pick indications where we can get interim data and then also put out and then move forward with clinical efficacy endpoints and do that in a shorter order than doing what would potentially be a very long-term and expensive study in IPF.

Makes sense?

Thank Yes.

Our next question comes from Devin Jonathatergy with Jones Trading.

Thanks for the presentation and congress on the data. So you mentioned that biopsy-driven interim proof of concept would be very interesting. So would you be able to help us frame the expected time line to clinical POC if you're pursuing the derm opportunities versus ulcerative colitis or IBD?

Yes. I think both would be similar, honestly, right, I think we could -- we believe in both indications that we would be able to get started in the first half of we think that interim data can be available in both studies in the first half of '28 and then be able -- now depending on -- this all depends on size and all the other components, but we think that in a modest Phase II trial, we'll be able to have data in '29 from this. And so it would build a nice set of inflection points that would validate what we've seen with 101 using 109 into indications in the derm and space, we haven't interrogated in the past, but have this interim data sets where we know that there are markers that are diagnostic for the disease that we think can move forward in early 28, and then that would validate and really get us the clinical end points. in within the year from that time plan.

Yes. And a quick follow-up. So if you ultimately prioritize a T7 driven derm indication, How should we think about the risk-reward tradeoff between pursuing dermatomyositis, HS or the classic D17 disease like psoriasis.

Yes. So I think it's -- each is interesting. -- each has its own components that we have to think about, right? So dermatomyositis the valid trial really nice data. The drug there is a JAK inhibitor. We saw an increase from 1% to 10% in infections in that population, something we don't see with our molecule it may, as we talk to folks, it may be that prebactually become the standard of care, and so you might have to run your trial on top of that. When you look at other diseases like hydrant Supertiva. Those indications is where patients can fail oil where we see kind of the ceiling about 30% efficacy with either a TNF inhibitor or 1 inhibitor.

[indiscernible] once they fail, then you can -- they can [indiscernible] then move to another therapy. So you don't have to have background therapy in this space. Again, in both of those indications, you're able to take biopsy to validate your findings and then move forward. I think the larger indications like a psoriasis and others, Those are big trials. They're in our feeling those are more inflammatory in nature, The where we are interested is really lean in disease populations where there is not only an inflammatory component but a proliferative impotent. -- that's where [indiscernible] is critically vol. We know that step drives both inflammation and the proliferative steps. And so I think when we think about where we can make the biggest impact in the res time frame, That's how we think about the overall cascade and then being able to run these trials efficiently in the U.S. but also ex U.S. and making sure that we can hit our regulatory time lines. as well as our clinical and interim data points.

Thank you. I'll hop back in the line.

Thank you, Dan. Our next question comes from Ryan Deschner with Raymond James.

Congrats on the update. I'm curious, I interpret the discontinuation in the 101 cohort of diarrhea, which appeared to be from a grade 1 adverse event in that table. And then for your new target indications and maybe for your potential derm indication, in particular, would you anticipate having to use a higher dosing level than what was used for IP?

Okay. So let me answer that in reverse No. What's interesting? And we've seen this across all of our models. -- whether this be the tumor models that we've run in the past, whether it be the GI models, whether it be the pulmonary fibrosis model, we actually see at least a 4:1 sometimes much higher ratio of our drug in the plasma of these animals relative to the disease tissue. And that's -- and so where we see target dependent engagement, and that's clear. And so we do not believe that we will have to see this. For example, and not -- there is a study just put out recently in 1 of the co-founders that we saw a greater than 8-fold increase in the target area and the disease, which was a GI study relative to what we saw in plasma.

So we do not believe that, and we've seen this commonly from that perspective. We think the recommended Phase II dose of 101, which was 400 milligrams BID or 800 milligrams total, the comment -- the equivalent dose is basically 1,000 milligrams or 500 milligrams BID 109, we don't anticipate ever go above that. So that's from that perspective, what we see. And then to your first question, around the grade one. It's interesting, right? I think when you look at that it's right here, what -- these are healthy volunteers, right? And so -- but when you look at the 109 data, it is clear that it looks to see it like in whether -- and particularly when you look at dirt duration, it's when you then look at 109 and you compare it at the top doses that the duration is to see we like for much longer for 101.

And I think that really demonstrates that there is some distinction here. in that -- and even in a healthy volunteer that we're seeing some changes that by eliminating the GI exposure of 101 with 109 that there is some sort of differentiation. And I agree with you, it is a great one. It was a Grade 1 discontinuation. But I don't know how to elucidate that any further. I think even if we didn't see discontinuation, I still think the time, the duration of time, which is placebo like 109 relative to what we think 101 is favorable. And we achieve our goal was here was really showing a distinction between the 2, even in a healthy volunteer from that perspective where grade 1 diarrhea, sometimes we just considered a loose stools.

Our next question comes from Etzer Darout with Barclays.

Just wanted to know if you could maybe characterize the abdominal pain associated with 109. Is it equivalent to what you saw with any distinctions that you could make there would be helpful. And then in terms of proof of concept, would you be leaning more towards maybe monotherapy proof of concept? Or would this be in combination, maybe with standard of care, best supportive care and the indications that you're thinking about?

Yes. So really, the abdominal pain, I think I think I don't -- there was nothing there that we can tell that seemed -- I know that the numbers seem to be more, and it's grade 1, but there is nothing there that seemingly was differentiated or from the placebo in the situation with 109. So I don't have -- if there's anything additional, we'll follow up on that point. I think that -- it's a really interesting point that you bring up about combination versus there. It depends on the disease -- it depends on the indication and it depends on the type of funding. In -- for example, in relative colitis or Crohn's disease, there is a sequential stepping where patients would come off their existing therapy and take 109 monotherapy.

You could also perceive that with potentially hydrate and to super tivo in dermatomyositis, as I mentioned earlier, we see a new drug coming to space, and that might be on top of a JAK inhibitor on top of scleroderma, you may be on top of mycophenolate. So it really does depend. But I think they're well defined populations. We understand what these diseases are doing. And so -- and then you would put in the requisite placebo arm depending on the trial you are so that you could potentially differentiate if you are on top of the standard of care. But I think 1 of the key things that for us is having being able to pull biopsies and using those biopsies to show that, hey, there's a change not only in acute, but markers that are indicative of the disease. And we see that across the space where there are those markers. And so that provides that kind of proof of concept. And then we will expect that those phenotypes within manifest into clinical activity when we have the full data set.

Our next question comes from Jay Olson with Oppenheimer.

Congrats on these results, and thank you for providing the update based on the full analysis of 101 and these new findings for 109, would you anticipate including any prophylactic measures in your future clinical development plans -- or does 109 superior tolerability profile, Aviate any particular GI concerns? And then I had a follow-up, if I could, please.

Yes. No, absolutely. I think at this point, I think it would be disease-specific, but we do feel like we've been able to obviate a lot of what we are seeing on the GI side. So -- but again, I think that would be informed study by study. If you look at the end -- or initial studies, everybody was prophylactically given loperamide, I think it was, and they still saw 2/3 of their patients having diarrhea. And so something we didn't do in the IPF study. And so it will be very disease-specific depending on what is the disease itself and if you're on top of background therapy, so that you can -- even though we believe we are aviate, it may be just to be assured that, that will be an issue. We're not seeing that issue. But again, we think there's quite a distinction with what we've shown here relative to relative to 101.

So I think for the most part, we feel pretty comfortable about our data about our indication. But if there is, we'll definitely let you know as part of the trial design.

Yes. And if I could please sneak in a big picture question. Between say, dermatology, GI and other potential indications, what area do you feel fits most closely with your vision for Tovardi, especially with your company's subsea oncology pedigree and the existing oncology development program for 101?

That's a great question. I see us as a set 3 company, and we know where the disease takes -- where the data takes us. And I think in oncology, we saw that there was a really nice signal in liver cancer coming out of the Phase I study. And now with 109, we see a really nice signal across the board. -- for immune disregulation, which is validated by what we saw in inflammation or proliferation. So because that 3 sits at like this slide shows a convergent note, there are a multitude of indications that this could be interesting in. And so the way we look at it is where is Stat3 necessary and sufficient and so the oncology trial is built to demonstrate that in -- as well as these trials in the future in dermatologic and GI space, we think we'll do the same. And so from our perspective, I would say these are dual paths because now we have 2 molecules.

And what we saw with 101 in oncology, which we've reported that Phase I data. that was published in early 2025. We did not see the kind of GI discontinuations like we saw with IPO. And so I think this as we think about kind of a path forward is really identifying disease is where it's not really -- we don't believe that what we were seeing was necessarily 101 specific. We really saw the majority of even in the IPF study, the majority of our discontinuations more GI related and it was top of muted. So I think what we're seeing here is dual pathways to have Stat 3, where we know it's necessary efficient in the non-oncology space, in the GI and derm space, and then a separate arm of the company focusing on oncology with 101, which seemed -- which was well tolerated in oncology in that space.

So it really is a dual path and having 2 molecules to interrogate multiple pathways is, I think, a way to build value for the company and be derisking for the company over time and as well as important for patients because no one's been able to get a STAT3 inhibitor across the line and having a STAT3 inhibitor could really allow us the convergence of signed cascades that drive these proliferative inflammatory diseases.

Great. Super helpful. on congrats again on all the progress.

Our next question comes from Sarah Nick with H.C. Wainright.

Congrats on the data. I kind of wanted to get a little more granularity on the PD part, specifically to start Were the immune population reductions you saw reversible on washout? And how quickly did those populations recover if you have? And then as a follow-up to that, kind of recognizing that this is still early in cross study. Do you have any internal benchmarks for how the magnitude of the population modulations that you saw stack up against biologics on the same like Th17, TFH and B-cell subsets, even any directional speculation?

Yes. No, fantastic question. So the first part, there was no we didn't do the washout part of the study. And that's a great point. So we didn't -- these were fax analysis done pretreatment basically day 0 and then after the last dose at date 21. So that's the only -- the information we have. What is interesting, and you highlighted is that not only did we see these changes in the core populations. We saw them in subpopulations. And let me delve into that a little bit. In the subpopulations, these are populations Th17 cells. -- of TA follicular harper cells and T cells, which have been published to be pathogenic in disease populations. So for us, that was quite remarkable because we know that in our peripheral blood, all these cells are circulating. And then those cells in a disease state become expanded.

And what we showed in preclinically to ask about the magnitude is that, for example, on the T17 side, when we looked at a healthy mix, we saw about a 50% reduction -- and so in a healthy amount, we saw a 2% reduction in the blood, and that led to very nice data. preclinically in disease dams. And that's both in the dermatologic and the GI spaces, where TH17 is measured. When we compare to what we've seen in other Phase I studies. There really not by many people who do this. It's not a trivial thing to say, because you have to take the blood, it has to be fresh. It has to be done immediately.

You can't freeze these cells because then you lose these signatures. So we can't do flash frozen necessarily from what we were told. And so we've only saw a few, maybe 1 really, honestly, and that was with the JAK inhibition. And with JAK inhibition, you would expect that they have their own such a black box warnings. And one of those is you would expect a potentially massive decrease in neutral. We didn't see that. So from our perspective, that's very encouraging because it ties to what we've seen now across 400 subjects is that we're not seeing those changes that would tie to toxicity. But we did see similar trends from that -- in some of the populations where we know that JAK is related to stack. But what I think is important is that there are a multitude of signaling cascades, even downstream of IL-6 that are independent of the JAK. So for example, when you see IL-6 induction that leads to a multitude of other pathways that are independent. And so when you can hit the node, you would potentially get a more dramatic effect in reducing these disease populations without getting some of the Black Box warning.

So it's hard to do cross comparison because very few folks have done the kind of work we've done to demonstrate what we've done here. But I think when we look at the population and then the subpopulations that have been implicated in pathologies of you've seen and GI and to see a consistent trend we saw in some of these greater than 60%. But for simplicity, we're just showing the 3 core. We feel pretty encouraged. And then I think the other point on this and harping on this, there's a lot of work that was done here is that because we can modulate both the humoral response and a cellular response -- when you look at across the space, both of those are important, and folks are focusing on 1 or the other and being able to hit both simultaneously to us is pretty encouraging.

That was very helpful.

It's a pretty deep dive, and we've had lots of conversations with KOLs on how to resolve the data. And so it's but we have to show it and I have 23 minutes to walk people through xAd so here is a top line and...

Yes, absolutely. Definitely appreciate that.

Thanks, Sara.

And our final question comes from Christopher Lu with Lucid Capital Markets.

Chris mention congrats on the data. So on the reductions in disease relevant immune cells based on the magnitude of reductions that we see in your mind, -- do you think that there is a stratification between which diseases could be higher probability of success or lower probability of success for 109?

I think what it suggests -- that's hard to say, right? Because I -- no one's done this kind of work before that I'm aware of. that would say, hey, okay, here's this inhibitor in a healthy population, let's see what happens in the disease population that doesn't happen. So we can't see that perfect translatability and saying, okay, now we can say this 1 works versus that one. I don't know, honestly, if that has been demonstrated and that's something we'll look into. And I'll follow back up with you on that purpose, but I do think that they are clearly indications where both are important and driving the disease.

And they work in tandem, honestly, because we see across a variety of these disease types that have an autoimmune component that the conversion of the B cells with the addition of -- with the aid of Tfilicearpocels turning into these plasma auto antibodies on top of the Th17 component. So I don't think -- and I'm not aware -- and let me put that way, I'm not aware of anyone said, okay, hey, -- this is driving this is driving that. And that's when you should take 1 or the other. It's -- we're looking for potentially convergent nodes that allow us to hit all of these simultaneously. And that's why we think step is in that mechanism. But if we -- when we dive deeper, well, I'll definitely follow up with you and see if there's additional commentary there as we identify indications.

Got it. And maybe 1 other question, if I may. So there was the 60% reduction across these immune cells. Just wondering if there's any literature to kind of gauge where that is in terms of how efficacious that might be?

Again, well, it's interesting. I mean, we have the data. We've shown it, right? And it's right here, right? We've shown that, hey, in a healthy mouse, we can reduce HLD producing sales by 30%, and then go look at all of our animal data, right, across the board that we see down regulation of a cellular and humoral response. We see downregulation information. Dorette. I think you just can't say, pick on 1 thing. It's the compendium of the data -- and then what you can see are in the UC and the CD data that the coins look the same, even though we've therapeutically treated them or in the release proliferative skin models, whether they be genetically delivered or story, we see reversions of fibrosis, and that ties to our other sets of data.

So I think it's a compendium Icafocusing on just 1 is interesting, and it's an interesting thought experiment, but I think you really have to take a step back. And I know we all get excited by, hey, it can -- 1 piece of data turn into everything else. I think it is I think you have to take it in as a holistic component to look at the data. But if we I am not aware of anything that says, okay, if you get 50%, you get this means activity. I'm not aware of that on top, but our data certainly suggests that preclinically.

Thank you for your questions, Chris, and to all of our analysts. I will now turn it back to Imran to close out the call.

Yes. Thank you all. Thank you for listening. It's been -- I think we identified this molecule years ago and to now come into fruition and be able to really demonstrate across all vertices. -- of where we think 109 can be interesting. We've hit this PK, the safety, and really validates where we could potentially be in a variety of disease types. And so we look forward to keeping you all informed of where we're going. And thank you for your time. I appreciate.