Tvardi Therapeutics, Inc. Common Stock KOL event

Good morning, and welcome to the Tvardi Therapeutics KOL webinar on the potential of TTI-109 in ulcerative colitis. At this time, all attendees are in a listen-only mode. A live question and answer session will follow the formal presentations. To the covering analysts, please use the raise hand feature to be added to the queue. As a reminder, this call is being recorded, and a replay will be made available on the company website following the conclusion of the event. A copy of today's presentation is available on Tvardi's website at tvarditherapeutics.com.

Before I turn the call over to Imran, I would like to remind everyone that this discussion and the accompanying press release will contain forward-looking statements, including statements concerning the anticipated benefits of Tvardi's product candidates, the potential benefits of TTI-109 as compared to TTI-101, Tvardi's ongoing and planned future clinical trials, and anticipated timing of reporting data from such trials, potential indications for its product candidates, Tvardi's development plans and such indications, discovery and development of its product candidates, its anticipated cash runway, and other statements regarding management's intentions, plans, beliefs, expectations, or forecasts for the future, as well as matters that are not historical facts or information. Various risks may cause Tvardi's actual results to differ materially from those stated or implied in such forward-looking statements.

For a list and description of the risks and uncertainties that Tvardi faces, please see the reports Tvardi has filed with the Securities and Exchange Commission, including its most recent annual report on Form 10-K for the year ending December 31st, 2025, and subsequent filings with the SEC. This conference call contains time-sensitive information that represents management's judgment and intention and is accurate only as of today, August 19th, 2026. Tvardi undertakes no obligation to update or revise any forward-looking statements except as required by law. I will now turn the call over to Imran Alibhai, Chief Executive Officer of Tvardi Therapeutics. Please go ahead, Imran. Thank you, Tara, and thank you to everyone joining the call this morning as we review our TTI-109 development program in ulcerative colitis.

Our discussion has four parts. Dr. Longman will open with the evolving ulcerative colitis treatment landscape and the case for targeting STAT3. I will then present TTI-109, our next-generation STAT3 inhibitor, the rationale for ulcerative colitis as its initial indication, and the phase I data we released in July. I will follow with our proposed proof of concept trial design, and Dr. Longman will close with his perspective on the potential clinical role of STAT3 inhibition in UC. For those newer to the story, Tvardi is a clinical-stage company developing novel oral small molecule therapies targeting STAT3, a convergent node downstream of multiple signaling pathways that drive immune dysregulation, inflammation, and uncontrolled proliferation, particularly in conditions like ulcerative colitis.

To that end, I would like to introduce Dr. Randy Longman. Dr. Longman is the Director of the Jill Roberts Center for Inflammatory Bowel Disease and Professor of Medicine at Weill Cornell Medicine. He is a gastroenterologist and a mucosal immunologist. His research focuses on the mechanisms driving IBD, with a particular emphasis on translating disease biology to new diagnostic and therapeutic approaches for medically refractory disease, and he has served as a principal investigator in numerous IBD clinical trials. His work has been published in leading journals and is supported by the NIH and major IBD foundations. In other words, he sits precisely at the intersection where our program lives. Dr. Longman, thank you for joining us. The floor is yours. Okay.

Super. Good morning. Can you hear me okay?

Yep. Great. Okay. Good morning.

Just as Imran said, I'm the Director of the IBD Center here at Weill Cornell. We are a very high-volume IBD center, so we see a lot of referral cases. The majority of what we see is moderate to severe IBD, and just as Imran said, we have a lot of experience in different phases of clinical trials, particularly phase II and phase III. Today we're talking about ulcerative colitis. Many of you are familiar with ulcerative colitis and IBD pathophysiology, and we'll go through this quickly. It is a chronic intestinal inflammation. The pathogenesis, as we'll touch on, really spans many layers, and I think that that's really the focus of today. A lot of the features of how we stratify ulcerative colitis are based on clinical presentation.

The clinical presentation of ulcerative colitis is usually diarrhea, rectal bleeding, increased frequency, and these are patient-reported outcomes that we use to clinically track disease activity, and that's meaningful because that's the basis of our metrics for many of these clinical trials. The diagnosis is based on colonoscopy and biopsy. Here you can see pictures of different stages of disease, and these are different endoscopic scoring systems. These are what we find to be really the most valid clinical metrics as outputs, right? We know that the PRO2 stool frequency, rectal bleeding is very good. Fecal calprotectin as a biomarker is also very good. But really having the endoscopic score and having evidence of histologic response is some of the most meaningful data that we have for clinical studies. Treatment spans many different types of treatments over the years, and you guys are probably familiar with many of these.

For mild and mild to moderate disease, we can start with 5-ASAs or steroids. But once we move into moderate to severe disease, we are really talking about a span of biologics, and we will talk about those and the therapeutic need. End-stage disease or very severe disease can be treated with colectomy. Next slide, please. This is just a high-level slide sort of highlighting the multilayers of inflammatory bowel disease pathophysiology. Ulcerative colitis, in particular, is a ulcerative disease, and so this is an ulceration of the mucosal layer. Although it could start with that, and obviously that is the diagnostic criteria that we are looking for, in contrast to Crohn's disease, which would be a transmural inflammation, there is inside out signaling. What do I mean by inside out signaling? Essentially that there are immune signals.

Some of these T cells and B cells now that we know play a role, and some of the macrophages that are able to now release these cytokines and result in inside out inflammation resulting in ulceration. Ultimately, this leads to chronic mucosal inflammation, which is the thing that we are trying to break, right? We are trying to figure out a medicine here that is going to allow us to break the cycle and to prevent recurrence of disease and allow for maintenance of remission. As we have touched on, disease phenotype is important to think about as we characterize ulcerative colitis. So we talked about different types of patients who can have a single flare and then go into remission. Some that have sort of this chronic relapsing, and some that are very acute and get very sick right away.

Immune dysregulation is the different types of immune cells that could be contributing, and we will talk a bit about this, and Imran will highlight some of the preliminary data that they have looking at specific cells. But then also thinking about this in the context of a genetic and environmental susceptibility as well. Next slide. What is the treatment paradigm as of today? Once we confirm ulcerative colitis, patients are stratified into mild to moderate or moderate to severe, more on the severe side. For the mild disease, as we mentioned, oral therapies, including 5-ASA, which are non-immunosuppressive, can be first-line therapies. But once you get past that and you really move into the moderate to severe or ASA refractory disease, we are talking about advanced therapies.

As of now, all of those advanced therapies, including steroids, which we are trying to minimize because that is the one medicine that really has the highest risks in patients with ulcerative colitis and IBD, are immunosuppressive therapies. These are all TNF-alpha inhibitors, anti-integrins, IL-23. These are all medicines for which we have to check for hepatitis exposure, for tuberculosis, and we counsel patients on different risks of reactivation of different infections. That is for first-line therapy. First-line therapy for many years was dominated, I would say, particularly in our practice, by alpha 4 beta 7 blockade. We have seen a shift in that practice, particularly to IL-23 inhibitors as first-line therapies. Kind of moved away from TNF-alpha blockade given the black box concerns and some of the safety concerns with respect to hematologic malignancies.

Although they certainly do have a role, particularly with respect to speed of treatment. We do think that those are one of the medicines that can act more quickly. When we talk now about second-line therapy, particularly in the moderate to severe, now you're talking about medicines that you would use as second-line therapy. We really don't use anti-integrin therapy as a second-line therapy. This is really IL-23 and JAK inhibitors, which take the cake primarily in this category. Next slide, please. 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.