Okay, great. All right, good afternoon, everyone, and thanks for everyone in the room and on the webcast for joining us for our next session. I'm Steve Seedhouse on the Cantor Biotech team, and really a privilege to welcome the next participating company at our conference, Tvardi Therapeutics, a company we recently picked up coverage of and are very excited about. I'm joined on stage by CEO Imran Alibhai. Apologies if my mic got out there for a second. Looking forward to the conversation. Maybe to start, I'll kick it over to you, Imran. Would love, for those not familiar, a fairly newly trading public company. Yeah. Just give an intro and an overview of Tvardi Therapeutics, the spaces that you're operating in, the history of the company, and we can dive into Q&A after that. Yeah, absolutely. First of all, thank you very much. A special shout out to Steve and the team for inviting and initiating on inviting us to the conference and initiating. I will say to the credit of Steve, he just had his third child, and on the day of his child being born, he's putting out notes. There's a truly dedicated analyst there. Tvardi Therapeutics was formed in 2018. It is a company focused on developing small molecule therapeutics against STAT3. Now, STAT3 is an incredibly well-known transcription factor. You put it into PubMed, you'll see maybe 40,000 maybe up to 50,000 papers describing its function. STAT3 has been canonically associated with proliferative disease. Period. End of story. It is a central catalyst for fibrosis and indications associated with fibrosis. We were formed and I think raised about $9.5 million in 2018. This was before I joined the company, and then I was brought in at the end of 2018. While we were running our first trial in oncology, we saw some really exciting data, really PK PD, tolerability, and really nice activity. We then raised $74 million Series B. As you mentioned, we reverse merged in April of this year. Between financing and that raise, that was about $50 million. That $50 million, $52 million actually, was really important to us because it paved a couple of ways. Things first. One, it gave us a cash runway into Q4 of 2026. More important to us is it took off any financing overhang as we have some really exciting readouts. Those readouts, as you well know, are in our lead program, which is in Q4 of this year. We will unblind our IPF readout. IPF is a, it's a two arms of our drug versus placebo, double-blind randomized placebo-controlled trial. In the first half of next year, we'll put out our data, the top-line data from our oncology work, which is again in a liver fibrosis or initial liver fibrosis that turns into cancer, hepatocellular carcinoma. Just a month ago or two months ago, we filed the IND for our next inhibitor, STAT3 inhibitor, which we're very, very excited about. I think net-net, that's kind of the background. We'll talk more about STAT3 and why it's such an important and relevant mechanism. We can talk more about that. I think that's kind of the backstory of the company. Just before we get to the mechanism in particular and IPF, STAT3, I think, is one of these targets that have been challenging to target historically. How did Tvardi overcome them and ultimately develop your two STAT3 inhibitors? Yeah, I think that's credit to our founders. In particular, we are founded by a gentleman named David Tweardy. He's the Head of Internal Medicine at MD Anderson. I would say his real claim to fame is he was one of the first three groups to identify STAT3 30 years ago. He understood the protein, and he understood its value as a transcription factor. He understood, more importantly, that what we should be doing is blocking its activation of transcription because that's what leads to these cascades of disease, the disease of not only proliferation, but immune suppression, which are intrinsic to IPF patients, for example. What he recognized early on is he said, let's build a molecule that binds to STAT3 non-covalently and simply inhibits its ability to become activated, but have no effect on the protein itself. The reason this was very important, whether it be fortune or foresight, was that the other STAT3 inhibitors at the time and then came after us, they focused on taking out the protein. There are multiple examples of compounds that were either covalent inhibitors or degraders that basically caused not only they show activity because they down-regulate transcription, but they also ended up causing other issues. In particular, STAT3 is part of the electron transport chain. Those molecules then went on to have issues with mitochondrial toxicity. What we've now demonstrated in our own work is that when we can simply down-regulate transcription, but have no effect on mitochondrial expression, and we show that in vitro, that's very exciting data. Beyond that, I think we have a database of over 200 patients now where we've treated patients with TTI-101, and we've not seen any example of drug-related mitochondrial toxicity. I think this is a better way to drug what has been one of those holy grail kind of pathways. That's a great intro. Yeah. In IPF then, help me and help investors understand where STAT3 fits in the fibrosis, fibrotic cascade in general. A lot of mechanisms have been tried in IPF, some recently successful. Why is STAT3 a good target here? Right. If you think about it, there are three classes of cascades we normally associate with fibrosis. It's either growth factors like TGF-beta, EGFR, LPA-1, there are cytokines like IL-6, and there's even non-receptor tyrosine kinases. Interestingly, all of them sit extracellularly, and they all signal into and activate STAT3. STAT3 then goes on to run these cascades. What's very interesting is if you completely knock out a cytokine like IL-6, or if you completely knock out TGF-beta receptor, these are the major drivers. There's a host of other ones. When you run these in animal experiments, you still see fibrosis. If you have haploinsufficiency of STAT3, meaning you only knock out one of the two alleles of STAT3, you completely protect animals from fibrosis. Genetically, it's very well validated. What we've been able to show in patients is that STAT3 expression correlates with mortality. If you have high STAT3, you die much, much faster than if you have low STAT3. We can also show and have shown and published really elegant data that shows that activated target of STAT3 is intrinsic to all the compartments that drive this disease. It's not simply a disease of deposition. It starts with clotting and coagulation, goes to inflammatory cell migration, then proliferation and deposition. Those compartments, whether it be the fibroblasts, the macrophages, the epithelial cells, they all, IPF patients are all in, have hyperinduction of our target activated STAT3. I think for all those reasons, it made it a very compelling target to go after in the context of a cascade of an IPF trial. I wanted to ask you, IPF, I mean, right now it's kind of a hot space from an investor standpoint. There's just a lot of interest because it'd been a decade or something without a phase III success. Then just a few months ago, you know, BI and then United Therapeutics last week. We'd love to just get your perspective on sort of those two emerging options and your thoughts on the data and what, you know, as you think about where STAT3 ultimately then fits into this new therapeutic landscape. Yeah. Any impact? No, great question. I'm just going to mimic what the people who know, and those are the KOLs in the space and what they've told me. I think first and foremost, this is fantastic. I think it is incredible. You're right. For a decade, we only had two drugs. Those two drugs really were impactful. They sold $5 billion in market and sales at peak sales, but they didn't really change the course of the disease for these patients. Now we've been back to, in a, what, a six-month span or whatever it is, we've had two trials that have read out positively. Both of them are interesting. BI's drug, ninerandomilast, goes after PDE4B. That's a very nice inflammatory target. The other trial that you were mentioning is United Therapeutics' Tyvaso, again, probably a vasodilator, right, in the way it functions. In both instances, we'll know more about Tyvaso's data in a few moments because in mid-September they're putting out their data to ERS. I think it's fantastic. I think we've published papers that show, look, STAT3 is a central mechanism. These targets all feed into STAT3. We have human lung slice data that shows one of the number one targets we down-regulate amongst the myriad of different targets is PDE4B. I think all of this data is very positive, one, mostly for the patients, but two, I think from our perspective, selfishly, these are mechanisms that are feeding into our own therapy. It really allows us for, it allows potentially, you know, a real upside to have truly something that is disease-modifying in the grand scheme of things. Yeah. If we stipulate that STAT3 is an interesting and viable mechanism in IPF, it still leaves the question of, are you hitting the target in a way that you need to in lung tissue? That comes down to just PK PD, lung exposure. What data do you have on hand? What gives you, I mean, do you know what your lung exposure is? Do you know how much STAT3 inhibition you're getting in the fibrotic lung tissue? If not, are there ways you can model it? What gives you confidence that you're at the right dose and active dose? This company initially, initial focus, the first trial we ever did was oncology. There is something you can do in oncology you can't do in an IPF patient, and that's take biopsies. What we were able to actually show in oncology patients, these were salvage line patients who had failed all other therapies. They were coming onto TTI-101 monotherapy, and we did a dose escalation and then a dose expansion. What we were able to show was, I think, pretty exciting because it showed the things you want to see in any trial, particularly your phase one trial, and that was pharmacokinetics. We could show that we had exposures at our trough, at our Cmin, that was above the IC90 for STAT3. That was fantastic. Two, those exposures were long-term. We had patients on trial up to two years. That was very exciting because. This is at 400 mg and 800 mg? This was actually at the recommended phase II dose, which was 800 mg. At 800 mg. Yeah, then. What is 400 mg predicted? Would that be an active dose, do you think? 100%. Okay. Because, and we'll talk about that in a few moments when we think about the animal data, we saw activity, biological activity in human beings at 400 mg. You continue to go up until you get to a max tolerated dose, and 800 mg was that dose. Beyond the PK, we showed pharmacodynamics in human beings. These are patients where we were able to take biopsies pre-treatment and on treatment. We saw every patient that had activated STAT3, a decrease in that target. The target was even, and it was over, I think, overall 55% decreases. In our patients who had stable disease or clinical benefit, it was almost 80%. Beyond that, a well-tolerated profile and very nice activity over, you know, salvage-related population, we were seeing over 50% of our patients have some sort of clinical benefit, including objective responses. That really set us up well to go in to think, okay, we know particularly STAT3 is not only necessary, but sufficient in IPF patients and fibrotic patients. When we then went to your question about how do you know you're actually hitting your target in these very compartments that are heavy stroma and these seem to be distinct from plasma? The first indication was in tumors, we show a 4X of our exposure to plasma. That was an initial, okay, that's interesting. When we repeated that same study in an animal, we saw the exact same thing. When we look at exposures, regardless of dose, low, medium, or high, right? These doses were basically equivalent to human equivalent doses of 200 mg, 400 mg, and 800 mg. What we show is that regardless of those doses, we saw 4X exposure in the lung relative to the plasma. From our perspective, that's exciting. Again, it looks like what you've suggested, target-dependent accumulation. To your other point, what's enough? How much reduction do you need of activated STAT3? Going back to that preclinical data where we did dose range finding studies, what we were able to show is that at approximately 50%, you're seeing activity. The activity we saw at 55% reduction of activated STAT3, and even at the higher doses is almost 85%. That was sufficient to restore lung function in these animal models. I think there's a lot of data that we lean on to help us. Most of it is human, which is fantastic because we have all this data from this previous trial, but also the data that we've shown in the models, the bleomycin models, are very encouraging. It doesn't matter the fibrosis. I mean, we've shown this in scleroderma models, genetically engineered mice, chemically induced mice. We've shown this in a MASH model. We've shown it in cardiac models. When there is fibrosis, we see a reversion of the fibrosis, and then often that correlates with restoration of whatever organ function of interest in which the models are associated with. The other set of data, of course, here that's relevant is there's been just the interim analysis of the ongoing phase II REVERT IPF study, which is the data that's coming up. Yeah. There are blinded data that you've shared that's in your corporate presentation. Yeah. Just for folks new to the story and for me as well, just to recap, what is the background on the interim analysis in that study? How many interims were there? Yeah. Why were they implemented? What data have you actually seen or not seen? Yeah, no, great question. When we actually started this study, the FDA suggested to us to do three doses of our drug versus placebo because that may actually, in the long- term, obviate the need to do dose range finding studies in the future. We did a 400 mg, we did an 800 mg, because 800 mg was a recommended phase II dose from the oncology trial, and then we included a 1,200 mg. Concurrent to running that trial, we're running, as I mentioned, a liver cancer trial. That liver cancer trial is in first, second, and third line. When we got to 1,200 mg in an open label study, we started to see adverse events, which was not surprising because we'd been to above that dose in the original phase I as well. Because the IPF trial is blinded to us, we went to the safety monitoring committee and we said, look, this is what we see in oncology. We think you should discontinue this arm. They went back and they looked at the data. This happened in June, July, excuse me, mid-July of last year. They said, you're right. We should discontinue 1,200 mg. However, we are now going to conduct a risk-benefit analysis. We are going to look not only at safety of 400 mg and 800 mg versus placebo, we're going to look at benefit and particularly look at pulmonary function. They told us, proceed forward. In September of last year, September 30th of last year, to be exact, we went back to them. This was when we had enrolled half the patients in the trial, so 38 of the 75. They repeated the analysis. They did another risk-benefit analysis and they said, proceed forward. At that time, we were a private company, and we shared that data with our investors. When we ended up becoming public through the reverse merger, we had to cleanse ourselves of the data. We had to put everybody on equal footing. That interim analysis is a product of going from being a private company to being a public company. We had to put everybody on equal footing. What we did is we've provided that data. It's all in the S4. It's the same data set. Since then, the trial is fully enrolled and we are moving to releasing the full data set here in Q4. We're right around the corner before we do that. I think what has been intriguing about the data sets is that the trial is randomized 1:1:1, so 800 mg, 400 mg, and placebo. What we've seen on a blinded fashion, now this is the same data that the SMC looked on in an unblinded fashion. What we've seen is approximately a little bit over a third of our patients are actually showing a decrease in the forced vital capacity. A quarter of our patients are stable. The remainder, a little bit over a third of our patients, are increasing their forced vital capacity. I think that's been very intriguing to us. We've shared that data with our KOLs, and they've said to us something very interesting. They're like, if your drug wasn't working, everybody would be below the baseline. The fact that you have a substantial population that's at or above baseline is very, very intriguing. I think we're excited to see what the future lies with this mechanism because it could be potentially disease-modifying. I think that's what we need in this space. We need drugs that could change the trajectory of the disease in patients. We're excited as well. Was September then the last interim? Were there any other interims subsequent to that? Right. Like the SMC, when we were a private company, that was the last interim that looked in. Clearly, the SMC constantly has oversight, but we have not reported any additional data from that. If something had changed, if there needed to be some other alteration or modification of the trial, like a discontinuation, we would have reported that. At this point, we said last patient in was in May of this year. It's a 12-week trial with a four-week safety follow-up. Now it's just a question of waiting for the RCRO to get a database lock and the statistical analysis plan. If there was a safety issue of concern, that would have been one stopping criteria. This was a risk-benefit analysis. Right. There was some efficacy threshold, I guess, that would have been. Yeah. Protocolized or included. I mean, what can you say about that? Yeah, there wasn't, let's be clear, this trial is a signal-finding study, right? There's approximately 25 patients per arm. At the end of the day, the protocol or the, we built it on discontinuation, right? That's what your stopping procedures were. This was something that the SMC, who was very accomplished, a bunch of folks who've been in the business for 30 years each, they made the commentary that, hey, we want to look at not only risk but benefit because we've opted to discontinue 1,200 mg, the top dose at the time. I think there isn't, you know, in oncology and others, we sometimes have futility analyses and those are based on certain stopping criteria. This is not that case. This was slightly different. From that perspective, this was based on the foresight and the experience set of the SMC members and their experience with IPF data. Okay. A couple of features of the study that I wanted to ask you about. Yeah. One, just broad inclusion criteria, low baseline ppFVC compared to some other. Yeah. Similar stage IPF studies. Pirfenidone not included as a background therapy. Yeah. Maybe you can just walk through some of those features. I think what we tried to do when we built this trial was basically get a population, one, that would allow us to enroll. It's a very competitive space, obviously. Pleased to say that we enrolled on time and made it from that perspective. I think what we ended up doing is, as we looked at the data sets and based on all the preclinical data that we had, it was very exciting what we had seen. They said, could we potentially be disease-modifying? Maybe over a 12-week period, that's probably not possible. What we really wanted to see is, hey, can we include a broader swath of patients to see if we can change the overall outcome potentially from a forced vital capacity perspective? The trial was built to include, you know, which has the broadest trial enrollment criteria that we've ever seen in this population. It was broader than other trials that have been in the space recently that were U.S.-based. Ours is fully U.S.-based. I think others have done ex-U.S. studies and there's a question of the data. That's been one question. Then two, we had said that we would try to see if we can enroll those kinds of patients. What we've seen and what we have disclosed is when you compare our data to other trials in the space, most recently, what we've seen is that the median forced vital capacity baseline of other trials has actually been higher than ours. If you're truly doing apples-to-apples comparisons, when you're trying to look at blinded interim data, it suggests that we're enrolling maybe more moderate patients than others who have enrolled more mild patients. I think that's one interesting. The other question you had was around pirfenidone. Pirfenidone was not included in this trial, but nintedanib was for one reason. That was that the FDA asks companies to do DDI studies because they don't want you increasing the exposure of nintedanib or pirfenidone because they have their own sets of issues. What was interesting is when we ran the DDI study, neither of those drugs had any effect on our exposure. We've seen that those drugs can, and it's true for, for example, nintedanib. We had no effect on nintedanib, but we actually decreased the exposure of pirfenidone. For us in this trial, it's a 12-week trial. It's a small trial. What do you really want to accomplish? Do you have to titrate these patients? How would you titrate them? We ended up saying, let's remove them for now and then let's figure out how we want to deal with them in the future. Do we want to titrate them or leave them out? Again, if you look at the data and the dollars spent, it looks like it's a 4: 1 ratio, or 3: 1 or 4: 1 ratio, of patients on nintedanib versus pirfenidone. I don't think, so we'll see how we deal with that in future studies. Given the new entrance to the market, we'll see. There are a lot of other studies that we'll, you know, just think about combination. This being a signal-finding study that it is, I mean, what's the signal you're looking for? What are the next steps? Yeah, great question. I think it's, from our perspective, you know, what we're interested in because of a signal-finding is truly separation of the curves. Can we show on a forced vital capacity compared to placebo that things are starting to separate? That would be a great outcome. If, however, we get patients or we get the arm to show that there's stability, meaning the patients are near their baseline, for us, that's a home run. I think that would be excellent. I think we were also running this trial in a fashion that will allow us to look at a bunch of other markers, everything from quantitative lung fibrosis, six-minute walk tests. We actually are the first group that I know of to incorporate a set of prognostic biomarkers that have not been validated. It was like 20 companies came together to identify these and 11 popped out of this validation and now that will be part of our experiment. I think what we were trying to do is build a fulsome trial, a trial that was around all U.S., everything centrally read, and a trial that will allow us to help us identify what the next trial is. That trial would be some sort of confirmatory study, right, in the next step. Actually, we would incorporate, I think where you're going to go next is with our next generation molecule. Yeah, we talked about that. What was the impetus for it? This is a prodrug of TTI-101. Yeah. Why did you develop that? Yeah. Are you going to essentially run the next IPF study with that molecule if this one's positive? The answer is yes. Okay. Okay. The reason we did that is we started seeing activity of 101 years ago. We said to ourselves, rather we put ourselves out of business than someone else put ourselves out of business. We said, is there a better, a differentiated version of our molecule? We ended up by, I mean, I guess simple is always best. We found that by simply adding a phosphate group to one of the hydroxyl groups, what it ended up doing is we generated a far more bioavailable molecule. It jumped up to 80% bioavailability. The really interesting component of this is that 109, our new molecule, converts almost instantaneously. Within 15 minutes, we see no more 109. It converts to 101 in the blood. 109 is ingested and then passes through the gut into the bloodstream. That's where it gets converted. We know that the current existing therapeutics out there tend to have GI adverse events. We are basically, by building a molecule like this, it allows us to basically potentially mitigate any active moiety in the gut. That drug, the drug is actually just in the bloodstream. I think it's just, it's a differential delivery system. We have NC patents that will get us out to the mid-2040s with it. The phase I for that molecule is sort of running in parallel with some of these. Exactly. Right, right. We filed the IND. We haven't given a timeline on that. When we get to the end of phase II meetings, we'll have a full package. We'll have the 101 proof of concept in IPF, and then the 109 data, we'll have the bioequivalent data. We've done bioequivalents in rats and monkeys and IND enabling studies. That's all done. Now it's simply repeating that in a human being. That data disclosure from that study will be sort of that simple, basically. Yeah. We've replicated the exposure. Exactly, right? We don't even need to do it, but it's really belt and suspenders to put ourselves in a really good position long term. Okay. Maybe just quickly on, I think you mentioned upfront, but I missed the specifics of it, as you mentioned it, the cash runway and the development plans. We didn't even touch on it, but you have the HCC data card turning over in the first half of 2026. Yeah. We're kind of up on time, but I guess in the last minute, maybe you can recap that and the next steps after these data readouts. Yeah. When we raised the $52 million, we disclosed that that would give us a cash runway into Q4 of 2026. Literally, what we've always indicated is that it'd be one year post the IPF data, and that's exactly where it seems to be heading. Obviously, if the IPF data is what we think it is, then we'll fundraise around that to really move that program into confirmatory studies. The HCC data is exciting to us. That data in its own ways is particularly tantalizing. We're doing a study in front, second, and third line as one study that actually has fast-track designation. We expect that data in the first half of 2026. If that data is positive, we would retain that 101, the initial molecule for oncology, and move 109 in fibrosis. Two different indications, two different mechanisms. We're excited to get that forward. If that data is positive, then we would fundraise around that as well. A lot of different pathways for success to really show, hey, a STAT3 inhibitor can be incredibly important in proliferative diseases. Very high-profile mechanism. Obviously, IPF right now has a lot of eyes on that. A lot of eyes on Tvardi, and you have an important readout coming up in fourth quarter. We're looking forward to it. Really appreciate you joining us at the Conference this year. Thank you for the conversation. Thanks, Steve. Thanks to the full Cantor team for the invite. Thanks for everyone on the webcast and in the room for joining in. Thanks.