CARA Chardan's 10th Annual Healthcare Conference

Yeah. Well, first of all, thank you for the invite this morning. Gautam actually initiated on us, so really nice report and appreciate actually the transparency and the balance there. Tvardi Therapeutics is focused on STAT3. STAT3 is an incredibly well-known transcription factor. Put it in the PubMed, there's only 45,000 papers that show up talking about its centrality to not only immune dysregulation but inflammation and proliferation, hallmarks of a variety of I&I disorders. We initially started in oncology. In oncology, across the board, we showed PK/PD of activity and tolerability in a phase I trial in solid tumors, which actually led the program into a phase II trial in liver cancer, which we'll report out later this year. Then earlier this year, we actually had data from our IPF trial.

Now in our IPF trial, that was really demonstrated there is. The background of that was we know that STAT3 is intrinsically important in fibrosis as well as inflammation. In our models, we could actually show reversals of fibrosis, not just stopping it, but actual reversals of. We went into a trial, this was an all U.S. trial, a trial where we enrolled patients that were on background. Majority of our patients, vast majority, were on background nintedanib. Now background nintedanib, 68% of those patients have diarrhea.

Right in their phase III trial.

We actually saw, unfortunately, a higher rate of discontinuations than we would've expected when combining our first generation molecule TTI-101 with nintedanib. From that perspective, it didn't. I wouldn't call it a failure, but it did not meet our goals. But what was interesting is, after the fact, we went back and we looked at the completers, so the patients who completed trial, and we saw an incredibly interesting trend. The main mark we look for is forced vital capacity. And forced vital capacity can be actually quite variable, even intra-patient, particularly for our 12-week trial. Even though all the other trials suggested you would see a decrease, we actually didn't see a decrease in the placebo arm, so that was a confounding factor. But so we went back and said, "Look, we know FVC can be indeterminate.

Right. Let's look at other pre-specified endpoints that could be very interesting." One of those was IL6.

IL6 correlates with inflammation. It directly sits upstream of STAT3 reactivation. We looked at that, and we actually saw a more than fourfold difference in the decrease of patients treated with 101 in IL6 relative to placebo. That was pretty encouraging. What we were very encouraged by was the data in fibrosis. The way we measured fibrosis in the trial is how everybody measures it. You look at high-res CT pre-treatment and post-treatment, and after 12 weeks, we saw an actual decline in baseline fibrosis. Most trials don't even report fibrosis because they don't see a change in fibrosis. We know a variety of molecules like JAK inhibitors and the molecules that are currently available, they don't show changes in fibrosis.

What we actually saw was a 7% placebo-adjusted rate in the decline of fibrosis. Most folks, when they show their fibrosis data, they'll say, "Well, we prevented an increase. We didn't actually see a decrease." From our perspective, that was very encouraging because it actually replicated our pre-clinical data. In the background, we'd told the street that we were always wanting to move our next generation molecule forward in I&I. It had been IPF, and the reason we wanted to do that is because we had identified years ago that we could make a very bioavailable molecule known as TTI-109 or 101's prodrug available. That was the phase I data that we reported out earlier this year. What is interesting about our next gen molecule is that 109, again, is the prodrug, but it's inert.

Right. It has no activity.

It's once at doses we're giving it to humans, and it's designed to pass through the gut, and because of all the phosphatases in our bloodstream, it would rapidly convert into the active moiety. We have systemic distribution, but we wouldn't have any exposure in the gut. That potentially would obviate any GI adverse events. The phase I data we reported showed exactly that. The phase I data showed we had converted quickly into the active moiety systemically. Two, it showed GI tolerability that looked like placebo as opposed to what TTI-101 looked like, and we ran that trial in the healthy volunteers across three arms. The most encouraging data from my perspective, and I think overall the company's perspective, is we had pharmacodynamic data.

Right. We were actually able to show that in healthy volunteers, in the published populations that are pathogenic in UC across T cells and B cells, that we could show reductions in a healthy volunteer.

We know those populations are pathogenically expanded in a diseased population.

Right. For us to show it in a healthy volunteer really portends well from the perspective of ulcerative colitis.

That was one of many reasons we will talk about why we really wanted to get into now the next-gen trial for us.