Noon. Thanks everybody for joining us. This is day one of the Leerink Partners Global Healthcare Conference. My name's Tom Smith. I'm one of the senior biotech analysts here at Leerink, and really happy to welcome our next company to the stage, Sagimet Biosciences, represented today by CEO Dave Happel, CMO Eduardo Martins, and SVP of New Products, Rob D'Urso. Gentlemen, thanks for joining us. Thanks, Tom. Thanks for the invite. Awesome. Dave, maybe you could just kick us off with some introductory comments, you know, what you guys have been up to over the last 12 months, and then I guess what you're looking forward to most here, in 2026. Great. Yeah. Thanks. Just really quickly, Sagimet is a clinical stage biopharmaceutical company, and our approach really begins with understanding a little bit about how overexpression, overactivity of fatty acid synthase or FASN plays such a critical role in the development of a number of underserved conditions like MASH and acne and certain solid tumors that are dependent upon FASN for progression of disease. We have developed a portfolio of novel FASN inhibitors led by our lead program, Denifanstat, that really target an underlying cause, target for all of these disease states that is common to each, and that is fat accumulation or de novo lipogenesis. The same mechanism works in MASH and in acne, surprisingly, and also in tumors. If we talk just a little bit about MASH for a minute and where we've been at recently and where we're headed. Back in May of last year, we announced that we were starting a combination program with Resmetirom, really targeting the cirrhotic population, the F4 population, the one that is in most need. This was really supported by preclinical data that we conducted with our FASN inhibitor in combination with Resmetirom that showed that when you combine the two molecules, there's an exaggerated response in reducing inflammation and reducing fibrosis, which is really key to resolving progression of disease in F4s. At the same time, we also showed that Denifanstat alone at EASL last year and then at AASLD, that in patients who were digitally diagnosed as having F4 stage disease, 11 of the 13 had a 1 or 2-stage improvement, meaning that they moved out of being in a cirrhotic state. We know that our molecule is very effective as the disease becomes more severe, and I'm sure that Eduardo Martins will talk a bit about that more here momentarily. When you combine it with Resmetirom, a fat burner or a fat oxidizer, that we do expect to see the same type of bump in F4s that we've seen preclinically in our preclinical model. What we're looking forward to here shortly is meeting with the FDA, settling on a Phase II study design that we will propose will be non-invasive. We will start the Phase II program, the study in the second half of this year, as I think we've communicated publicly. On the acne side, really quickly, our partner in China, Ascletis, has conducted two clinical studies, a Phase II and a Phase III, that show the same exact results, roughly a 20% placebo-adjusted reduction in lesion count, total inflammatory, non-inflammatory across the board, as well as about a 20% improvement in IGA, all stat sig. Based on the strength of their Phase III data, they submitted an NDA to the Chinese regulatory authority, the NMPA. That NDA was accepted in December, and that functions essentially like a PDUFA for China. They're expecting to receive approval of Deni in moderate to severe acne in the second half of this year, maybe the beginning of next. We have a next gen molecule, as you know, that we're taking forward into the clinic. We're in Phase I with the next generation FASN inhibitor. That we should wrap up the Phase I here, which will help us select dose to go into Phase II. We'll wrap up the Phase I in the next couple of months, and then we'll be prepared to start Phase II in the second half of this year with Phase II proof of concept results in the second half of next year. Awesome. Let's talk about MASH. Yep. We generated some really nice Phase II data. Efficacy on histology looked exceptional, I think, as a monotherapy. maybe just talk about, I guess, how, you know, how you viewed the monotherapy F2, F3 population, and then ultimately the decision to target more of the F4s with a combination approach, like strategically, I guess, what went into that decision? Maybe I'll touch on it and I'll let Eduardo chip in here. I think strategically what made the most sense to us is that clearly the F4 population is one that is really underserved right now. There's really one molecule that's demonstrated a lot of efficacy, and that's efruxifermin. As you point out, our data looks very comparable to that molecule. Taking it into F4s based on our F3 and our F4 digital data made a great deal of sense. Plus, the whole space is moving towards combination therapies, and that was an important part of our decision, especially coming off of the preclinical data that we generated in combination with Resmetirom that showed such a nice effect in inflammation and fibrosis. Therefore, carrying it forward, into the F4 population made a great deal of sense. Eduardo Yeah. No, I think, you gave a very good overview. The, as you may recall, Tom, the Data on the F3s and of now going back to our Phase II in F2, F3s, showed a significant improvement actually, with a delta over placebo of 36%. When we looked at the very stringent measure, two stage improvements, it was a 30% delta. We also looked at AI digital pathology, which was preset for this study. By digital pathology, there were 13 patients that were diagnosed as F4. Of those 13, 11, well regressed cirrhosis, by one or more stages. Taken together, the data confirmed our expectation based on preclinical studies that the drug was going to be effective and was a potent antifibrotic drug. Take that to F4s, we believe that the same could be reproduced in F4s given the antifibrotic potency. The combination is something that we've been talking in the field for a while, but there was never really something that you could find that combined well. The two molecules, Denifanstat and Resmetirom, they actually get along very well. One, different mechanisms of action. Denifanstat reduces fat by inhibiting production, and Resmetirom reduces fat by increasing oxidation. In other words, burning the fat. In addition to that, as our data have demonstrated in a preclinical and clinical way, you do have the effects, direct effects on the other two critical cell types, Kupffer cells, so inflammation and stellate cells fibrosis. Direct effect of Denifanstat in all those three cell types added to the defatting potency of res. The two molecules are metabolized differently and, which again, increases the likelihood of increased potency. The two more things, res upregulates fascin, and by doing that, it actually loses potency, if you will, and we inhibit fascin. Finally, small molecules that are well suited for a combination tablet, oral once daily. No need for dose adjustment. Got it. That makes sense. Let's talk about the deal that you announced recently with Teva API for the IP rights that cover 20 different polymorphs of Resmetirom. Maybe just talk about, I know you were engaged with a number of different generics manufacturers. Maybe talk about like why this deal with Teva and then I guess like logistically, practically, like what work needs to be done across this portfolio of polymorphs to, you know, get this into the Phase II proof of concept study. Yeah. No, it's an important part of this discussion, right, on how we're moving forward. Once we announced that we were moving forward in May last year with a combination program, I think virtually every potential manufacturer of a generic or a similar version of Resmetirom reached out to us, and that included all of the known generic manufacturers. All of them have, they have filed applications for various forms of Resmetirom that work outside of the Madrigal IP, and not all of them are necessarily polymorphs, and some of them are crystalline anhydrous salts. And it's really choosing the best molecule that we can combine with and also one that shares a lot of the same properties while functioning outside of the IP. You know, to be perfectly honest, I think that there are probably going to be several different versions of a generic form of Resmetirom monotherapy in the next 5 years or so. That seems pretty clear. They all seem pretty intent on filing. To answer your question specifically, we certainly could have waited for that time, but it was important for us to be able to take any risk of not being able to work with some that were approved and to be able to identify that partner now, select, begin the process of selecting a form of Resmetirom that will be comparable from bioequivalence, bioavailability, and to be able to take that forward, and that's how we ended up working with Teva. They're obviously very credible in the work that they do in developing, similars and generics and it made the most sense. That makes sense. You've generated phase I data. Our phase I data was actually with Rezdiffra. Yep. Yeah. The Phase II will be with the form one polymorph that is actually, Rezdiffra as well, and then during Phase II, we'll conduct the necessary, you know, PK/PD to show dissolution stability. With the generic form the, or the, I would say the innovative form of Resmetirom that we're planning to take forward as a fixed-dose combination into Phase III, but all of that work will be done concurrently while we're involved in the Phase II study. Currently we're evaluating several molecules, going through assays and again through stability and dissolution to make sure that we have a molecule or a series of molecules that we can work with. Are there any considerations or challenges with, I guess, changing the form that you're using kind of midstream in a clinical development fashion? Going from Rezdiffra in Phase II to some other salt or crystalline form in a Phase III. No, I think just I mean, they're pretty standard studies. I would say if the molecule were more complicated, that could be an issue, but it's not. It's not a complicated molecule, as we're learning. Really, we will do the adequate bridging studies to assure that the bioavailability, bioequivalence, and comparability is the same. I mean, that's the goal. The PD profile of the molecule that we select should be the same, frankly, as Resmetirom or Rezdiffra. Got it. I guess coming back to the Phase I study, I think you've given some qualitative high-level details over what you saw there, obviously supportive of you moving forward into a Phase II study. Reasonable to expect we could see some detailed data around EASL or AASLD, and I guess maybe help orient us, like what we should be tuned into with that sort of Phase I dataset. Sure. We anticipate, of course, hep strike being approved, accepted EASL presentation, where we are going to be showing the clinical details and also a number of other analysis, several different omics that might actually be helpful come a Phase II, but in particular later on in a Phase III, as of course the field has moved in clinical practice away from biopsies. What we learn, what did we learn? The molecules were well tolerated. We knew that. We haven't disclosed the doses, but we know what to do. Perhaps the final and most important thing is the fixed-dose combination will not be weight based. It's one size fits all. Yeah. Got it. Okay. Maybe just help us connect the dots on kind of Phase II and Phase III and with a combination product proving out contribution of parts is how do you guys think about like a clinically meaningful improvement over monotherapy? Yes, we have to show an improvement, of course, over placebo and to be meaningfully better than the parts. The study is, in a sense, no different as far as arms are concerned from combination trials for pretty much any indication. The important and perhaps biggest difference is we're going to propose to the agency for this study to be non-invasive, 100% non-invasive, again, reflecting clinical practice. Therefore, the final design is dependent upon discussions with FDA. Again, pretty much like any development for any study anyway. Phase III, we are a few years away from Phase III, of course. Our, we would like to see a move from the regulators towards non-invasive in Phase III for patients with cirrhosis, similar to what they have done with non-cirrhotic patients. I think the just one comment on the FDA, of course, the division, most of them are actually hepatologists, who know and who have former colleagues in clinical practice. They're very attuned to it and they want products that when approved are as close as possible to how they're going to be used on the field. That makes a lot of sense to me. I guess we are in this kind of evolving FDA-. Mm-hmm ... view around non-invasives. Feels like we're kind of in like the middle innings, I think, of that. Just thinking through, I guess, some of the regulatory precedents for moving from kind of like non-invasive or lack of biopsy data into a Phase III, I think of like Lilly's retatrutide. Mm-hmm. Mm-hmm. Is that, I guess, the sort of the precedent that you're basing this on? Yeah. Okay. Basically what the agency expects is that a test is a good surrogate for outcomes. Non-invasives have demonstrated that to the satisfaction of the agency in non-cirrhotics. Assessing all the data that exists so far, we believe that the same would apply to cirrhotics. I think that would be the opinion of the KOLs out there, that's why we're going to be requesting and proposing that as our endpoints. I think, again, the agency will listen to us and of course, I cannot tell you what they're going to decide one way or another. That makes sense. I want to talk a little bit about just broader combination strategies, because you have Madrigal, who, obviously they've done a number of in-licensing deals, and it seems as though that is their development strategy, du jour going forward. Are you guys contemplating, I guess, other mechanisms to potentially pair with your DNL-RES combo? Like how do you, I guess, how do you think this space plays out with respect to all of these potential fixed-dose combo options? Sure. I think the most important thing going to the basics is for a fixed-dose combination, you need to have either two injectables that you put in the same syringe or two orals that you put in the same pill. That's that precludes an injection and an oral. It was done once in hepatology by then Schering-Plough in hep C. There was an outcry for good reason. Therefore, two molecules that are administered the same way, hence DNL and RES. Other mechanisms being complementary or having shown an increased effect can be there as background and example GLPs. We have from our Phase II data that GLP patients on a stable GLP-1 had a statistically significant, robust 42% delta response against placebo. Placebo had no response in that population. Combining with the GLP, even though you have orals, out there, is extremely difficult because you have to titrate the GLPs. You would have to have such a number of iterations and combinations because GLPs, you titrate up, and then you titrate down and up again and slowly. It's impossible for a fixed dose. How the other drugs injectables are going to be used, time will tell. There are a number of other mechanisms that could be considered at some point if the data support, nothing right now. The nice thing is because of the mechanism of DNL, impacting all three key cells involved in MASH and being the only one that really impacts the de novo lipogenesis cascade at the Goldilocks point, it could be the ideal backbone for different combinations. Our goal, RES and DNL, we keep an eye on things out there, because data are data. We follow the science. That makes sense. Last question on MASH, then I wanna switch to acne. Obviously we're gonna have a very important readout for Resmetirom in F4 patients, outcomes data in cirrhotics in 2027. Just how do you guys view sort of like probability of success for them in that setting? Like, do you expect this to work for them in that setting? Then I guess, how does that influence your potential development strategy and development plans? Sure. Of course, commenting on probability of success is difficult. I think for the patients, it would be very nice to see a successful trial. Regressing fibrosis in patients with cirrhosis, in other words, a lot of fibrous tissue, requires potent mechanisms of action. Resmetirom is dependent upon defatting and then downstream effects of that defatting. Although patients with compensated cirrhosis do have fat, so there is a role for defatting, it may not be enough to really block all the other mechanisms to allow for the body natural ways of removing that fibrous tissue, at least in a meaningful amount of time. Because it inhibits, because it eliminates fat, to a nice degree, as I said before, the complementary defatting of DNL, we can potentially remove at least that part of the equation, which, if anything, helps the direct effect of DNL downstairs. Patients with cirrhosis don't have time. As for the study, again, hope that for the patients that's the case. Clinical events in patients with compensated cirrhosis, starting with a you know, expecting that in four years or so, it's possible, but may not happen. Therefore, even with a drug that could have some effect, you may not see enough events to have that delta that could be small to be statistically significant. That's why the histological regression is an important endpoint, because then you're seeing, okay, this is going away, fibrosis is going away. Got it. Okay. Let's move to acne. Yes. We'll see what happens. Let's talk about acne. I know Debbie brought up the China partner data looked really good. They filed in China. Maybe you guys like will just take a step back, kind of like frame the opportunity and I guess frame how you're thinking about pursuing this acne opportunity relative to MASH, where we also have... Sure. Yeah, good kind of mid-stage development going. Rob, you wanna tackle that one? Yeah, maybe I can just summarize the acne program. As Dave said, we have a partner in China that took Denifanstat 50 mg forward. They've completed a successful Phase II and successful Phase III programs, both 12 weeks. All clinical endpoints were met statistically for efficacy, and in both studies, the product was well-tolerated. In addition to the Phase III, they completed an open label extension where patients were dosed for an additional 40 weeks. Primary endpoints were safety. In that study, product was well tolerated. No new safety signals popped up. There was a little bit of dry skin, both on the active and the vehicle, and some dry eyes, but nothing of concern to us. Based on that, in December, they filed and the NMPA accepted their application for moderate severe acne. Based on the timing in China, we would expect sometime in late this year or early next year to have that approval come through. That's Denifanstat in acne. Based on that efficacy data and data can translate very well into the U.S.. We have had a pre-IND meeting with the FDA to understand their opinions on that Chinese data. There could potentially be a path forward with Denifanstat in acne in the U.S. as well. We'll continue to explore that. Our primary development plan is focused around TVB-3567, which is a follow-on molecule. Sister molecule, similar chemical structure, just has its own IP portfolio. We're currently in a phase I program with that in standard single-dose, multiple dose cohorts. At the end of those, we will also have a 28-day cohort of patients with moderate to severe acne, where we'll get some data around sebum reduction and makeup of sebum. From there, we will take that program subsequently into a Phase II sometime by the end of this year. That's a 12-week study to find the dose. Just to answer your question really quickly about the relationship to MASH. Certainly, if we elected to take Denifanstat forward in acne, into a Phase III, that dose is at 50 mg as Ascletis used. If we go forward and as we go forward with the MASH combination program, the likelihood is that we would use a lower dose of Deni. Patients who, as you know, are hepatically impaired and their drug concentrations are higher, so the likelihood that we would have the same dose in both is really remote at this point. We would have Deni at 50 mg in acne and a lower dose in the MASH program. Interesting. If you moved forward with Deni in acne, I guess how much time do you think that would save you versus advancing the second gen compound? Yeah, somewhere, just around 2 years, maybe 18 months to 2 years, would make. Yeah. Okay. It's not invaluable, and I think now that the FDA and Makary has stated that 1 Phase III study for a known mechanism of action, that specific known mechanism of action, certainly lines up very favorably for Denifanstat to do a single Phase III study in acne if we elect to go that route. That makes sense. You would presumably be able to leverage the China safety- Yes experience as part of. That's our anticipation. Okay. That's part of the discussion that we could have. Interesting. Okay. If we, I guess, assume that we move forward with TVB-3567, would the development path be kind of like lockstep the way that Ascletis developed this in China? It's kinda like. The acne development plan for the U.S. FDA is very clear. It's a 12-week study. Endpoints are very similar to what we saw in China. IGA, which is Investigator Global Assessment, is the scale that you would use, and so 0 to 4, and it's a two-point improvement with patients ending 0 or clear or almost clear to 0 and 1. That's your primary endpoint with lesion reduction as well. Very similar pathway, Phase II, and then subsequently Phase III. Got it. Is acne an indication you think you could commercially develop yourselves? Oh, for sure. Would you look for a partner? Absolutely. Yeah, absolutely. Okay. Maybe just last question. I know we're up against time, just remind us on cash runway and then, you know, the things that we should be kind of tuned in for. Obviously, like EASL, we're going to get some health- Yeah ... volunteer data on TVB-3567. Yeah, just remind us cash and milestones. Yeah. At the end of the third quarter last year, we announced that we had $125 million in cash, and at that time, that covered about two years of runway. Taking us to nearly the end of 2027, which would allow us to complete the Phase II proof of concept with our next-gen molecule in acne, as well as getting to basically enrollment, near enrollment for the MASH combo. Those are the kinda the near term milestones for us. As Rob pointed out, Ascletis is on the brink of an approval, which would trigger milestones for us and royalties, that are, that'll be very meaningful as well. Awesome. All right. Well, unfortunately, we're up against time, wanna thank the Sagimet team. Thank you. ... for joining us.