All right, good day, everyone. Thank you for joining day one of Cantor Global Healthcare Conference. For our next session, we are very excited to host Sagimet Biosciences, and representing Sagimet, we have Dave Happel, CEO, and Eduardo Martins, CMO. Gentlemen, thank you for joining us. Thank you, Prakash. Maybe to start off, for those who are less familiar, can you give a brief overview of the company and where you are at? Yeah, sure. So Sagimet was founded back in 2007, with a group of internal medicinal chemists that were really trying to sort through this interesting target called fatty acid synthase, or FASN. That's really how our approach begins, with understanding how overactivity or overexpression of fatty acid synthase or FASN plays such a critical role in the development of a number of underserved disease states, including our primary targets in MASH, but also in dermatology and acne, as well as in certain solid tumors that absolutely are dependent on FASN for progression of disease. To solve for this overactivity of FASN, we have developed a portfolio of FASN inhibitors led by our lead program, denifanstat, that really seek and target an underlying root cause, or a primary culprit, that is common to all of these conditions, and that primary culprit is de novo lipogenesis or fat accumulation. So what we offer is something very unique in this space, and it's highly differentiated. We are the only fat inhibitor in a world of fat burners, fat oxidizers, fat mobilizers. Eduardo, I'm sure will talk a little bit more about that in a minute. Most of the bulk of our work is really in MASH, although we do have really provocative data in acne and some oncology studies as well. All of our data to date, MASH, preclinical and clinical, has been incredibly consistent, shows the same thing, and that is that denifanstat significantly targets and reduces the three drivers of MASH, fat, inflammation, and fibrosis, independently and in parallel, again, making it rather unique. We don't rely just on burning fat peripherally and, to a degree, in the liver to translate into downstream benefit in inflammation and fibrosis. We've completed two clinical studies, a phase IIa study that was a dose-ranging study, and then we just finished a phase IIb study in which we had phenomenal biopsy results that frankly are industry-leading. Based on the strength of the IIb outcome, we launched an IPO about a little over a year ago, and then with the release of our top-line data this past January, we had a follow-on financing, so at this point in time, we're prepared to start our phase III study in MASH by the end of this year, and an effort that Dr. Martins here will share with you. I will also say that we have really interesting data in acne. Our partner in China, Ascletis, released phase II data a year ago May, in which it showed that denifanstat significantly reduced lesion count in moderate to severe acne patients. And so we are planning to, we're filing an IND on our next-gen molecule and plan to launch a phase I study at the beginning of next year. Got it. And maybe on the mechanism, wanted to dig in a little bit more. How does it work in MASH? And if you can explain the differences of denifanstat's mechanism versus, let's say, FGF 21, THR-beta. Mm-hmm. Sure. I think the biggest difference between our mechanism of action and others that are out there, as Dave said, fat mobilizers or burners, is the fact that, we, the drug, but not we, denifanstat, works on all aspects of NASH, all drivers, in fat inflammation, fibrosis. Most drugs benefit from reduction in fat and the downstream effects of that. That's great, but what denifanstat goes beyond that. So we defat the liver, but through the mechanism, we also reduce inflammation and reduce fibrosis. And why is that? Fatty acid synthase, as Dave mentioned, is an enzyme that processes metabolites from sugars, from ingestion of sugars, of course, and that leads to a very toxic fatty acid, palmitate, tripalmitin. Palmitate is important not only on toxicity to hepatocytes, but activation of inflammatory cells and activation of stellate cells, leading to fibrosis and then subsequent complications, cirrhosis, decompensation, and sometimes liver cancer. Got it. So is the mechanism more closer to, let's say, ACC inhibition and the DGAT2, or are there differences? It's a good question. They are all in the same pathway, the DNL. ACC is just above where denifanstat works, just above fatty acid synthase. The big issue with ACC is mechanistically it's a more complex mechanism, but mechanistically, it leads to a significant increase in triglycerides that limits the ability to reach the ideal dose. denifanstat, through all those effects that I mentioned, is in a kind of like a Goldilocks position in that cascade. DGATs are next, if you will, so downstream of that cascade, reduce the production of triglycerides, but that toxic fatty acid palmitate remains. Think about it as butter and olive oil. denifanstat that leads to olive oil, the others, in particular, DGATs, will really go towards butter. Got it. Maybe moving on to the clinical data that you guys have presented. So talk about the phase IIb FASCINATE trial and MASH. What did you see there? Sure. The study delivered in all key points, both primary endpoints, ITT and MITT then, of course. Before I go into the rest, important point, our definition of intent to treat analysis, ITT, is exactly the same that FDA uses for phase III studies, missing equals failure. A patient that did not have a second biopsy, so the trial was a biopsy study, biopsy at baseline, biopsy at the end of fifty-two weeks of treatment, patients that did not have that second biopsy were considered treatment failures, so it's as strict as it gets. Importantly, and in addition to the primary endpoints, we hit two secondary endpoints, which are precisely the ones FDA used for approval in phase III, MASH resolution without worsening of fibrosis, and the most important of all, fibrosis improvement without worsening of MASH. Now, put all this together, it not only differentiates a drug in effect, and we can talk more about the impact on patients with more advanced disease, F3 patients, where we really saw a very robust reduction in fibrosis. If we looked, say, for instance, at one stage improvement, and I'm only doing, not, of course, not head-to-head look at things, but if you adjust for placebo, looking at that delta, we are class leading. We have the best results in class. The only numbers that you would see if you do that math would be with the FGFs at week 96, where they have a higher efficacy. Well, give us another year, we'll equal and most likely improve, go beyond that. Right. So at one-year time point, what was the fibrosis delta versus placebo or? Twenty-three percent. Twenty-three percent. Yes. If we look at the one-stage in F3s, is 30%, that's three times Resdiffra, for example, and... Sorry, 36%, and if we look at the two-stage improvement in F3 patients, that's 30% delta, so very, very significant results. And finally, fibrosis is the driver of prognosis in MASH. Right. I think one other thing, I mean, the lack of progression to F4s, right? Yeah. We, uh- So what did you see there? Yes. So twice as many patients on placebo progressed to F4s, and we're going to see more at the liver meeting in San Diego later this year on artificial intelligence-based digital pathology. There is more interesting information coming on that impact on progression. Got it. That's very interesting. And so this is just a one-year trial, right? This was a one-year trial. Of course, the phase III will be a multi-year study, one year for accelerated approval, and then going on until about four and a half years for clinical outcomes and full approval. Right. And how did the efficacy vary between patients who were on GLP-1s and who were not on GLP-1s? Good question. The trial allowed for enrollment of patients on a stable GLP-1, and what we saw was no effect on placebo and about 42-43%, when we looked at MASH resolution, without worsening of fibrosis or the most important, fibrosis improvement without worsening of MASH. In summary, we did not see anything with the placebo, and we expect something similar in the phase III. When you have a patient that is stable, and those represent the majority of patients that receive the GLP-1, you don't see an impact on the disease, so, that we augment that. One quick comment, this, reproduces what we saw in preclinical studies that we presented last year at AASLD, exactly the same. The GLP was semaglutide, no impact on fibrosis when combined, then, we, quote-unquote, "rescue that and increase it. Got it. That's essentially what we saw with the preclinical data in combination with resmetirom as well, another fat burner, fat oxidizer. We showed that denifanstat was better at reducing fat and inflammation and fibrosis, but when you combine the two, there is an enhanced benefit, fibrosis reduction, just like we saw with the GLP. Right, so in preclinical models, you're seeing synergistic effects with Resdiffra. Correct. Okay. Got it. Correct. What about some of the other efficacy endpoints, such as lipid markers, triglycerides? What did you see there? Sure. LDL comes down, so essential in patients with a high incidence of cardiovascular disease. Triglycerides is very interesting. We saw a small increase, but that increase is composed of polyunsaturated fatty acids, the olive oil part of the story, and placebo maintained that very negative profile that you see in those patients. The triglycerides were saturated fat-containing. So again, that beneficial metabolic impact seen in this case in two parameters, LDL, in patients, in particular with LDL above a hundred milligrams at baseline, and of course, the composition of triglycerides. Got it. And you also had some data on a novel biomarker called- Yeah - tripalmitin. For folks who are not familiar, what is this marker? Sure. What did you see on the correlation with efficacy? Sure. So as we mentioned, all fats accumulate as triglycerides, one sugar molecule, three fats. Tripalmitin is the triglyceride that has the three chains of palmitate- Mm ... that high lipotoxic fatty acid. Tripalmitin levels drop dramatically with denifanstat very early on during treatment. That is a very good precision medicine aid, not a companion or diagnosis. We're not registering or trying to approve that, but we're trying to provide physicians and patients with the tool to know whether or not the patient is responding early on. That's important. MASH is a spectrum, if you will. Most of those respond to deni, but having a tool to decide what to do is good for the patient, but also for the payers, because they will see that unnecessary treatment doesn't go on. Mm. So that small proportion of patients that don't respond go to, say, a combination. Got it. We've talked a lot about the efficacy side, but on the safety side, if you can walk us, what did you see in patients? Sure. Drug is very well tolerated. To date, we have over 740 patients treated with doses in oncology, for example, going over 10 times the dose we use in MASH. We see no issues with drug-induced liver injury, DILI, no issues with bone mineral loss, no issues with muscle wasting, and no GI adverse effects, so very favorable profile. What we saw in some cases was hair thinning. About 6% of patients discontinued because of that, which is actually consistent with the 7% reported with one of the GLPs in a late-stage study presented recently. Now, other adverse effects that you may hear about denifanstat, dry eye. We actually had more dry eye on placebo in our trial, as well as our partner in China, Ascletis. They also saw the same dry eye, more common on placebo in their acne study than with the drug, and so was the use of eye drops. So if you ask the population, you're going to see more, so no issue there. Got it. Definitely wanna dig into these two events. On dry eye, there were cases of dry eye on placebo as well, as you mentioned right now. More. More than the drug. We haven't seen that in that MASH trials previously, I believe. So what's driving that? Why are these cases seen in this population and has not been seen in other trials? Sure. I think what is driving is basically, the ability... Asking patients. Yeah. Going directly to that, we tell the patients this ahead of the study, and we did this because of the oncology trials. Okay. With those very high doses, we saw that, so we wanted to be careful on the MASH studies. Now we know it's a non-issue. Okay. And on hair thinning, mechanistically, why is this happening? Sure. Denifanstat dries some of the oils on the head, and then some patients can have that. One actually interesting thing that we observed was that two patients on placebo and two patients during screening had sudden hair loss. So this is something that our KOL dermatology advisors tell us that does happen in this population. But most importantly is before this study, in MASH, we had only seen two cases out of 102. So we believe that there were factors associated with the timing of the study. We did it through COVID waves. COVID is a factor. COVID vaccines, the use of Paxlovid, that increases the level of drug. Again, we entered the cancer stage. We had a patient that accidentally took cancer-level doses of the drug. So finally, we know how to handle that. That's what our derm advisors gave us, the roadmap if that were to happen. So scalp oils, biotin supplementation, vitamin D, everybody is deficient on that, and if need be, dose reduction. Why. Let me just touch briefly on dose reduction. Yeah. Of the patients that had hair thinning and stayed in the study, those that stayed in 50 milligrams, five patients- the hair thinning stabilized, so there was a little drop and stabilized. There were three patients that reduced to 25 milligrams. The moment you do this, the hair grows again, and of those three, two had histological response. One had FAT, PDFF response. I hypothesize that those patients are actually super responders, hence the adverse effect. Got it. So these patients were able to reduce their dose but still got the efficacy, right? Correct. Okay, got it. And so in the phase three on hair thinning, you said you will be implementing certain steps to mitigate this? Yeah. Okay. Yeah. Scalp oils, biotin, vitamin D, and if need be, dose reduction. We don't expect to see as much because the factors that were associated with this study were concentrated in that period. Our expectation for phase three is to go back to what we observed before the IIb. Got it. I think it's important to remember that, we're trying to normalize FASN levels in these patients. In oncology patients, we're trying to ablate FASN levels, but in MASH and in acne, we're trying to normalize it. And the dermatologists that we've spoken with have all sort of guided us to this idea or rationale that very similar to levothyroxine. Everybody who is hypothyroid that goes on levothyroxine tends to have hair thinning, and then it rebounds after six, nine months. What they were most interested in, frankly, were the five patients that stayed on and had hair stabilization. Their conjecture is that over time, it would start to regrow even on 50 milligrams. So, I think it's an important consideration as we think forward. They've also indicated that we should manage this just like GLPs do. They see it quite frequently. They give them, as Eduardo indicated, biotin, scalp oils, vitamin D, and it works in a majority of the patients. So we plan to use the same mitigation if it's necessary within the phase three, but our idea is we would like to keep them on at 50 milligrams. They have the highest chance of treatment response. Got it. And maybe talk about your phase three plans- Sure. where you are, what discussions you have had with regulators. Sure. The main goal of the phase three is to reproduce the robust results we saw in the IIb. We had around a phase two meeting with FDA, and as with any company developing any drugs for any indication, you have continuous conversations. We have not disclosed details of those. And as soon as we have a final agreement, we will be starting the study. Nevertheless, the plan to start is before the end of the year, but nevertheless, we are taking all the steps to have that ready, vendors, CRO, and everything working. Now to the design. Madrigal set a very good footprint, so there is no reason why not following that, and the FDA has very strict guidance. It will be a global trial like the phase 2, only F2, F3 patients, like the phase 2, enrich towards F3s, the patients that need drug the most. One year of treatment for accelerated approval, biopsy, and then the patients go on for probably about four and a half years or so because it is event-driven to full approval. It will be a global study. It will still be a biopsy study because- Oh, yeah- -maybe, yeah. Unfortunately, for cost and all that- Right ... biopsy is the requirement, but as we saw, the label will not require biopsy, all things being equal. Sure. Got it. And do you have plans to test it in F4 as well? F4, yes. We have indicated that we want to pursue F4, and the mechanism makes a lot of sense. As the disease progresses, there is less fat in the liver. F4 has less fat, so you need a drug that doesn't depend solely on fat reduction. You need a drug that will impact the other two key drivers, inflammation, but in particular, fibrosis. That's the critical thing to do in F4, is you need to reabsorb that fibrosis to be able to regress the cirrhosis back to a liver that is a little more normal. Right. And you talked about, you know, synergistic effects with GLP-1s and Resdiffra, maybe combination strategy. Could this be like a fixed-dose combination with a drug like Resdiffra in the future? It's possible, actually. The drugs, Resdiffra, for example, burns fat. It's a perfect combination because you're acting in two different areas, so we are probably going to increase the potency just like what we saw in our preclinical models. We saw in the study, GLP-1s, the effect is enhanced. We are going to allow GLP-1s as long as they're stable in the phase three, and we expect a much higher proportion of patients. So yes, the unique mechanism, the unique position allow us to be the perfect backbone for combinations. Right. Important to remember that THR-beta actually induces FASN, so by blunting it, we actually can, you know, have this sort of complementary and enhanced effect, I think, in fibrosis. Got it. What about any overlapping safety profile for ThR-beta or FASN? We don't expect any. There is no. The mechanisms are totally different. Okay, got it. Got it. And lastly, on in MASH, and maybe just broadly, so what's the IP situation for denifanstat? Yeah. So we have two really strong broad patents. Our composition of matter for the molecule is in 2032. We filed our first IND back in 2012, so we will easily have the five-year patent term extension. I think importantly, the one we will almost certainly use, and we have to make that decision today, is on our method of use patent, which expires in 2036. There is no precedent for a FASN inhibitor used in MASH, so our IP counsel is guiding us very strongly to apply the patent term extension, which would get us until 2041. Got it. And you're testing this drug in other indications as well. Yeah ... like acne. So maybe talk about the rationale of why, why acne? Sure. FASN is also critical in acne. The oils on the face, in particular, sebum on the face, is part of the mechanism through which people, especially teenagers, of course, develop acne. FASN, by inhibiting FASN, you are targeting the key event, and then with that, you have the improvement of the disease. Our partner, Ascletis, as Dave mentioned, is running a phase 3 study in acne. They already had very successful studies with the phase 2 in acne, which allowed to see that the 50-milligram dose again, of denifanstat, is the most consistent dose. As Dave mentioned, we are developing our second-generation molecule for acne. Yeah. Go ahead. They have a phase 3 readout at the beginning of next year. They're halfway enrolled with their phase 3 study now. It's a 480-patient study. I should note that through halfway through, they haven't seen any hair thinning, not one case in that, in those patients. Got it. And so it's the same dose, 50 milligrams- Same dose. It is 50 milligrams. Same, same drug. Yep. Got it. And that phase three reads out later this year? Next year. Uh- Next year. Early next year. Early next year. Yeah. And so what, what are you? I know you're developing a second-generation molecule for that indication. What, what are you hoping to see? The same. Exactly the same. Dave was talking about patent, and perhaps, you can talk more about market strategy. Yeah. But the molecule targets exactly the same FASN. Our next gen molecule has very nearly identical PK profile to denifanstat, so we have a high degree of confidence that it's going to be as effective. As I indicated, we plan to launch a phase one study at the beginning of next year. That will coincide roughly with the phase three outcome from Ascletis. Got it. So that's still in preclinical stage, your second-gen molecule? It's IND ready. IND ready. It's IND ready. Yeah. Got it. So maybe in the last couple of minutes, talk about the cash runway and what exit options you're exploring to extend that. Yeah, that's a great question, and what we're trying to solve right now. We, as we reported in our last earnings, have roughly $188 million in cash from our IPO and our follow-on financing. We need a little over twice that to get to data readout for phase 3, and we are exploring a number of facilities that will help us achieve that, and those include potential strategic relationships with pharma. I think we've been quite fortunate. Our data is exceptionally strong and been well, very well received, and we have attracted a fair amount of attention. Got it. So in terms of that, strategic interest, is it more specific to geographies, or is it for the broader asset? Yeah, that's a really good question. Both. Actually, we're looking at both regional deals and potential global deals. Obviously, a regional opportunity would allow us to retain the U.S. rights, which is highly attractive. And if we can do that, then certainly we can raise whatever remaining amount of cash that we need to for the phase three. On the flip side of that, if we do a global deal and some sort of co-co arrangement, then we can almost certainly nearly finance all of the phase three. So these are options that we're weighing, and we're gonna make the best decision for our shareholders. Got it, and maybe just broadly on the MASH market, Madrigal's Resdiffra launch has been going pretty well. Agreed. What are you watching from that launch as to your development strategy and just broadly for the asset in general? I think we all should be really pleased with the commercial uptake and the adoption at this stage. And I think that's what I'm looking to. What is the... How many prescriptions are being written? What is the receptivity to treating MASH patients? The lack of biopsy needed to diagnose these patients is really important. And I think, you know, that's... They're off to a great start. Got it. That's all the time we have today. Thank you for joining us. Thank you, Dave, and thank you, Eduardo, for coming. Thank you. Thank you for coming.