Hello, and welcome to the eighth annual H.C. Wainwright MASH i nvestor conference. My name is Ed Arce. I'm one of the senior biotech analysts here at HCW, and I'm very pleased to have with us our next presenting company, Sagimet Biosciences. And representing the company is CEO Dave Happel, as well as CMO Eduardo Martins. Gentlemen, welcome. Thank you, Ed. Great to have you with us. So let's just get rolling here. We had some technical difficulties, so we're starting a couple of minutes late. But for those investors who may be new to the story, maybe just a quick overview of the company, and where you are with your three therapeutic programs? Yeah. Thanks, Ed. I'll go ahead and kick it off. Sagimet Biosciences is a clinical stage biopharmaceutical company. We started back in 2007 with a group of internal medicinal chemists who really were had ambitions of solving a rather interesting target called fatty acid synthase, which is a regulating enzyme in the body, that when it becomes overexpressed, as it does in a number of conditions such as MASH and acne and certain solid tumors, then it kind of throws things out of whack, and if you can inhibit FASN and normalize FASN levels, as we do in MASH and in acne, then it can have a settling effect and can have a rather pronounced treatment effect. We've demonstrated that certainly in both preclinically and clinically in MASH, where we have done the bulk of our work. By doing so, we have this rather unique, differentiated molecule that has the capacity to do things that other molecules have not demonstrated yet, and that is to target the three main drivers of MASH, and that's fat, inflammation, and fibrosis. We bring forward the only fat synthesis inhibitor in this space, in a world of fat burners, of fat oxidizers, fat mobilizers, and recently received acknowledgement of that in our data with breakthrough designation from the FDA, which we're very pleased with. Great. Absolutely. So, back in January, you reported top-line results, 52-week results, from the phase II-B FASCINATE-2 trial of denifanstat. This was a readout in modified ITT population, which excluded dropouts, and then you later on reported the full ITT results as well. Maybe go through some of the key data, and really how that differentiates from other agents in the field. Yeah. Eduardo, you want to go ahead and tackle that? Sure. So Ed, yes, you are correct. We're very pleased with the very positive data presented earlier in the year. So just as a reminder, we hit both primary endpoints on ITT and mITT, one-sided, two-sided p- values. However, the most important data were related to fibrosis improvement without worsening of MASH. As we know, fibrosis is the driver of prognosis. And we saw a benefit on ITT and mITT, but perhaps most importantly, we saw a great benefit in the patients that had F3 fibrosis. If we look at the patients with greater or equal to one stage improvement of fibrosis without worsening of MASH, we had 49% for denifanstat versus 13% for placebo, so a 36% highly statistically significant delta. If we look at an even more difficult two-stage improvement of MASH without... of fibrosis, sorry, without worsening of MASH, we had a delta of 30% in the F3 patients, 34% versus 4%. If we look at those two deltas, we are leading the pack, if you will, in MASH. We are much better than all drugs that have presented data at one year, and given a little more time, we would be passing also ahead of those that developed two years. As Dave said, our mechanism of action is unique. We are the only drug that target all three drivers of MASH. We defat the liver quite potently, but we also prevent activation of immune cells and activation of stellate cells that deposit scar tissue. We are unique in that sense. Excellent. Okay. So, I also wanted to ask about a rather unique biomarker for DNL inhibition, tripalmitin. It is important, not least of which because it is also, beyond being a marker for on-target activity, it's a reliable marker of early treatment response. And so I wanted to ask, what was some of the data that came out of the study there? Sure. What we've seen with tripalmitin, and you're absolutely correct, we are looking at it as a marker of response in precision medicine to help clinicians once a drug is approved. Please bear in mind, precision medicine does not equal licensing a diagnostic. It's a tool for the office. Now, in the phase II-A study, we saw a clear correlation between decline in tripalmitin, which is expected with a potent inhibition of fatty acid synthase and fat response by MRI-PDFF, that decline. In the phase II-B, we are analyzing the data as we speak, looking at the correlation between tripalmitin decline, which happens as early as four weeks, and then it continues on. So very early on, you can tell how a patient is doing. We're looking at correlation against liver biopsy and against other markers, in particular, those related to a large panel of lipids and other metabolites. We expect to be presenting those data at the EASL conference next year. Right. And I wanted to get back on a point that you made earlier, which is as robust as the data was at 52 weeks. It is interesting to note that your drug, as was just recently confirmed by Scott Friedman at an earlier session, a direct anti-fibrotic. Mm-hmm. And so with that in mind, I'm wondering if, as was seen with Akero's drug, EFX, at two years with a improved response rate, would you necessarily expect a similar improvement in your own response with denifanstat? We actually would expect a better response, more fibrosis response than what has been observed at two years. Of course, the current study that we have disclosed all the data, the phase II-B, was a one-year trial. Nevertheless, the continuous response based on the potency of this drug directly impacting fat production, directly impacting inflammation, directly impacting fibrosis, those would be reflected in the long run, leading to a repetition or a repeat, sorry, of the response at one year, and then looking down the line, prevention of disease progression. Which actually, if I may add one thing to my reply to your question, we also observed in the phase II-B, twice as many patients on placebo progressed to cirrhosis at F4 than compared to denifanstat. So already early on, we are seeing one clinical outcome. Right. Okay, fantastic. And then, switching gears a bit, I wanted to ask about how you will work to mitigate the AEs seen in the phase II-B. Obviously, dry eye and hair thinning were two areas that you saw. And wanted to ask, how easily will physicians be able to manage these, not only in trial, but you know, in clinical practice? Sure. Dry eye was actually more common with placebo. Not only more common, but also patients on placebo used more eye drops, so it's not an issue. Hair thinning, we know how to manage. We had not seen before in a large number of patients other than two. Two patients out of 102 patients, we had observed hair thinning before. In the acne studies that our partners are conducting in China, the same was the case. No issues with 50 milligrams, including with the study that is ongoing phase III, about 225 patients enrolled so far, blinded, but nevertheless, no cases whatsoever. Now, the phase II-B, and you are correct, we saw a little more. The phase II-B happened during the Omicron waves and a few other things also. Patients had several cofactors that are associated with hair thinning. Use of thyroid medications, so levothyroxine, for example, there was a large number. We had about nine patients on that. We had patients that had COVID, and some took Paxlovid. Both COVID is associated with hair thinning, and Paxlovid bumps up our drug to cancer dose levels, which, of course, then you observe more. We had patients that accidentally took cancer-level doses of the drug. We did speak, and we do have dermatology advisors who said that these are expected with all those cofactors. They don't expect us to see anything different to what one expects in a MASH population in our phase III study. If need be, we will supplement biotin and other vitamins. One other thing that we can do, which we did, is-... to drop the dose to 25 milligrams. And when we did that, one hair regrew, and two, we had three patients that did so, two of whom had histological response. The final two things are, one, the rate that we had discontinuing, 6%, was actually what has been reported with one of the GLP-1, 7%, in a current publication. And so we do not expect really to see more than in previous studies, and we know how to manage. Those are the two important things. Great. Thanks for clarifying that. So now I want to turn the attention to GLP-1 agonists for MASH. Obviously, a lot of interest, a lot of off-label use for this patient population. But how do you think about physicians treating F2, F3 patients with GLP-1s? And is the injectable mode of administration and the high dropout rate really conducive to a long-term chronic therapy? That's. Those are excellent questions. Let me tackle the F2, F3 first. The effect in that population is really not quite there. It's going to be, as more come to the clinic, modest at best. Those drugs will impact either F1 patients or those that don't even have fibrosis. They'll benefit from that. Now, the question on the injectable and tolerability, this is the big issue. Our advisors tell us in their clinics that up to 50%, some of them, are seeing dropouts at the end of one year on GLP-1s, which is a problem. Nevertheless, there is a role for those drugs in patients with type 2 diabetes and obesity, so they will be there. And in our data, we have seen in about 10% of the patients in our study that did receive... Or let me rephrase, who were receiving a GLP-1 before entering the study, were on a stable dose, we saw responses only in the patients receiving denifanstat. 42%, either for fibrosis improvement or for MASH resolution, compared to 0% on placebo. And those human data reproduce what we've seen also in animal experiments, where the GLP-1s, in this case, semaglutide, was not able to show any fibrosis effect. But when you added FASN inhibition, then you saw an effect, and actually again, when compared to either drug alone. Great. Okay, obviously, AASLD is coming up soon in November. What do you plan to present there? Sure. Good questions. We'll be presenting an oral on artificial intelligence digital pathology. Mary Rinella will be presenting, and those will be the full data. We showed one snippet of data at EASL with quantitative AI. Again, a statistically significant benefit of denifanstat compared to placebo. The other presentation is going to be treatment of patients with difficult-to-treat disease. So we're going to be talking more about the F3s, patients with diabetes, so all those populations with at-risk MASH or accelerated disease. Of course, you are still actively in discussions with the agency about the phase III design. Can you give us the latest update on where that stands, and if you remain on target for your timeline? We don't comment on the specifics of our discussions with the agency, as we mentioned, previously. Fair enough. The protocol, the very first draft of the protocol, is up on ClinicalTrials.gov, so you can take a look at that. We only expect minor tweaks between that and the final one. And, as Dave mentioned, we have indicated that our intention is to start the study by the end of the year. And then perhaps just one last question. Of course, you did mention that denifanstat, through your partner, is in a phase III for both acne and recurrent glioblastoma. What are the timelines there to receive data? Sure. The glioblastoma study is fully enrolled. It is event-driven, so but given the unfortunately the aggressive nature of the disease, in particular in the trial, you're probably going to have events at some point in the first quarter of next year. The acne study is actively enrolling, more than halfway through, and in the first half of next year, we're probably going to have the results. Just one quick thing: they published, sorry, they disclosed and presented the data with acne in their phase II-B, and the results were phenomenal. Excellent. Dave, Eduardo, thank you both for your time and perspectives. This was very helpful. Appreciate it. Thank you, Ed. Good. Thank you.