Greetings, and welcome to Sagimet Biosciences post-EASL key opinion leader call. At this time, all participants are on a listen-only mode. A question-and-answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Dave Happel. Thank you. You may begin. Thank you, Rob. Good morning, afternoon, everyone, and welcome to our presentation today. We are excited to share with you the MASH data with denifanstat that we presented last week at the EASL conference. We are extremely pleased to have Dr. Rohit Loomba presenting his thoughts today on denifanstat, especially the outstanding one-year data in the more severe MASH patient population, as well as his perspective on how the MASH space is continuing to evolve. Next slide, please. Before we begin, I would like to remind our listeners that our comments today will include some forward-looking statements. These statements include statements regarding the presentation of the data from our clinical trials, our clinical development plans, and related anticipated development milestones. These statements involve a number of risks and uncertainties, which are outlined in the press release and on slide two of this presentation. Actual events or results may differ materially from those projected in the forward-looking statements, which contain known and unknown risks, uncertainties, and other factors that may cause actual results or performance to differ materially from those projected. Next slide, please. Joining me on the call today are Dr. George Kemble, the company's Executive Chair and Acting Chief Science Officer, Dr. Eduardo Martins, our Chief Medical Officer, and Dr. Rohit Loomba, who is a board-certified gastroenterologist and professor of medicine with tenure, Chief of the Division of Gastroenterology and Hepatology, and the founding director of the MASLD Research Center at the University of California, San Diego. As a transplant hepatologist, Dr. Loomba works with transplant surgeons in the pre- and postoperative care of liver transplant patients, and he is an internationally recognized scientific thought leader in MASH and has published more than 500 papers in his field. He is an elected member of the American Society of Clinical Investigation and the Association of American Physicians and served as the lead principal investigator of our phase 2 biopsy trial. Next slide, please. I'm confident at this point that we have established the importance and the role of inhibiting overactive fatty acid synthase, or FASN, which, if left unchecked, will lead to progressive disease in a number of underserved disease states, including our primary focus in MASH, but also in other diseases such as acne and certain solid tumors, where we have generated compelling clinical data. To solve for this overactivity of FASN, we have developed a portfolio of novel FASN inhibitors, including our lead program, denifanstat, that target fat accumulation or lipogenesis, a root cause that is common to the disease states and conditions we are pursuing development. With denifanstat, a once-daily oral small molecule, we offer a highly differentiated approach to treating these diseases. In fact, denifanstat is the only fat synthesis, synthesis inhibitor in an ocean of fat burners, oxidizers, and mobilizers in development for MASH. We have completed a number of preclinical and clinical MASH studies with denifanstat, including successful Phase 2a and Phase 2b studies that have been presented over the past 2 years, most recently at EASL last week, where Dr. Loomba presented deeper analyses of our industry-leading 1-year data, especially in more severe F3 stage MASH patients, where denifanstat demonstrated a pronounced fibrosis improvement. All the data across all the studies show the same outcomes, that denifanstat consistently and significantly impacts the key drivers of MASH. That is, fat, inflammation, and fibrosis. In fact, it can be argued that denifanstat is the only molecule in development for MASH that directly targets all three drivers of the disease in parallel, not relying simply on reducing liver fat to translate into downstream benefit in inflammation and fibrosis. Based on the repetitive positive results on both an ITT and MITT basis, we believe denifanstat has removed the mystery about the outcome of the phase 3 study we plan to start by year-end. Denifanstat has been evaluated in over 700 patients to date across multiple disease states with a favorable safety tolerability profile, and therefore, we do not perceive any limitations in the target treatment populations for any of the disease states we are pursuing development. With an eye toward commercialization in the payer landscape, we are developing predictive biomarkers that tie target engagement of denifanstat with patient response. Our lead effort involves tripalmitin, a saturated triglyceride that denifanstat significantly reduces in the first several weeks of treatment. Historically, this early reduction in tripalmitin has correlated with key biomarker improvements in patients. This represents another highly differentiating feature of our program that no other molecule in the space is pursuing, and we look forward to presenting further data on our predictive biomarkers at upcoming congresses. A quick word about our balance sheet. We have a little less than $200 million in the bank based on the IPO in July of last year and a follow-on offering earlier this year with the announcement of our successful 2b data. We anticipate bolstering our balance sheet in the coming months and are considering a number of financial vehicles to help us achieve our capitalization objectives… Next slide, please. As noted, we are poised to begin phase 3 in MASH with denifanstat by the end of this year, but we are also focused on a couple of other catalysts that may bring value to our investors. Our partner in China, Ascletis, who has rights to denifanstat in China only, is in the middle of two important phase 3 programs with denifanstat, one in acne and one in recurrent glioblastoma, that may provide inflection points by the beginning of 2025. In acne, Ascletis initiated a phase 3 study in moderate to severe acne patients at the end of 2023. Based on the strength of a very positive 180 patient phase 2 study, in which denifanstat significantly reduced lesion counts with a generally well-tolerated safety profile comparable to placebo. We should see a readout from this phase 3 study by the beginning of 2025. The phase 3 GBM study, in combination with bevacizumab, has completed enrollment and was initiated based on the strength of a strong progression-free survival signal seen in an earlier phase 2 study. We expect to see interim readout from this study also by the beginning of 2025. Next slide, please. But for now, all eyes are on the MASH landscape. The MASH market is growing rapidly, with projections that it will triple in size in the next two decades and approach prevalence rates associated with other blockbuster cardiometabolic diseases. In summary, in denifanstat, we are bringing forward a highly differentiated oral, once-daily small molecule, and as noted, the only FASN inhibitor in late-stage development. Based on denifanstat's unique mechanism of action, the data to date, and tolerability profile, we anticipate denifanstat will be an excellent standalone monotherapy or combination therapy choice for F2 to F4 MASH patients. With that, I now invite Dr. Loomba to share his thoughts on denifanstat and our data to date. Thank you, thank you, Dave. Delighted to be here. I look forward to our presentation on denifanstat that we did at EASL on the phase 2b trial data. Next slide, please. Denifanstat is a specific and potent oral inhibitor of fatty acid synthase. It functions through three independent mechanisms in MASH. It blocks steatosis via inhibiting de novo lipogenesis, which is an important pathway in propagation of lipotoxicity in the liver, leading to steatohepatitis. It reduces inflammation via preventing immune cell activation. And thirdly, it blunts fibrosis via inhibiting stellate cell activation. Next slide, please. Here we can see the effect of denifanstat on stellate cells. DNL pathway is needed for fibrogenesis and activation of stellate cell. To the right, I'm showing you the effect of denifanstat on primary human stellate cell and it inhibiting fibrogenic activity. This is important where denifanstat is a direct antifibrotic, in addition to its mechanism of action of reducing lipotoxicity and inflammation. This is important and will be addressed further as we look at our clinical data. Next slide, please. This is showing you the design of the phase 2b trial. The aim of the study was to examine the safety and efficacy of denifanstat versus placebo in improving fibrosis and NASH resolution after 52 weeks of treatment. Patients with biopsy-confirmed NASH stage 2 to stage 3 fibrosis were randomized 2:1 to denifanstat 50 milligrams versus placebo. Our pathologist for this study was Dr. Pierre Bedossa, who's very well known in the field and has also read several other phase 3 programs, in particular, the MAESTRO-NASH trial. Via digital pathology, HistoIndex was also assessed. The primary endpoint was NAS of 2-point or greater improvement without worsening of fibrosis or MASH resolution, plus NAS of 2-point or greater without worsening of fibrosis. We also looked at 1-stage improvement in fibrosis, digital AI pathology, and MRI-PDFF-based liver fat reduction. Patients underwent a biopsy and MRI-PDFF at baseline and also at week 52. Next slide, please. These are the baseline characteristics of the study cohort. This is very typical of a NASH stage 2 and 3 study population. You can look at the mean FAST score was 0.6. Mean liver stiffness was 11.6 kPa and MRI-PDFF of 17.5%. 55% of the patients had stage C fibrosis in this study, and 61% had type 2 diabetes. 33% of the study population was Hispanic or Latinx. Next slide, please. These are the primary endpoint results. To the left, I'm showing you NAS improvement by two points or greater without worsening of fibrosis. To the left is intention to treat population. In the middle, you see the modified intention to treat. Both the results are statistically and clinically significant. Then to the right, I'm showing you MASH resolution plus NAS of two-point improvement without worsening of fibrosis. You can see a clear 15% treatment effect delta on ITT and pretty significant treatment effect delta on MITT. These results are important and also clinically significant. Next slide, please. Now we look at those patients who had at least one-stage improvement in fibrosis without worsening of NASH. You can see 41% on denifanstat versus 18% on placebo. This is a 23% treatment effect delta, which is very significant. Next slide, please. Now we are providing you even greater data and granularity about different outcomes that are of clinical relevance. One-stage improvement in fibrosis without worsening of NASH on top with ITT population, MITT, and then specifically among Stage three population. You can see 49% response rate in denifanstat group versus 13% on placebo. What about two-stage improvement in fibrosis just within one year? With MITT, 2% on placebo, 20% on denifanstat. In F3, we're looking at 34% on treatment versus 4% on placebo. What about progression to cirrhosis? We had more patients progressing to cirrhosis on placebo, as expected, at 15% versus 5% on denifanstat. These results are not only important, but clinically meaningful. Next slide, please. This is data now looking at a different modality based upon AI-based pathology assessment by HistoIndex. Now, I'm showing you a patient who had stage 3 fibrosis pre-treatment. With 1 year of treatment with denifanstat, this patient had 2-stage improvement, down to stage 1 fibrosis. To the right, I'm showing you qFibrosis improvements that are also significant with denifanstat compared to placebo. This validates the data internally by looking at a different modality based upon AI-based assessment of liver fibrosis from a totally different modality for the results that we are seeing on histology, as I previously showed on fibrosis improvement by 1 stage. Next slide, please. Here, I'm showing you data on a subset of patients who are on a stable GLP-1 receptor agonist dose. To the left is resolution of NASH: 42% compared to 0% in placebo-treated patients. So denifanstat improves those patients who are on a baseline GLP and continue to lead to resolution of NASH in 42%, and also one-stage improvement in fibrosis in 42% of patients. This is also clinically meaningful in clinical practice if and when denifanstat comes to clinic after the phase 3 program readout. Next slide, please. These are the FASCINATE-2 safety results. You can look at adverse events, with 88% on treatment versus 82% on placebo. Adverse event related to denifanstat was slightly higher. Severe adverse events were not significantly different, and treatment-associated adverse event leading to just drug discontinuation, 19% versus 5% on the placebo. You can see adverse event affecting 10% or more patients. This trial was conducted during COVID-19. You can see 17% versus 10%, and hair thinning of 18.8% versus 3.6% on placebo. We did not observe any DILI signal and no muscle wasting, and GI symptoms and AEs were comparable to placebo. These are important aspects of the drug if we were to think about in future of combination approaches. AE of hair thinning stabilized within two to four weeks of dose hold, and hair thinning was reversible. 6% of patients discontinued from the study with hair thinning, consistent with other MASH-related medications that we've also seen. In previous clinical studies, less than 2% of patients experienced hair thinning at 50 milligram dose. Next slide, please. We've had series of discussions with KOLs, both in hepatology but also in dermatology, and this has led us to think about hair thinning in two different ways. Hair thinning mechanisms could be autoimmune. That typically leads to alopecia, but in the case of denifanstat, that's not the case. In case of denifanstat, we think it's related to DNL inhibition and reduction of fatty acid synthesis in the hair follicle, leading to hair thinning. So this would be dose-dependent and also reversible with dose hold or drug holidays. Reducing the dose may also improve the side effect. Of 8 patients who experienced hair thinning and remained on denifanstat, 5 remained at 50 milligrams, and the hair thinning stabilized. 3 down-titrated to 25, and hair thinning improved. We are developing extensive phase 3 mitigation planning currently. We encourage patients' retention for the expected small subset of patients who experience hair thinning at 50 milligrams with the use of biotin for prevention and scalp oil. And this should lead to retention and as well as reduced effect on hair thinning. Another possibility is dose titration down to 25, plus medication pause for 2 to 4 weeks when appropriate.... We do believe that these mitigation strategies will further improve the tolerability of the denifanstat in this study population. Next slide, please. Denifanstat also led to significant reduction in MRI-PDFF to the left 65% compared to 21% on placebo, with a PDFF response rate. These data corroborate with the NASH resolution and fibrosis improvement and provide us good reliability that we will be able to replicate these findings in phase 3. To the right, I'm showing you FASN improvements. They were also consistent and actually continued to improve beyond week 26, which is also significant. Next slide, please. Here you can also see improvements in ALT that are significant and improvements in AST that are also significant. These are important aspect of a study drug, where denifanstat not only leads to NASH improve, NASH resolution, but also fibrosis improvement. On top of it, you get the PDFF response. You also show improvements in FAST. You see significant improvements in ALT and AST, all that in a phase 2b trial. For an oral therapy, this is, outstanding results. Next slide, please. Here we also see improvements in LDL cholesterol with denifanstat. What we also see is a change in the, triglyceride profile with more polyunsaturated triglyceride compared to saturated triglyceride with denifanstat. So this is actually changing the CVD risk into a more favorable CVD risk with LDL reduction and polyunsaturated triglycerides. Next slide, please. We also have a biomarker of DNL inhibition called tripalmitin. This could tell us about target engagement as early as week 4. So we can predict response to denifanstat at week 4 and week 13 for a histologic response at 1 year. This is really important as we develop therapies for going to clinics where physicians and clinicians can use which patients are responding to the treatment and are likely to have a therapeutic response. Next slide, please. Now I'll invite George Kemble to discuss the efficacy that we are seeing on both fibrosis and also NASH resolution with you. Over to you, George. Thank you, Rohit. So let me just walk through the next two slides quickly. Obviously, a lot of these data are new in the field, and so what we wanted to do was compare in this slide that you're looking at, the effect of our drug in the F3 population, clearly a population that needs to improve their fibrotic damage. So if you look at our blue bar, 36% against placebo adjusted rate of one stage or more improvement on the F3 population, certainly better than the other data for the other oral drug in the class. If you look from the Lilly, Akero, 89bio, the injectable, whether it be tirzepatide or the FGF 21 class, you really see our placebo-adjusted effect is certainly higher than what you see until you all get all the way up to that 96-week endpoint for the FGF 21 class. But again, this really tells us that certainly for an oral drug, we've got a really big impact in this population that is absolutely in need of drugs like ours. So if you go to the next slide, please. This is now what I would call the depth of the response. So this is the 2-stage or more improvement in fibrosis. Again, placebo-adjusted, 18% of our patients have a 2-stage or greater impact on fibrosis, and that's significantly higher than the other oral drugs shown here next to us. Again, well outpaces the other drugs in the class, again, until you get to that 96-week endpoint for Akero's FGF21. Again, you realize this. These are not head-to-head studies. But that said, these are the data that are reported out there in the literature or on corporate websites. And I think what it shows us is that we've got a really clear industry-leading capability with our drug in the F3 stage and the ability to penetrate two stages or more of improvement. So with that, I'm going to hand it back over to Rohit to take you through the end of our phase 2b and our plans at this point. So Rohit, back to you. Thank you, George. Now I just wanted to bring your attention to the newly published and released EASL guidelines. This was released at EASL, and what we are saying here is that currently there's only one therapy in the United States that's approved for treatment of stage 2 or stage 3 fibrosis, and that's resmetirom. And that's the only therapy that hepatologists will be using in their clinical practice. For the background use, those who don't have fibrotic disease and have comorbidities, you may have use of GLP-1 analog. So I think it's important to clarify that. And you also have SGLT2 inhibitors, metformin, or insulin in the setting of type 2 diabetes, and the dyslipidemia treatment would be, you know, relying on statin use. Those with morbid obesity, you know, GLP-1 receptor analogs such as semaglutide, tirzepatide, or tirzepatide, may be used in the setting of obesity, but not particularly those who have stage 2 or stage 3 fibrosis. Next slide, please. Here, you know, I think this will clarify as to patients who have high-risk disease, such as those with stage 2 and stage 3 fibrosis, they are likely to benefit from a liver-specific therapy and therefore would potentially require a treatment that reverses fibrosis. That has been shown in the setting of a phase 3 trial. So in my clinic, we will only be using medications that have been shown to improve fibrosis in the setting of phase 3 trials before their clinical use in patients who have NASH stage 2 or stage 3 fibrosis. Just wanted to summarize that here. Next slide, please. In summary, denifanstat, a fatty acid synthase inhibitor, was better than placebo for both the Subpart H approval pathway endpoints, including MASH resolution with worsening of fibrosis or fibrosis improvement with worsening of NASH. Denifanstat delivered clinically meaningful and statistically significant improvements in liver histology. We also noticed fibrosis regression by two-stage improvement, as well as significant improvement in those who had NASH with stage three fibrosis. Noted improvements in MRI, PDFF, FAST, ALT, AST, and LDL. Tripalmitin is being developed as an early biomarker of target engagement and treatment response. That differentiates denifanstat from other drugs in clinical development. Denifanstat was generally well tolerated. Combination of a fat synthesis inhibitor with a fat burner synergistically may improve outcomes of disease if shown in clinical studies in future. These results support continued clinical development of denifanstat to phase three clinical trials in MASH-related fibrosis. Thank you. Next slide, please. I'll hand it over back to George. Oh. Thank you. Yep. Thank you, Rohit. Yeah, so let's talk a little bit about our development program. So let's move to the next slide, please. So you can see we're really in the transition phase from our phase 2 to our phase 3, and I think some of the important elements to take away are, again, our phase 2b study was essentially only F2 and F3 patients. That set of patients we think are in most need of these drugs, we delivered on the primary endpoints of this study, as well as those endpoints that are required for subpart H approval. And so again, there's not a lot of mystery left, and I think Dave said that in the beginning. Same patient population, same endpoints into our phase 3, which we plan to start by the end of this year. So we're very excited about that. Next slide, please. One of the other things that we think is important with our program is the ability to assess whether a patient is responding to our drug or not. So we talked about a couple. Let me really focus on this top one, which is tripalmitin. So we've shown, and you saw just a few minutes ago, that our drug has a very significant impact on reducing tripalmitin and saturated fatty acids is a direct reflection of FASN's activity. So by lowering it, we know that we're inhibiting FASN and providing, we think, a very good profile to predict the response to our drug. So here's the idea. We'll take, give our patients their, their drug, wait for a month or two, measure their tripalmitin levels, and those changes, and we will be then predictive of a beneficial response. So we think that's very important. It gives the patient, it gives the physician a place to talk about the response to treatment, and it also, we believe, will give payers insight into a very short period of time where they can have a very solid likelihood of an outcome. And we think that's very important in this population and something that we continue to work on. There's still more work to do. As Dave said, you'll be seeing more data on this over the next many months as we go through our data set, but we're very excited about the promise of bringing this to patients, physicians, and payers. Next slide, please. What about additional opportunities in MASH? Well, obviously, given our data and the, if I will, you know, two-stage improvements, our ability to work in the F3s, we did a press release, and we've done a study in hepatically impaired patients, for drug levels earlier this year. We really think that getting into compensated cirrhotics is an important area for us to be engaged with. As Rohit showed you, we do directly target those stellate cells. That's what's causing a lot of the fibrotic damage in these folks. The compensated cirrhotic population still has functional hepatocytes. They're still making those lipotoxic fats. And so we really think that we've got an excellent opportunity now to move into that population, something that we'll be looking for, as we move into our phase 3 registration study, but then also thinking about an independent F4 population. And then on the bottom is pediatric NASH. Not talked about a lot, but it's a very important disease. So right now, about a quarter of the kids in the U.S. who've got steatotic liver disease have MASH at the time of their diagnosis. We're going to compile the safety data across all of our studies. We've got a non-clinical toxicology study to perform in juvenile animals. We plan to initiate that by the end of this year, and that potentially gets us to a phase two study in pediatric MASH. And we think that's really important, particularly given our safety profile, that we're one of the few, if not only, drugs that we think has a viable opportunity at this stage, to move into this population. So we're very excited about really getting into these kids who need some help. Next slide, please. And then what about combinations? At EASL, we just released some data with two different mouse models with resmetirom. So as Dave said at the beginning, here we are a fat synthesis inhibitor, whereas many of the others in the class are fat burners, and the resmetirom certainly falls into that category from our perspective. So putting the two together could potentially lead to some really interesting additive or even synergistic effects. So you can certainly take a look at these posters, but what you can see is whether it's a LDL knockout model that we had just really impressive improvements of the liver enzymes, AST, LDL lipoproteins, as well as some histological improvements in those animals. Then in a more traditional diet-induced obese model, again, we did this a short-term release of data, where again, we saw really important improvements of the biomarkers and on liver histology. And I'd encourage you to go look at those data. We're really excited that this combination is both fulfilling sort of the mechanistic idea that we had behind it, but it's also an important drug, resmetirom. It's different because it's certainly on the market, and we think that it's important that we be able to work well, and we think we have a very good opportunity here. So in this last slide, sorry, you can go to the next slide, please. Just wanted to remind you, you know, we've had an opportunity now to see a drug that actually directly interacts with stellate cells, in addition to providing relief from inflammation and signals from the lipotoxins that the hepatocytes generate. We showed you some very strong results on the fibrosis axis, including, not limited to, working in the F3 population as well as two-stage improvements. So with that, we're excited to continue to develop this program and to look forward, both for these patients, and for the company's investors. So with that, I will hand it back over to Dave, who can take the questions and answers. Thank you. Thanks, George. I think we're ready to begin the Q&A session. Thank you. At this time, we'll be conducting a question-and-answer session. If you'd like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment please, while we poll for questions. Our first question comes from Ritu Baral with TD Cowen. Please proceed with your question. Good afternoon, guys. Thanks for hosting after all the activity and drama at EASL across the conference. A question on your upcoming FDA meeting. Have you had it, or are you done preparing for it at this point? And what sort of topics do you anticipate will be the big topics of discussion for phase three design? Particularly, I'm wondering if you're going to use tripalmitin in some capacity, either for enrichment or prospective sub-analysis, for efficacy, or anything else. Thanks. And I've got a quick follow-up for Dr. Loomba. Thanks, Ritu. This is Dave. I'll take the first part of this and then turn it over to George. Yes, we have begun discussions with the FDA, just very recently, through our end-of-Phase 2 discussions. Obviously, we don't comment publicly on those discussions until we reach resolution, but we hope to do so, in the very near future. And in terms of what hot points there are, I'll let George talk to that. But again, generally speaking, we don't comment on the interactions. George? Yeah. Thanks, Dave. Yeah, I think it's clear to say we will not be using it as an intervention marker. That's really a bridge too far, and it's not something we actually think we'd want to do, which is to, you know, pull patients out early in the study. We need to see the data. As far as will it be used in the phase 3 for sub-analysis later on, I think, again, the assay itself still has some evolution to do, but some form of it absolutely will be part of our SAP at the end of that study. I think it will be an important criteria for us to be able to communicate at the end of the certainly the end of the 52-week biopsy portion of the phase 3 study. Great. And then, just a quick follow-up for Dr. Loomba. Thanks again for the time, Dr. Loomba. Your comment on the atherogenicity score and the sort of rebalancing of the unsaturated versus saturated triglycerides, can you, can you comment on how that and the LDL comes together, either on, like, an accepted score or in your mind, to balance out or increase or decrease, atherogenicity risk with treatment? How do you see that? Yeah, I think, definitely LDL cholesterol decrease would be associated with a improvement in or reduction in CVD risk. So I think that's absolutely given. And I think with the larger sample size in phase three, we would be able to document that, and it probably will get into a statistically significant, you know, domain. In terms of increase in triglycerides, that, you know, you have to see based upon, from my thinking is, if this is atherogenic and the risk with increased TG is associated with saturated fats, in my opinion. So saturated fatty acids are considered to be bad. Polyunsaturated fatty acids are considered to be good. And so it's possible that what we are seeing here is a lot of polyunsaturated fatty acids, and those are associated with reduced risk in general. So I think that's what, you know, I would hope that in combination with a decrease in LDL cholesterol and changing the saturation to more polyunsaturated. So this will be something similar, where if somebody's taking, you know, PUFAs and other things, that you would have improvements related to TG. Another possibility one could consider is using fish oil and other supplements in such a case. But I think overall, it appears to me to be more favorable. I also noticed that, based upon another abstract that we've been working on from an independent study, that this profile that is more saturated fatty acid is seen in the setting of PNPLA3, and when we reverse it, you may start seeing more polyunsaturated. And so that's another thing that possibly this drug would have impact, also in those patients who have PNPLA3 homozygosity. So those are two of my observations, but independent, from this study. Great, thank you so much. Thank you. Our next question comes from Thomas Smith with Leerink Partners. Please proceed with your question. Hey, guys. Good afternoon. Thanks for putting this event together and for taking our questions. Just a couple on our end. For Dr. Loomba, and it seems like a potent antifibrotic that's oral, and it doesn't seem to have any real notable GI toxicity. It'd be a pretty attractive option for use in combination with a THR-β or a GLP-1. I was just wondering if you could comment on denifanstat's profile with respect to its potential for use in combination regimens and, which of the other late-stage mechanisms you would be most excited about trying denifanstat with in a combination setting? Thank you. I think this is really important. That's why I emphasize that, you know, in terms of the GI side effects, we see not too different than placebo. So this is attractive because majority of our other drugs, particularly, thyroid hormone beta receptor agonist, GLP analogs, GLP/GIP, and FGF21, all have GI side effects. So this is favorable in that setting where denifanstat could be, you know, easily used. Another thing to consider is that if you block fatty acid synthase, then you're probably shutting or shuttling some of the lipid moieties into beta oxidation. So you could actually be synergistic. So not just additive with thyroid hormone beta receptor agonists, but you could be synergistic. So, you know, you could actually significantly improve your fibrosis improvement with these two oral drugs, as a possibility would be a hypothesis that I will be interested in testing. Similarly, you could consider in the background use of GLP analogs, the use of denifanstat. And then another aspect that we didn't mention here is the idea that if you look at NASH-related hepatocellular carcinoma, that is really linked to de novo. And because the cancer cells really generate their own energy using de novo lipogenesis. So when you block it, you're probably reducing future risk for hepatocellular carcinoma as well, at least pathogenesis viewpoint in NASH related HCC. So, this is potentially another beneficial side of denifanstat that could be useful as people are thinking about combination approaches. Got it. That makes sense. Thanks very much for that. And then, one for the company, just, with respect to the tripalmitin reductions, I mean, you presented some new data here, and you've noted, some correlation with biomarker improvements. Could you just comment on what you're seeing, with respect to the liver histology changes? How do these correlations look? When can we look forward to seeing some of those data? And then just, how are you thinking about implementing this into a clinical development program? It sounds like you aren't going to use it in the phase 3 explicitly, but how should we think about your ability to incorporate this into a label or, at some point into, clinical use? Yeah. George? Yeah, great question, Tom. So, let me start with the beginning. So yeah, we don't have the correlations yet with the histological data. Those will be coming sometime in the next, you know, period of time. No definite date yet. But yeah, I think it's important to think of this not as a classical companion diagnostic, where you're developing it in order to approve it for, you know, patient selection. This is really something more of a tool that would give the physicians, the patients, payers something to work on. So we're still looking at all the various attributes of how to get the assay, how to make it work, how to get the right leveling done. That's still something that will be done, obviously now and concurrent with the phase 3. There's still a lot of work to be done. You'll see some more data, I'm sure, again, it doesn't have that same level of scrutiny right now because we're not trying to make it something that a physician must use in order to either guide the patient or select the patient. Got it. That makes sense. All right. Thanks for taking the questions, guys. Appreciate it. Our next question comes from Yasmin Rahimi with Piper Sandler. Please proceed with your question. Good afternoon, team. Thank you for this webinar. Pretty helpful. Team, I guess the first question that I have for you is, given the strong results you see in the F3 population, are you contemplating to maybe enrich a higher percentage of F3s into your phase 3 study? Are you thinking about, given also the encouraging data on top of the GLP-1, to maybe stratify a subgroup of patients that could be part, and I'm making this up, but a certain percentage that could be on combo, that could be really meaningful to do stats on in your phase 3? If you could kind of talk about that, given the encouraging results you showed. And then maybe a question for Dr. Loomba. Obviously, we're still really early in the first step for our launch, but you know, a lot of investors are wondering, you know, how has enrollment been affected since the first approval? And now that, you know, Sagimet is gonna be embarking on a phase 3 study, like, just kind of put into perspective, you know, what is the appetite now, for enrolling patients into it? Would appreciate your color on both topics. Okay. I think we'll start with George on this one, and then Dr. Loomba, if you could just complete the thought. Sure. Yeah, so let me start with the phase 3 design. I mean, I think it's obvious we had a lot of GLP-1 use in our phase 2b. That will continue and probably be an even greater proportion of the patients in the phase 3. Of course, that will be an important group to be looking at. As far as Rezdiffra, we are not planning at this point, certainly not in the first, you know, 52-week portion of the trial to be including that. But obviously, given the strength of our preclinical data, it's something that we're very interested in. And I'd say our future plans on exactly how to address that, we're not ready to bring forward yet, but something that I think as you can see from our data and, and our interest in it, is something that's very, very intriguing to us. And George, just- Thank you. Yeah. I'm sorry, just one more question. Go ahead. Will you get more F3s... Will you try to get more F3s in the study, given in your Phase 3 than F2s, rather than a mix of both? Sorry, Rohit, for cutting you off. Sorry. I forgot about that part. Yeah, look, we'll have both F2 and F3s in our study. Will it be slightly more F3s than you saw in the phase IIb study? Certainly an opportunity, a target that we're looking very seriously into. Can't give you numbers today. We're not quite that far into the tactical planning, but certainly has caught our attention as well. Got it. And then for Dr. Loomba, Go ahead. his thoughts on enrollment. And yeah, David, yeah. Yeah, sure. I think this is going to be a, you know, moving target as we see with adoption of, you know, Rezdiffra into clinical practice. Given that the Phase III landscape is really broad and Phase III are likely to be international trials in multiple countries, I think that impact will have to be monitored and also be assessed in the setting of a trial. You know, statistically, we would be, you know, looking at various approaches and not talking, you know, in particular about, you know, what will be done in this program. But just generally speaking, as a clinical trialist, you know, we'll have approaches that could be done at the back end, but also could be upfront, listed if those who will be exposed to any treatment we think could be effective, whether it's Rezdiffra, whether it's GLP-1 analog, we can control for that. We can also see that over long term, say, you're looking at long-term clinical outcomes over four or five years, patients may be exposed to any of these drugs that may have potential benefits. And so we could account for the dropouts related to that, still account for them in the overall study population for safety and co-administration, but not count them for the, you know, long-term outcomes. We also may include the event rate in the placebo, if that may change. So I think it will have some impact on sample size estimate, but I do agree that for subpart H portion of it, it shouldn't have a major implication for phase 3 trials that are currently in making in the next, you know, 2 or 3 years. Once we have more than, you know, 2 therapies approved for treatment with NASH stage 2 or 3, I think things may change at that time. But I think for now, for subpart H approval endpoint, which is typically at 1 year, for either NASH resolution or fibrosis improvement, I don't see that to be an issue. If a drug gets a full approval, not a conditional approval, then having placebo would be an issue. But currently, because the drugs have conditional approval, as it looks like, I think the issue about keeping people on placebo for one year is not a problem. Thank you so much, Dr. Loomba. Thank you. Our next question comes from Andrea Tan with Goldman Sachs. Please proceed with your question. Hi, this is Tolani Usman on for Andrea. Thanks for taking our questions. First, for Dr. Loomba, how do you envision using denifanstat, if approved, in your treatment paradigm, given Rezdiffra and other liver-directed agents and GLP-1s? And then is there a particular patient subtype that you would preferentially use denifanstat in? And then a second for David and the team after. Yeah, I think the most important issue would be, you know, replicating the efficacy data in the setting of a phase 3 trial. And, you know, typically what we will be doing is, you know, doing a network-based assessment where we have a placebo and a network. And based upon that, we can look at relative efficacy of each of these drugs compared to placebo, and then we could potentially even do rank order assessments. But that would be, you know, once we have the phase 3 data. Looking at where things are currently, I think the denifanstat looks, you know, really not only positive for fibrosis improvement, but also for NASH resolution, that too, in the setting of a phase 2b, with both results statistically and clinically significant. I think the utility would definitely be there. I think by the time denifanstat comes along, it's also possible that there may be a appetite for combining drugs that are oral. So I think there's potential synergism there as well. So I do think that the use would be pretty easy for any oral therapy in the setting of NASH stage 2 or 3. And then, you know, I think future would depend also on safety and efficacy in the setting of stage 4 fibrosis. And because in that particular setting in cirrhosis, if you don't lose weight and actually remain weight stable, and if you can maintain that potentially could be beneficial in those who have cirrhosis by avoiding sarcopenia. So I think there are potential benefits that you can see with oral therapies, particularly denifanstat. And then the issue that we previously talked about, based on Tom's question on side effects, I think no GI sort of AE profile, I think is beneficial, again, either as monotherapy, but also as potentially, you know, combination you know approaches, as well as we go into more advanced diseases. Thank you. Thank you, Dr. Loomba. Sorry, one more from there. Can you... Sorry. For the combination study in the phase 3, would you need to use the orals in combination, or can you just elaborate on that a little bit more? Well, I think that may happen in the setting of phase 4, where, you know, clinicians would start looking at combination approaches. For example, even now, if you see, you know, we have data on baseline GLP-1 use on top of it, can you use, you know, denifanstat, and you're seeing, you know, positive data for MASH resolution at 42%, and also for fibrosis improvement. I think something similar may happen, where in the phase 3, we may have some patients who are taking resmetirom. On top of it, you add, you know, denifanstat or whichever drug you are studying, and you actually may develop that data. We did something very similar with vitamin E in the past, with obeticholic acid. So I think one is able to assess whether there is any benefit of combining two drugs that may just happen in a real-world setting, even in the setting of phase 3 trial, because those sample sizes are large, particularly on the outcome side, and you may be able to see benefits. Then based upon that, we can, you know, utilize the combo approach. Thank you so much. Then just one more, if I may, for Dave and the team. Could you provide a little bit more color around what financing options you're considering to bolster the balance sheet? Yeah, sure. I'll go ahead and take that one. Yeah, we're considering everything on the table, surely at this point. We need to—I think everyone knows the cost to run these studies. We have a little bit less than $200 million, and we have a gap to fill, and there are certainly dilutive and non-dilutive vehicles at our disposal. And I think we've been very fortunate with our data to not suffer for attention. So we're considering those options and the elasticity involved between, for instance, looking at a potential relationship with a strategic that involves territory rights, and how much territory rights to give up in exchange for cash to bring in to help support the phase three study. In addition to that, we're obviously considering other vehicles that will allow us to reach the conclusion of the phase 3 study to, at minimum, data readout, while also allowing us to pursue the other programs that we have a high interest in evaluating. And specifically, that includes acne, where we have, as I mentioned upfront, near-term milestones that will allow us to, I think, categorize that opportunity more clearly. And we anticipate that the phase 3 readout from the Ascletis is going to be quite positive, and we expect to see that inflection point at the end of this year, beginning of next, and that should have a nice carryover effect for us as well. There are a number of things we'd like to move forward with this molecule, and we have the means to be able to do that. Great. Thank you. Our next question comes from Jon Wolleben with Citizens JMP. Please proceed with your question. Hey, thanks for taking the question. Just one for Dr. Loomba. You mentioned that you wouldn't use any NASH drug that didn't show a fibrosis benefit in phase 3, but with multiple drugs showing benefit in phase 2, wondering, you know, how do you, and how should we think about fibrosis benefit and, you know, the decision matrix on which drugs to use, in the real world? Is it just the one-stage improvement? Do you care about the deeper two-stage improvement or lack of progression if someone has a 20% improvement but 20% progression? You know, how do you factor in these different metrics when you're thinking about fibrosis in the real wor ld? And what are important for your decision matrix? Thanks. Yeah, thank you, John. I think it's really important, you know, to look at data from not only just phase 2b, but also in phase 3, because we have much larger number of patients. We're able to see the safety, efficacy, and nuances related to the medications. And also validation on the fibrosis response is important. And so we think we, as a field would, you know, come together and, you know, probably say something about this, where, at least at UCSD, we wouldn't be, you know, recommending a treatment that's not gone through, a, you know, FDA approval process for treatment of, you know, NASH-related fibrosis. However, if you have patients who have earlier disease, I think you could certainly use and manage their comorbidities, based upon existing FDA approval and other indications. I think documentation, and, where at least two trials are positive is important because, you know, it, as it's a clinical trial, a trial could be positive or negative, and I think validating that consistently and showing that data and safety in a broader population is important. And also, geographic diversity is important as we show in these trials with, you know, Phase 3 trials typically are looking at, you know, somewhere between, you know, 500-900 patients for the subpart H. And that really, you know, gives you, a resounding data that the drug is efficacious for improving histology. And then you're looking for long-term clinical outcomes. That's also important. So I think the field is gonna come together in terms of, you know, which drugs will be used for fibrosis improvement and which drugs will be used for treatment of obesity or type 2 diabetes. That's helpful. And then, maybe just one last question for the team: Any differential response on diabetes status? George, you want to take that one? Yeah, John, good question. We'll see more of those data, types of data as we get to AASLD. All those, various subgroups and patients at higher risk, yet to be disclosed, still working on the finals, but you'll see that, later this year. Got it. Thanks again, guys. Our next question comes from Ed Arce with H.C. Wainwright. Please proceed with your question. Hi, everyone. It's Thomas Yip asking a couple questions for Ed. Thank you for taking my questions. First question, given the Phase 2b response we've seen with denifanstat, including fibrosis improvement, do you believe there's a chance that efficacy could get stronger over time, especially considering the recent 96-week data that we've seen from Akero? Yeah, I'll maybe I'll start, Rohit, and then you can take over. I think we're all really encouraged by the fact that the placebo-adjusted differential on fibrosis increased from 24 to 96 weeks with Akero's molecule. And we'd like to believe that we would see something similar to that given another year of therapy on denifanstat. And that would certainly be our expectation, but I'll leave it to the experts to convey their thoughts. Dr. Loomba and George? Thank you, Dave. Yeah, I think this is really fascinating to see, I think a continued improvement and actually, further consolidation. And I do agree that long-term treatment should lead to further improvements, for therapies that are efficacious. And we see that non-invasively, I think, in terms of 2-year and 3-year responsive, responses, improve with, say, liver stiffness and other, parameters. And if we were to then repeat the biopsy, I think you would see those improvements. So I do believe that, over 2 to 3 years, you would have even greater response rate than what you see in 1 year. Great. Thank you for- Yeah, nothing, nothing more from me. Yep. Okay. Great. Thank you. And perhaps one more question from us. Regarding the primary endpoint in the Phase 2b study of 2-point improvement in NASH without worsening of fibrosis. Can you explain what are some factors that you could attribute to the 14% difference for the denifanstat treatment group that we're seeing, 50% from the original analysis with the biopsy group, and then 38% with this latest data set that was announced in the total ITT population? Again, Rohit and George, I'll let you tackle this one. I didn't understand the question. Perhaps I could clarify. So, from the original data set that was announced a few months ago, with the MITT population, that was back in January. With that endpoint, we did not 2-point improvement without worsening of fibrosis. That was 52%. I believe MITT was defined as patients who completed biopsies. And then with this EASL data set, with all patients, so ITT population, it was 38%. So just wondering what some factors that you believe could attribute to the difference? Maybe I'll defer to George on that. That's not a question for me. Yeah. Yeah, thanks, Rohit. Yeah, Ed, I think I get what you're asking is: Why is the ITT differential lower than the MITT? It's a very simple explanation. In the ITT, it's every patient who took a dose at the beginning of the study. So if someone dropped out of the study, we had to do something, or they didn't have an end of biopsy study, we had to attribute a value to them, and that value was no response. It's a very traditional, and it's also a very conservative way of looking at it. But what that does is it simply depresses the rates that you see in both placebo and active populations. So it's natural that the differentials are a little lower. But again, as we move into phase 3, as we put our mitigation plans into place, we're expecting our primaries to look more like the MITT for the phase 2b than the phase 3. It's a very natural, sort of evolution in most drug programs. Got it. Thank you again for taking our questions, and we look forward to advancing into phase 3. Thanks, Ed. We have reached the end of the question and answer session. I'd now like to turn the call back over to Dave Happel for closing comments. Okay. Thank you, everybody. I know it's, we're just a little bit past the hour. I appreciate your participation in the call today and your ongoing support. We look forward to connecting with you soon. We're obviously quite excited about our molecule and continuing to take it forward and thrilled with the data, frankly, that we were able to present last week, that Dr. Loomba presented and where we're headed. So, appreciate your time and have a great rest of your day. This concludes today's conference. You may disconnect your lines at this time, and we thank you for your participation.