Good afternoon, and welcome to the Sagimet Biosciences KOL event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the Sagimet website following the conclusion of the event. Before we begin, please note that this presentation, including all verbal remarks, contain forward-looking statements, the accuracy of which depends on future events outside the company's control, and therefore might cause actual results to differ materially from those forward-looking statements. In the case of any questions or discrepancies, we defer to the company's public documents available from its website and filed with the SEC. I'd now like to turn the call over to Dave Happel, Chief Executive Officer of Sagimet Biosciences. Please go ahead, Dave. Thank you, Tara. Good morning. Good afternoon, everybody. Welcome to our presentation today. We're very excited to share with you an update on our MASH data with denifanstat, and we are extremely pleased to have Dr. Scott Friedman presenting his thoughts on denifanstat as we head into an important part of the calendar with EASL just right around the corner. Joining me on the call today are Dr. George Kemble, the company's Executive Chair and acting Chief Scientific Officer, Dr. Eduardo Martins, our Chief Medical Officer, and as I mentioned, Dr. Scott Friedman. Dr. Friedman is the Dean for Therapeutic Discovery and Chief of Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai. He has performed pioneering, pioneering research into the underlying causes of scarring or fibrosis associated with chronic liver disease, affecting millions of patients worldwide. Dr. Friedman was among the first to isolate the... and characterize the hepatic stellate cell, the key cell type responsible for scar production in the liver. His work has spawned an entire field that is now realizing its translational and therapeutic potential, with new antifibrotic therapies for liver disease, reaching clinical trials such as denifanstat. Next slide, please. So to begin the presentation, just a brief overview. Our approach starts with understanding how overactivity of fatty acid synthase, or FASN, plays such a critical role in the development of a number of underserved disease states, including our primary focus in MASH, but also, interestingly, in acne, in oncology, and potentially other disease states as well. To solve for this overactivity of FASN, we have developed a portfolio of novel FASN inhibitors, led by our lead program, denifanstat, which seek to target an underlying cause of the disease or a primary culprit in the development of the disease. That primary culprit is fat accumulation or de novo lipogenesis. By doing so, denifanstat presents a very differentiated mechanism to target MASH and bringing forward a program that really targets the key drivers, the three key drivers of the disease: fat, inflammation, and fibrosis. While we have some provocative data that we hope to share with you at some point in both acne and oncology, our primary focus today is going to be on MASH, where we have accumulated a significant body of preclinical and clinical data, including two clinical readouts. All of our data has shown exactly the same thing that denifanstat consistently and successfully reduces fat, inflammation, and fibrosis. It is arguably the only molecule in the space that does exactly that. It doesn't rely on just simply burning or oxidizing fat to translate into a downstream benefit in inflammation and fibrosis. We have now exposed over 700 patients to denifanstat across multiple disease states. It has proven to be generally well-tolerated and safe, and therefore, we do not see any limitations to the treatment populations that we're pursuing development. With an eye towards commercialization and the payer landscape, we're also unique, or this molecule is also highly differentiated in the fact that we are developing predictive biomarkers, such as tripalmitin, which is a nasty saturated triglyceride, that denifanstat significantly reduces, early in the treatment period, and historically has correlated to treatment response. I mentioned that we have interesting data in acne, and in oncology. and I just want to refer quickly, as we'll get to on the next slide, please, that our partner in China, Ascletis, has completed a very successful phase 2 study in acne with denifanstat in 180 patients, and demonstrated a very significant reduction in lesion count. Based on the strength of this data, they embarked on a phase 3 study at the end of last year, and they expect to see top-line results at the end of this year, beginning of next. We ourselves have a lead backup FASN inhibitor that we plan to take forward in acne, also based on the strength of Ascletis' results, and we hope to get that program started this year. Ascletis has also successfully completed a phase 3 glioblastoma study, and we expect to see interim results in that study in the second half of this year. This follows a successful phase 2 study in which we saw a nice signal in progression-free survival with denifanstat in combination with bevacizumab. Next slide, please. All eyes right now, however, are on MASH, and for obvious reasons, the population is quite large. It still is a significant unmet need, and what we are bringing to the table is an oral small molecule that has successfully demonstrated the ability to reduce fibrosis in this population. We expect denifanstat to be used in the F2 to early F4 staged MASH patients. We expect to have this program ready to seek approval in 2028. So with that, I think I will now invite Dr. Friedman to share his thoughts on denifanstat and our data. Thank you, Dave. I'm delighted to be here and share some of this very exciting data. I'm excited for many reasons, which will become clear in the subsequent slides. Can I have the next slide, please? Next. So, to review briefly the impact of denifanstat on the stages of MASH or metabolic dysfunction-associated steatohepatitis, I refer you to the diagram on the right-hand side. We believe that the disease really starts in hepatocytes, where cells are injured, damage signals are elicited, they provoke inflammation, and in turn, both the damage to hepatocytes, but also the inflammatory signals converge on the hepatic stellate cell, the liver's main fibrogenic cell, to drive them to produce fibrosis, which progresses to cirrhosis and, in many cases, hepatocellular carcinoma. All of these elements of the pathogenic sequence are attenuated by denifanstat, and I'm particularly excited, based on my own interest in its direct effect on fibrosis. So in summary, there are three independent mechanisms: blocking fat accumulation by inhibiting de novo lipogenesis and hepatocytes, reducing inflammation, and blunting fibrosis by inhibiting stellate cell activation, both directly by effectively depriving the cells of the energy required to activate, but also through its collateral beneficial impact on attenuating inflammation. Next slide, please. So just to dig deep, a little deeper, in a study that we performed in collaboration with the company several years ago and published, as you see in the lower left-hand corner, we show that there's direct anti-fibrotic activity of the drug in isolated hepatic stellate cells from humans. We compared the capacity of this drug to inhibit collagen production by ELISA in comparison to the most potent inhibitor we have available, which is an ALK5 inhibitor, which is not suitable for human use, but provides a very effective positive control. What's quite clear is if you look at the green bars, there's an inhibition of collagen secretion across all the concentrations you see from 30 nanomolars to 1,000 nanomolars. As an aside, the cells were pretreated with TGF-beta, which is a very potent fibrogenic stimulus, so they were maximally stimulated, and in the setting of that maximal stimulation, you see very significant inhibition of collagen production, which is, of course, the signature hallmark of fibrogenic disease. Next slide, please. This is the simplified description or study design for the phase 2b trial. It was enrolled initially 168 patients with biopsy-confirmed F2 or F3 MASH. Patients or controls were treated for 52 weeks, where the drug was distributed in a 2-to-1 fashion with placebo in a double-blind fashion. Biomarkers were obtained at onset, along with biopsy, and then an interim biomarker fat assessment using MRI PDFF, and then the same endpoints with an end of study biopsy at 52 weeks. The primary endpoints you see listed here was a NAFLD, what is, I guess, now MAFLD, activity score greater than 2 points improvement without worsening of fibrosis, or MASH resolution, including a MAFLD activity score of 2 or greater without worsening of fibrosis. There were additional endpoints that you see enumerated below, an improvement in liver fibrosis of greater than 1 stage without worsening of MASH, and which is one of the more conventional endpoints we see a lot. Digital AI pathology, which I'll show you, and then, a decrease in fat as assessed by MRI PDFF, with, both measured as an absolute decrease, as well as a percent change from baseline, with a percent of patients of greater than 30%, greater than or equal to a 30% reduction from baseline among responders. Next slide, please... So, these are the biopsy results that address the primary endpoints. As you can see, there were both endpoints hit by the drug or reached by the drug, with 52% responding with a NAFLD activity score of greater than 2-point improvement without worsening, as well as 36% demonstrating MASH resolution in those with a NAFLD activity score of greater than 2 without worsening of fibrosis. You'll note, by the way, that the totals of patients don't add up exactly to 168 because of dropouts. Intention-to-treat analysis is to be presented by Dr. Rohit Loomba at the upcoming EASL meeting in Milan. Next slide, please. The fibrosis endpoints were significantly improved, and in particular, an improvement in liver fibrosis by greater than or equal to one stage without worsening of MASH at 41%, as well as a resolution of MASH without worsening of fibrosis at 38%, and these were highly significant effects of the drug, in treated patients. Again, fibrosis, as Dave alluded to, fibrosis is the sole endpoint currently on biopsy that correlates with improvement in clinical outcomes. So this is a very significant finding, apart from being statistically significant. Next slide, please. As I mentioned, digital analysis was performed to better quantify the changes in fibrosis. I'll say either this or other methods of digital analysis to obtain an absolutely quantitative measure of fibrosis, both at onset and following the therapy, instead of using what I call, you know, an earlier stage or earlier iteration of scoring with F1, F2, F3. Much more accurately, but also to assess modest but important method, which is second harmonic generation from a company, HistoIndex. There was, as you can see, both quantitatively and qualitatively, a significant impact on fibrosis, as shown in the treated patients in the left-hand green bar. And more dramatically, perhaps, the photomicrographs on the right show a single patient before and after treatment, where the green demonstrates thick bands of collagen or septa that are developing. It's quite clear that, after 52 weeks of therapy, there's a significant diminution in the green staining representing the fibrosis. Quite an exciting result. Next slide, please. An obvious question now, for all trials is: What is the impact of the current weight loss therapies, most notably GLP-1 receptor agonists, on the efficacy and importance of effects on MASH by different agents? Here the drug shows a very favorable benefit, even in patients who are on stable GLP-1, comparing a placebo, of course, in a smaller number of patients on the overall trial, but nonetheless, a striking, albeit not yet significant, because of the small numbers, an effect on resolution of MASH without worsening of fibrosis. Even at this small number of patients, however, the impact on fibrosis in patients who are already on GLP-1 receptor agonist was statistically significant. 42% of the 12 patients who were already taking GLP-1s had an additional benefit. So this speaks well to the prospect of combination therapies, and as many of you will know, there's no evidence yet that GLP-1 receptor agonists have any direct effect on fibrosis at all. In fact, I would extend that comment to say, to my knowledge, none of the current drugs that are in phase 2 or 3 have any direct antifibrotic benefit. And unlike denifanstat, which, as I've shown you, has direct antifibrotic activity towards the fibrogenic cells in liver. So that's an exciting differentiator. Next slide, please. This is the list of AEs. Let me just make a couple of summary comments, and George, I'm sure, will be happy to jump in as questions arise. The denifanstat was generally well-tolerated, and all treatment-related AEs were grades 1 or 2, mild or moderate. All grade 3 or higher treatment-emergent AEs were unrelated to the study drug. There were more treatment-related AEs and treatment-related AEs, leading to discontinuation observed with denifanstat than with placebo, and the most common treatment-related disorders listed in the table. And in particular, as in previous studies, there were no treatment-related or treatment-emergent serious adverse events and no deaths. So in short, the safety profile supports the further development of denifanstat in patients with MASH. Significant AEs can be discussed more in the question and answer, but the prominent ones were either eye symptoms or hair thinning. The hair thinning occurred with a 10% incidence, leading to 6% discontinuation rate, which, interestingly enough, is comparable to the, the rate seen in, the recent tirzepatide trial of 7% in their phase 3 trial published in Nature Medicine. So we'll be happy to discuss that a little bit more if, if need be. Next slide, please. As you know, fat is one of the hallmarks of, both MASLD and MASH, and, owing to its ability to block de novo lipogenesis, there was a significant impact on MRI PDFF, the most quantitative measure of fat in, patients with 65% showing a greater than or equal to 30% relative reduction in fat, at least 60 to 52. This corresponded to a very nice effect on the FAST non-invasive score, which is basically a score combining the liver stiffness using FibroScan with the serum AST as a marker of both fibrosis but also inflammation. And here you can see that there was a significant effect already observable at the halfway point at 22 weeks, but a more significant impact on the FAST score at 52 weeks, and you see the numbers down below. Next slide, please. As a marker of liver damage or injury, we usually look to AST and ALT, which are considered serum biochemistries. Again, robust evidence of a decrease in injury associated with reduced change or reduced ALT and AST, both at 26 weeks and at 52 weeks. I won't read the numbers, but this is reassuring and also reinforces the so-called hepatoprotective effect by reducing damage to hepatocytes through the administration of denifanstat. Next slide, please. Another consideration, because MASH is part of the metabolic syndrome associated with significant cardiovascular risk, is whether this or any drug has a beneficial impact on these other cardiovascular risk markers. Here you can see a significant impact by decreasing LDL cholesterol both at 26 and especially at 52 weeks, with a known on-target effect of increasing triglycerides. But important to note that that increase is both expected as a result of fatty acid synthase inhibition, but more importantly, is driven by an increase in a protective kind of fatty acid, the polyunsaturated fatty acids. So there may be some additional carry-on benefit, not only on LDL cholesterol, but by changing the composition of triglycerides to those that are more hepatoprotective and healthy. Next slide, please. Here's a head-to-head comparison between denifanstat and the leading contenders. You can see the data on the far left, at a 52-week endpoint, showing a 41% improvement in fibrosis greater than one stage without worsening in MASH. Again, that's a standard endpoint. This measures up almost identically, the 24-week endpoint with the FGF 21 drug from Akero in the same study group. And at 96 weeks, Akero has a 75% response rate. But obviously a different route of administration and a different AE profile. The others I won't go through in any detail, except to emphasize that Madrigal, the only approved drug for MASH at present, has a 26%, at the high dose, a 26% likelihood of improvement in fibrosis by one stage. One of the challenges we're all grappling with is, how do we increase that number from 26 to many or most patients with MASH? And will that come about through combination or through different agents? At least here, the data with and the unique mechanism of action of denifanstat would suggest that it might be ideal for combining with existing or impending drug approvals for MASH. And I'm referring here particularly to resmetirom. Next slide, please. So just to sort of review in a simplistic fashion, what we're seeking with this and every drug, in fact, in the NASH or MASH space. And first of all, we stratify risk, as you probably know, based both on fat, inflammation, but especially fibrosis. And of course, the likelihood of fibrosis and liver-related or cardiovascular events is greatest in the two highest fibrosis stages, F3 and F4. From a treatment perspective, where you have multiple targets and diseases we're treating at once in metabolic syndrome, which is of course, one of the challenges of this disease. Wherein we're trying to improve glucose homeostasis, lipid control, reduce weight. What that translates into in the liver is either resolving steatohepatitis at early and intermediate stages, preventing fibrosis progression or inducing regression at more advanced stages, F2 and F3, and ultimately, either preventing progression to cirrhosis or preventing decompensation. We will have to wait and see whether drugs that are effective in F2 and F3 are equally effective in F4. From a mechanistic perspective, there's reason to think that not all drugs that work in intermediate stages are gonna work in cirrhotic patients. Of course, in some respects, the cirrhotic patients represent the highest unmet need because they're the closest to developing decompensation, and I might add, the risk of hepatocellular carcinoma. I'd also interject that in our published study that I referred to earlier, we saw a significant benefit in reducing hepatocellular carcinoma in our MASH model with denifanstat. And the mechanism remains to be sorted out. We don't know whether that's directly as a result of blocking fibrogenesis that predisposes the cancer and/or also reducing the substrate, of, availability for cancer cells to grow, which depend on fatty acids. So, there's reason to think that the drug at least has a rationale for not only attenuating fibrosis, but also potentially reducing the emergence of cancer, and possibly even, amplifying the treatment effect from existing drugs for HCC, but that remains to be established in clinical trials. And so you can see here on the third bar, the third row, is the approach currently is metabolic and obesity drugs when fibrosis isn't yet a significant problem as it is once patients reach F2 and F3. And here, we're really in the very earliest days of thinking about combining metabolic and antifibrotic drugs. And as I mentioned, as we move more towards very advanced liver disease, F3 and particularly F4, we really need to get rid of scar. Blocking its production alone may not be enough. So, again, antifibrosis that needs to be established as effective in this stage, but there's reason to think it may be. Next slide, please. At this point, I'll just refer to some upcoming presentations planned at EASL in Milan, I guess, about two or three weeks from now. Next slide, please. I will just list these so you can capture the gist of the studies. What they mostly address through one oral and two poster presentations is the prospect for combined efficacy by adding the thyroid hormone beta agonist resmetirom to improve markers of MASH and cardiovascular health in mouse models, and that's both the poster presentation in the middle, as well as the late breaker poster presentation shown below. In addition, I alluded to the study that Rohit Loomba will be presenting as an oral in the plenary session, looking at additional data from the human trial I've described to you in detail, specifically with intention to treat data. I'll take a moment to also acknowledge what most of you hope already may know, which is the untimely death of the senior author, Stephen Harrison, who was an extraordinary person, a great investigator, and therefore, his death represents a tremendous loss to the field that in some ways is irreplaceable, and I want to acknowledge Steve now and forever. Next slide, please. So this is just a little bit more depth on what I've described in the posters, so I won't go into it in much detail. The two posters described include data in animal models that suggest that combination with thyroid hormone beta agonist resmetirom has or these data have established a rationale for combining these, and that certainly makes some sense from a mechanistic perspective, because whereas FAS inhibitor blocks liver fat synthesis, resmetirom increases liver fat breakdown. So combining the two has the prospect of further attenuating fat accumulation in hepatocytes. And of course, let's not forget the direct inhibitory effect on fibrosis by hepatic stellate cells. Next slide. So at this point, I'll turn the stage back over to George, and he'll follow up with some details about the MASH development program. George? Great. Thank you very much, Scott, for that overview of our data and the program. So with that, if we go to the next slide, let me just give you a little framework for where we've been, where we are going. So this is really just sort of a roadmap through the program, starting our Phase 2b that Scott just described in September of 2022, and then our top line results in January 2024, which you just saw, and I think we're all very excited about. What we're doing now is we're obviously in communication with the agency to start to design and put in place our Phase 3 program. And I think importantly, you need to take away a couple of very important concepts from the work that we're doing. Number one, the patient population in our phase 2a and phase 3 programs are going to be virtually the same, which is the F2, F3 patients, those who we believe certainly for first indication, are at utmost need of oral drugs for therapy. Secondly, we showed you in the data just now, Scott showed you in the data just now that using the draft guidance, where the FDA has outlined endpoints to use in phase 3 studies for MASH, we hit positively on both of those. That is one stage improvement of fibrosis without worsening of MASH, or MASH resolution without worsening of fibrosis. So we're really excited. We've got the right population, we've got the right endpoints. We've already established that we have utility and effect in those endpoints in this population. So we're very excited to get this study up and running, certainly planned by the end of this year. Next slide. And then one other thing that we think differentiates us from many of the other programs out there, is that we are looking for ways to help a physician and a patient, and ultimately a payer, understand very early on in the course of treatment that the drug is doing something. So we've shown before in our phase 2a study, we'll be showing more of these data very shortly, that there's a, as Dave alluded to, a saturated triglyceride in the bloodstream called tripalmitin. It reflects our drug's ability to inhibit FASN and reduce that triglyceride. So we can take, in theory, the blood out of a patient a month or two after being treated, look at their tripalmitin levels, and then predict that they're going to go on to have a good clinical response. And so, so that's something that we're extending and working on right now so that we can provide the physician, the patient, the payer, a framework to really understand very early on in the course of therapy, the drug is doing what it should be doing. We've also talked about using a predictive marker. This is something that is a little more complex, something that we're continuing to work on. But as we showed in our phase IIa study, we have some evidence of some rather complex markers in the blood at baseline before you treat that could potentially predict response. Now, neither of these is gonna be a gate for including a patient in this study, but certainly, we'll be looking to see how they perform once the patient is enrolled. Next slide, please. And then what else is adjacent to the F2, F3 development program? Scott already alluded to potentially getting into compensated cirrhotic patients, those who are at the F4 stage of fibrosis. As we pointed out, we know the drug hits the stellate cells. We know these patients tend to still have functional hepatocytes. And so we have completed, and we've released this already, that we did a phase I study to show that the drug could be used in patients with hepatic impairment. And so the next stage really is to come up and show the plans for a mid to late stage clinical trial in F4 patients. And then pediatric MASH. This is like many elements of MASH, an increasing population. There's about a quarter of the kids who have fatty liver disease already have MASH at the time diagnosis. So it really is a silent disease, and it's something that's getting out of control. Many of our advisors have, based on our tolerability profile, we don't see a limitation in this group, are very excited about us understanding if we have an impact here. And so, right now, we're obviously compiling a large safety database across all our studies. We've got some non-clinical tox studies to do in juvenile animals. We plan to initiate those this year, and then the results of that could put us into a phase II study in kids sometime thereafter. So again, we think because of our good tolerability profile, because really the lack of limitations of where the populations our drug could work in, something that we're very excited about pursuing. These kids really have very few, and I'd say virtually zero options at this point in time for drug therapy. So something that we're very excited about. Next slide, please. So just to sum it up, I want to go back to the mechanism of action of denifanstat. As Scott alluded to, as we've said, it directly targets three key drivers. In the hepatocyte, it blocks the steatosis or the buildup and synthesis of fat. In the immune cells, it blocks inflammatory pathways. In the stellate cells, importantly, that drug gets there and blocks the fibrotic machinery. So it's doing all three of these things simultaneously in the damaged liver. What we showed in this current FASCINATE-2 study is that this mechanism translates into a clinically meaningful and statistically significant improvement in fibrosis, including two-stage fibrosis improvement, and improvements in the F3s, which you'll see more at EASL in the next couple of weeks, and then, of course, MASH resolution. So again, generally well-tolerated. The AE profile is balanced between the active and placebo groups, excluding some skin and sub-Q adverse events, all of which were grade one or two, well managed and reversible. The preliminary results support further evaluation of denifanstat as a fat synthesis inhibitor in combination with the other drugs out there, which tend to be fat burners, fat mobilizers, GLP-1s, thyroid hormone, beta agonists. We've got tripalmitin moving forward as a potential early target engagement marker, again, giving us that tool to get the physician and patient and payer aligned early on in therapy. And all of these support the progression of denifanstat to phase III trials in MASH, which, again, we would like to get started by the end of this year. And then on the final slide, please, next slide. As Scott pointed out, I, I want to give my thanks and memory to Dr. Stephen Harrison, friend, colleague, leader. He was absolutely critical for many of the data that you just saw. The field has relied on his expertise and guidance for a number of things, and his abrupt and unexpected passing several weeks ago has hit us all quite a bit. He will be greatly missed, and we honor him with continuing to develop treatments for patients with MASH. And with that, I will hand it back to Dave, who will help us move through the question and answers. Thanks, George, and thanks, Scott. We greatly appreciate your thoughts as you work through this. Tara, maybe move to, maybe the beginning slide. So we're gonna open it up for questions here, and I have a number to go through, most of which, Scott, are directed to you. The first one I'll throw to you is: How long do stellate cells last? Is there a lag period between stellate cell activation and potential fibrosis effect, and any other mechanism in clinical development to inhibit stellate cell activation, to your awareness? Yeah, I'm pleased that the depth of that question. So, we're still studying the half-life of stellate cells. I think the key issue is that they not only make more scar during injury when they're activated, but they also proliferate. So it's not as though the liver is dependent on a fixed number, but rather there's a dramatic amplification of the total number, in addition to each cell making more scar. Just a couple of other points that may or may not address your question, and you may have to repeat the other part, Dave, is that what we're learning using single-cell methodologies is that there are many different subtypes of stellate cells, much as there are for us... most other cells, and there are probably different subsets that serve different functions, some of which are fibrogenic, some of which are more metabolic. But, it looks like that they're all, as far as we know, they're all dependent on, to, to a large extent, on fatty acids for fuel. So we would anticipate that all would be attenuated by FASN inhibition through denifanstat. And Dave, I think I missed one of the other parts of the question. Yeah, the last question is, any other mechanism in clinical development? Right. that you're aware of that targets? Yeah. I would say the most direct antifibrotic mechanism or that's, you know, reasonably mature, is the approach of inhibiting integrins. Integrins are cell surface receptors that at least in some cases are responsible or contribute to the activation of latent TGF-beta, which is the major TGF-beta, the major fibrogenic cytokine in liver. And so there are at least three that I'm aware of, three companies looking at integrin antagonism, using either small molecules or antibodies to specifically block TGF-beta activation. It's important in that setting to avoid systemic TGF-beta activation, but rather direct it only to the stellate cell and the immediate fibrogenic milieu. Scott, another one for you. Any overlap in denifanstat's antifibrotic mechanism with FGF21, to your knowledge? Well, to my knowledge, there's no direct antifibrotic effect of FGF21. We had looked at it with a drug that is no longer in development and didn't see any. And so, yes, there's a difference in that. To my knowledge, there's no direct antifibrotic activity towards stellate cells. The presumed mechanism of action for FGF21 is primarily through its beneficial impact on metabolic homeostasis and dysregulation and hepatocellular injury. Okay, another one for you, Scott. How do you expect GLP-1 mono and dual agonists will be used in MASH going forward? And how do you expect denifanstat to fit into the treatment paradigm in patients with advanced fibrosis F2, F3 patients? Yeah, so this is really the 800-pound gorilla hovering over the field, is what will the impact of both GLP-1 specifically and weight loss drugs or combinations that are coming out more generally? First of all, we're very early days, and so there isn't a clear picture, except to say that the one study we have in phase 2 of semaglutide showed no benefit in fibrosis. I would say that was reinforced by the additional additive benefit of denifanstat in the animal data that I showed earlier in the presentation. I do believe that, you know, substantial weight loss is going to take a chunk out of the MASH market, but I don't think it's going to be universally effective. I think one of the things we're learning about MASH is that it may look the same in the microscope across different patients, but the way they get there may not be. And so, you know, there may be some patients who respond very well to weight loss. We can't identify who they are, but they may respond well, and not only in terms of weight loss, but in terms of the effect on liver, and there will be others who do not, and we won't be able, at present, to differentiate. That's sort of the goal of personalized medicine, is identifying subtypes of a disease that infer specific treatments that are effective for that subgroup. We're not there yet in MASH, however. How do you expect denifanstat to fit into the paradigm, for these patients going forward? Yeah, so I think there's really, you know, at least three different points of consideration. One is, as a primary therapy, particularly with respect to fibrosis, you have a 41% effect. I think so, given the tolerability and the safety and the fact that it's oral, you know, one could make a cogent argument for a primary therapy. Or alternatively, combining with resmetirom based on the preclinical data that looks extremely promising. And then, remember that at least for resmetirom, which is the only approved therapy, almost three-quarters of patients are not gonna respond with respect to fibrosis. So there will also be a sizable fraction of patients who've been treated ineffectively with resmetirom or Rezdiffra, who need an alternative therapy. I don't think we can predict whether failure to one class of drugs predicts efficacy or lack thereof for a second class of drugs. But it certainly makes sense that since the targets of resmetirom are very different from denifanstat, that one could envision offering that drug to patients who have failed Rezdiffra or potentially other metabolic drugs as they come online. So really, all sites, either primary therapy, combination therapy, or primary treatment failures, I think, are open for potential treatment. In the long run, if the data about HCC holds up, and I think that's a big if at this point, you know, that promises yet another indication as a protective. But doing the preventative cancer trials is very, very challenging, and so I wouldn't presume to suggest that that's a near-term goal for the drug. Is there a specific patient type or patient profile to whom you would prescribe denifanstat? You know, I think I pretty much answered that. We don't know. There you know, apart from the possibility that genetic polymorphisms like PNPLA3 may predict responsiveness, and I think the company is looking at that, but there's no definitive data yet. That would be the closest or the fastest way to get to a subgrouping of disease patients who are more likely to respond, but we don't have that information neither for denifanstat or any other emerging therapy as to who are the likely who can we predict the likely responders, and we can't. Not yet. We will, I believe, but we're not there yet. So short of a genetic predictor, how about how compelling do you think a precision biomarkers such as tripalmitin would be valuable in correlating treatment response with deni in a, in a- Well, I mean, that's a great and perhaps unique differentiator. There are, you know, I think all the companies are looking for target engagement markers, as well as predictors of response. And certainly, the compound for denifanstat looks promising, and I would say that could be yet another advantage of this agent. Do you feel that deni has the potential to work in cirrhotics, has the best potential to work in cirrhotics, given its mechanism? Yeah, that's- I've been thinking about that a lot. And there are certainly, without fat in the liver, that's one sort of arm of the efficacy that it may not be as important as in earlier stages where there's more fat. On the other hand, unlike other drugs, we know there's still a direct effect on stellate cells. So one could hope that there may be a disproportionate activity compared to other drugs in F4, because there's still an anti-stellate cell or anti-fibrotic activity. We've also shown in a paper in mouse and in human tissues last January, that the nature of signaling between stellate cells changes as the disease advances. Meaning that you go from signals coming from inflammatory cells and hepatocytes converging on stellate cells, to a state where most of the signaling is among stellate cells themselves in a so-called autocrine loop. What I can't say is how much, FASN contributes to that autocrine signaling. But to come back to my primary point, inhibition of fibrosis, by blocking fatty acid synthase is likely to be as important in advanced disease as it is in intermediate disease. George, sorry to make you feel lonely there. I'm just- No, I'm writing notes furiously, Scott. Well, you'll get, you'll get his opportunity here shortly. Okay, we'll ask you one last question, Dr. Friedman, here, and then I'll shift it over to George for a few others- Sure. and then we may come back to you, as questions come in. This one is: Are you concerned about the on-target side effects, dry skin, dry eye, and hair thinning? And in your opinion, are these manageable? Not only in my opinion, but based on the data, and I'll pivot to George, except to say that, no, I'm not concerned. You know, NASH is a life-threatening disease. The hair loss occurs in a small percentage of patients, is manageable, seems to be static, and worst case, hair thinning reverses when the drug is stopped. But I'll toss it to George to fill that out a little more. Yeah, and it's a great question. I mean, it's interesting. Before this study, we had looked at this dose in well over 100 patients, and less than 2% had any hair thinning. So there was something different in this study that we weren't expecting. But I think, look, as Scott said, mediating these effects, it's a similar magnitude as you see with tirzepatide will mediate, much like they do. And the other thing is, look, in the next study and going forward, the patients know the drug has the ability to improve their liver. That was not known in the phase 2b study. So I think all these things tell us the study kinetics itself will work better, and it is a reversible side effect. So it is manageable by reducing the dose where we see stabilization, putting a small dose holiday on. And I think all of those aim to the point that we've got the ability to control it, and it's already, at a level that's not a problem. So we'll take it from a not problem to no problem. Maybe, George, just to tag along to that, maybe you could discuss, maybe more generally, how you feel we can plan to reduce the incidence in the upcoming phase 3 study. Yeah. So there's a couple of things that we're doing. Obviously, we're working with some KOLs in the field who are giving us some good advice. One is, there certainly are some products out there that are being used, things like, Nutrafol, which are again, people who are on GLP drugs tend to use when they start to experience hair thinning. We can look at biotin levels in our patients, again, predictors. All of these things will go into helping us mitigate, manage, and potentially prevent the onset. And again, once experienced, we have the options of potentially down dosing, dose holidaying, to let the hair to, you know, relatively, in short period of time, either stabilize or reverse. And so I think all those are options at our fingertips and something that we'll be learning how to use more effectively as we get into the next study. So, George, here's another one for you. When do we plan to start a phase I trial in combination with the fat burner, fat mobilizers of the world, the THR-beta, the GLP-1? Yeah, that's a good question. I mean, we will, as pointed out, we will be presenting some preclinical data on the THR-beta work. We already presented preclinical data on GLP-1 combinations, along with the phase 2b data that you saw here. And so I think there's really a good strong evidence now that we will be able to combine with those drugs and potentially have an improved effect. As far as the actual timing of starting the phase 1, look, our sights are on getting the phase 3 up and running, so that's number one. The GLPs will be part of our patient profile in the phase 3 program, so that will be something that will not be a surprise, that we will certainly allow our patients in who are on GLP-1 therapy. As far as the THR- betas, that's a little bit different. I'd say the timing is still a bit unclear, but the rationale for it is very strong. You touched on the MASH population, the potential for pediatric MASH, a bit. Your thoughts on when you would ideally like to begin a trial and look at that population? Yeah. So we've got some, you know, groundwork to do first, and that's the juvenile animal tox studies. If we initiate those this year, that gets us dated sometime, you know, late 2025, and we would expect to then put a protocol in place where we could potentially jump beyond a phase 1 and maybe even into a mid-stage phase 2-type trial in pediatrics. There's a lot of work that needs to be done there, and of course, until we have the results of the tox studies, it's a little bit vague to try to put a timeline on the start of the clinical study because many things will depend on the results of those studies. But I think starting those juvenile tox studies this year is the, you know, next milestone to look for. Hey, George, another one for you. Were the patients in the phase 2b study on a specific diet as well, and did they stick to the diet? The short answer is no. They were not. There was no prescribed diet or compliance to it. They were allowed to eat what they normally ate. George, I'll let you take this one, too. Have you committed to an alternative FDA approval pathway similar to Madrigal, with a Subpart H approval, accelerated approval into F2, F3 population, and then an outcome study in F4 to support full approval in both groups? That's certainly the concepts. As we said, we're in communication with the agency. That's not finalized. But yes, I think you could look at Madrigal's program as a very strong blueprint, for the way that we're approaching ours as well. Okay, just looking through quickly for any more scientific questions. There are a couple of company-specific questions that I'll take. Why does the market value the company negative? How does it value the negative enterprise value with all the good news? Certainly, I think we would add to our confusion and being a bit perplexed as well in that regard. Certainly, a lot of the attention to date has been on different mechanisms. I think as George and Scott both alluded to, fat burning, fat mobilizing, fat oxidizing mechanisms of action, and certainly the narrative has clearly been focused in that arena. Our data and the fact that we are a completely different mechanism of action, being a fat synthesis inhibitor as opposed to a fat burner, has not gained quite the attention that we feel it should, and certainly that it will, as we continue to release data and demonstrate how exceptional this molecule is. So I think, and we're pretty confident that as we are able to unveil the full data set as we get towards EASL, and thereafter, get the data published in a high-end journal, I think will go a long ways to helping people understand more fully what this molecule can achieve, and I think what Scott and George have already referenced. So I think we'll start to hit some key milestones here near term that'll help that along. We've heard repeatedly, I will say in many of our investor discussions, that the market is not normally this inefficient when it comes to evaluating a molecule of this magnitude. So we anticipate that we'll start to rebound here relatively quickly, and as we prepare to move into phase 3, will certainly be another key milestone for this molecule. We'd also like to explore the use in other disease states as well. The data in acne is clearly provocative, and the ability to take a backup molecule into that space, where there hasn't really been an oral anti-acne med for close to 40 years, will certainly be well-received. And of course, our continued exploration in other disease states where FASN plays an outsized role, as it does in certain solid tumors and potentially other disease states as well. And I think that is our last question, and with that, I think we'll go ahead and wrap up the hour. I certainly want to thank Dr. Friedman for his time, and for all of the individuals that have called in to listen to our update. We thank you as well, and thank you for your support, and, we look forward to seeing you at EASL and continuing to update you on our progress. Thank you, and have a great day.