Greetings and welcome to the Sagimet Biosciences post-ESOL key opinion leader call. At this time, all participants are in a listen-only mode. A question-and-answer session will follow the formal presentations. As a reminder, this conference is being recorded. 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 and anticipated development milestones. These statements involve a number of risks and uncertainties, which are outlined in the press release for this event 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. I'd now like to turn the conference over to your host, Dave Happel. Thank you. You may begin.
Thank you, Tara. Good morning and afternoon, everyone. We are delighted to have you join us today to discuss our Denifanstat data and potential for combination use in severe MASH patients. For today's presentation, I will be providing a brief corporate overview of Sagimet, highlighting our Denifanstat development programs. Dr. Rohit Loomba, our esteemed scientific advisor, will then review the strong phase 2b data from our recent FASCINATE-2 trial of Denifanstat in MASH, particularly the exceptional data in severe MASH patients, and discuss the rationale for developing a combination therapy to potentially improve outcomes in this severe patient population. Lastly, Dr. Eduardo Martins, our Chief Medical Officer, will discuss our planned clinical development program for a Denifanstat and Resmetirom fixed-dose combination. We will then open up the call to your questions. Next slide, please. We are very honored and pleased to have with us Dr. Rohit Loomba, who is a board-certified gastroenterologist and tenured professor of medicine, Chief of the Division of Gastroenterology and Hepatology, and the founding director of the MASLD Research Center at the University of California, San Diego. He is an internationally recognized scientific thought leader in MASH and has published more than 500 papers in his field. Dr. Loomba served as the lead principal investigator of our phase IIb biopsy trial and is a scientific advisor to Sagimet for our ongoing development programs of Denifanstat and MASH. Next slide, please. Our pipeline is focused on FASN inhibition to leverage this unique mechanism of action across diverse and underserved disease states. Our lead asset, Denifanstat, is a once-daily oral small molecule and offers a highly differentiated approach to treating these diseases. Denifanstat works by inhibiting overactive fatty acid synthase, or FASN, which, if left unchecked, will lead to progressive disease and a number of underserved disease states, including our primary focus in MASH, but also in other disease states such as acne and certain solid tumors, where we have generated compelling clinical data. Denifanstat targets fat accumulation, or lipogenesis, a root cause that is common to the disease states and conditions we are advancing. Based on the strong clinical data from our FASCINATE-2 phase 2b biopsy study, particularly in advanced MASH, and the continuing need for differentiated therapeutic interventions for patients living with MASH, Denifanstat was granted breakthrough therapy designation by the FDA for the treatment of non-cirrhotic MASH with moderate to advanced liver fibrosis. The end of phase two interactions with the FDA have been successfully completed, supporting the advancement of Denifanstat into further development.
We recently announced that we plan to initiate a phase one PK study of a combination of denifanstat and resmetirom in the second half of 2025, with top-line data in the first half of next year. We are very excited about this development program, which builds upon the successful results of the phase IIb clinical trial, as well as on preclinical data demonstrating the synergistic effect of FASN inhibition combined with the THR-beta agonist resmetirom on important liver disease markers. We are also looking forward to two near-term phase III data readouts from our licensed partner, Ascletis, who owns rights to denifanstat in China. Ascletis initiated a phase III study in moderate to severe acne patients at the end of 2023, based on the strength of a positive 180-patient phase II study in which denifanstat significantly reduced lesion counts with a generally well-tolerated safety profile comparable to placebo. We expect to see a readout from this phase III study of 480 patients this quarter. FASN inhibition is a novel oral mechanism in the treatment of acne, and we believe it could offer significant benefits to patients and shareholders alike. The phase III glioblastoma study, in combination with bevacizumab, has completed enrollment and was initiated based on a strong progression-free survival signal seen in an earlier phase II study. Since the study is event-driven, we did not have and do not have certainty on the timing for when Ascletis will report the results. Next slide, please. All eyes are focused on MASH for us. We have previously talked about the sizable market MASH, which remains an underserved condition, particularly in more severe MASH patients. The MASH market is growing rapidly, with projections that it will approximately double in size in the next two decades and approach prevalence rates associated with other blockbuster cardiometabolic diseases. Our proposed combination program with Resmetirom will be aimed at the more severely ill and also more readily diagnosed population of F4 patients who have a more urgent need for treatment options. This is a large patient population expected to reach at least 3.5 million patients within the U.S. ,in the next two decades. Our hypothesis is that the combination treatment may have a synergistic effect, and the novel and differentiated mechanism of action of Denifanstat could potentially increase the efficacy already demonstrated by Resmetirom in MASH patients. Next slide, please. As you can see on the top row, late-stage F4 patients, even those with compensated liver function, have higher risks of major adverse liver outcomes and cardiovascular events. The treatment objective for this group is primarily to prevent decompensation, which requires potent antifibrotic medications with or without a metabolic component. Next slide, please. Now, let us turn it over to Dr. Loomba to discuss our phase 2b data in more severe patients from the FASCINATE-2 trial that were reported last year and what these results suggest about the potential benefits of a combination treatment.
Thank you, Dave. Delighted to be here to discuss data for Denifanstat and really excited about our programs in development. Next slide, please. Just a brief look into the mechanism of action of FASN inhibition and how it's important, how it might be synergistic, we will review in the next few slides. In patients with MASH, we see three distinct histologic features, importantly steatosis, inflammation leading to cellular injury, and fibrosis. With Denifanstat, which is a FASN inhibitor, we not only reduce de novo lipogenesis that is leading to reduction in hepatic steatosis inside the hepatocyte, we also see that it has an effect on immune cells leading to reduction in inflammation, particularly related to lipotoxicity. Denifanstat also has an impact in inhibiting stellate cell activation. Together, we think this would lead to reduced progression to cirrhosis and also potentially, because DNL is critical in malignancy, I think it's highly likely that DNL inhibition would be an important mechanism in driving increased rates of hepatocellular carcinoma. By inhibiting that, you have a potential plausible mechanism that it may reduce future risk for hepatocellular carcinoma in patients with MASH-related fibrosis and cirrhosis. Next slide, please. This is the trial design for FASCINATE-2 phase 2b trial. It was a 52-week biopsy-confirmed trial in patients with stage 2 or stage 3 fibrosis. We randomized 168 patients. They had MRI-PDFF, various biomarkers, and liver biopsy at baseline. At week 26, we did MRI-PDFF assessment, and at week 52, we performed MRI-PDFF and liver biopsy along with other biomarkers.
Patients were randomized 2:1 ratio to 50 milligrams of Denifanstat versus placebo in a double-blind randomized placebo multicenter trial. Liver biopsies were read by Dr. Pierre Bedossa, who has significant experience in MASH pathology. We also looked at AI digital pathology using the HistoIndex platform. Primary endpoint was two-point improvement in NAFLD Activity Score without worsening of fibrosis. We also looked at NASH resolution plus two-point improvement in NAS without worsening of fibrosis. Secondary endpoint also included improvements in liver fibrosis by one stage without worsening of MASH, as assessed by biopsy, and then digital AI pathology, and then MRI-PDFF responses. Next slide, please. This is the baseline characteristics of the study cohort that participated in the phase 2b trial. You can see 81 patients in the Denifanstat group and 45 on placebo. Average age was about 56 to 59 years. 60% of patients were women and 90% white with Hispanic ethnicity at 33%. Body mass index was 34.6 in the Denifanstat group and 36.5 in the placebo group. Diabetes status about 60%-68% of individuals had type 2 diabetes. Baseline ALT ranged from 57 in Denifanstat to 67 in placebo and AST of 48 and 52, respectively. Liver fat content ranged from 16.6% in the Denifanstat group to 19% in the placebo group. The stage II to stage III distribution was 51% at stage III fibrosis in the placebo and 58% in the Denifanstat group. Statin use at baseline 47% for each group, and about 9%-15% of patients were on GLP-1 analogs at baseline. Based upon ELF, we were looking at 9.6%-9.8% and FAST of 0.6%.
This tells us that this study cohort had rib-rolling steatohepatitis and diagnostic for stage II and stage III fibrosis based upon these NITs and the lab variables that we see. Next slide, please. This is looking at adverse events related to Denifanstat. Overall, Denifanstat was generally very well tolerated. No drug-induced liver injury signal, no muscle wasting was detected, and GI effects were comparable to placebo. This is important as we think about combination approaches with this drug. AE of here stabilized within two to four weeks dose pause and then reversed with dose titration or study completion. About seven percent of patients discontinued from the study with treatment-related hair thinning. Hair thinning in patients receiving GLP-1 analog could potentially range from 7%-10% also. In two previous clinical studies of Denifanstat, two percent of patients of Denifanstat experienced hair thinning at 50 milligrams. This is something that we are looking into in terms of risk mitigation in future. Next slide, please. Here I'm showing you the primary endpoints related to liver histology. To the left is two-point improvement without worsening of fibrosis. We have intention to treat all patients included here, 38% response on treatment versus 16% on placebo. If you look at modified intention to treat, 52% versus 20% on placebo. What about MASH resolution plus two-point improvement in NAFLD Activity Score? This is important data because this is something that you can then start thinking about comparing with some of the other medications where we have phase IIb and phase III data available. 26% response versus 11% on placebo, and in modified intention to treat, 36% versus 13% on placebo. Both statistically and clinically meaningful responses on MASH resolution, either in ITT or MITT. Next slide, please.
This is looking at fibrosis improvement to the left and MASH resolution without worsening of fibrosis to the right. So we're looking at 41% one-stage improvement in fibrosis without worsening of MASH in Denifanstat group versus 18% on placebo. This is amounting to more than 20% treatment effect delta on one-stage improvement of fibrosis with an oral therapy. In terms of resolution of MASH, and we look at 16% on placebo and 38% on Denifanstat. Very significant results and clinically meaningful for both of these regulatory endpoints if this were to be true in a phase III trial. Next slide, please. Now we'll dig in a little bit deeper. On the top panel, we're looking at one-stage improvement in fibrosis without worsening of MASH, and you can see in ITT rates, MITT, and then particularly in stage III patient, 49% versus 13% on placebo. The drug is working even in advanced disease, and we see actually a greater treatment effect delta. We also looked at two or more stage improvements in fibrosis without worsening of MASH. MITT, you can see 20% on Denifanstat versus 2% on placebo. For stage III patients, 34% on Denifanstat and four percent on placebo. Progression to cirrhosis was five percent in Denifanstat and 11% on placebo. These all provide you a good estimate about the antifibrotic effects that we are seeing with Denifanstat and why we think it could be a useful treatment, particularly in those who have stage III or advanced stage III or stage IV disease. Next slide, please. This is looking at digital pathology and assessing the responses, particularly in those who have stage III fibrosis. On the top, the green fluorescence that you see on the slide is representing the fibrotic scar.
This patient has pretty extensive stage III fibrosis. On Denifanstat, you can see this patient had significant improvement, and anyone who, even if not very familiar with liver histology assessment, could see that there is a pretty significant reduction in the green fluorescence. This is suggesting this patient has improved from stage III fibrosis to stage I fibrosis. We used a measure that has been applied in several other trials using HistoIndex, looking at QFibrosis as a continuous value. In placebo, there was a slight increase in QFibrosis score. Denifanstat had pretty significant reduction, and this was statistically significant. Next slide, please. If you look at QFibrosis zone analysis, this has also been done in other programs and demonstrated that Denifanstat improved parameters that are linked to liver outcomes. What are those parameters? Based upon previous studies done over the last two decades, we have known that periportal and portal fibrosis is linked to worsening progression of disease and worse clinical outcomes. Here is a unique way of looking at it through QFibrosis zonal assessment, and we see that we see those improvements with Denifanstat compared to placebo in those patients with progressive disease. Next slide, please. This is looking at Denifanstat potential in cirrhotic or stage IV patients. We know that patients with stage III fibrosis may go on to 20% of them may go on to progress to cirrhosis within two to three years. This is based upon data from previously published trials and longitudinal follow-up of stage III patients.
In vitro data with Denifanstat has demonstrated reduction in pro-fibrotic signaling and hepatic stellate cell, suggesting that Denifanstat has the potential to remove fibrotic scar tissue and reestablish the basal extracellular matrix scaffold even in cirrhotic patients. This proof of concept ability and some of the data that I previously showed you provides us biological rationale to test this drug in the setting of stage IV fibrosis. Clinical data from PK profile in cirrhotic stage IV patients in the phase I impaired hepatic function study is also available that provides assurance that the drug will have good PK profile and kinetics in that patient population. Positive impact on advanced fibrosis in patients with FASCINATE-2, as I previously showed you, including the QFibrosis quantification of fibrosis stage based upon AI-based digital pathology, is promising. The next step is to think about a potential proof of concept study in patients with stage IV fibrosis. Next slide, please. Can I have the next slide, please, Tara? Thank you. Here we can look at the Q4 in the placebo at baseline and its improvement. You see there were, in a small here, just three patients, no significant change that you see. When you look at the 13 patients who had QF4 at baseline, we are seeing pretty significant improvement in these patients. Eleven out of the 13, 85%, have a Q4 patient decreased by one or two QFibrosis stages measured by AI-based pathology. Five out of the eleven of QFIR patients showed more than one stage in regression, with four of these being two-stage as measured by conventional pathology. AI may be able to detect fibrosis regression at an earlier time point. Of course, these are preliminary data, but this provides good rationale for us to move forward based upon the data that we see. QF4 population defined on AI platform by HistoIndex are likely the most advanced subgroup of patients with stage III or bridging fibrosis that we have recruited in the previously conducted phase IIb trial that I just showed you the data on. Next slide, please. Looking at rationale for combination therapy. Next slide. This is looking at some of the data that we have in terms of FASN inhibitor and semaglutide, which is a GLP-1 analog in terms of improved histological features in mice models of MASLD and MASH. In a mice model, combination treatment with FASN inhibitor and semaglutide had an additive effect on fibrosis reduction, as shown in the panel to the left.
Then in the middle, you can see reduction in liver alpha SMA immunohistochemical staining. This tells us about its impact on hepatic stellate cell and a synergistic effect to the right shown on NAS reduction. You can see improvements with GLP-1 analogs in combination with FASN inhibitor, which is a DNL lipogenesis inhibitor. Why is that? Because semaglutide per se improves liver histology, particularly the data from ESSENCE that we've seen based upon metabolic actions that are outside of the liver. Combining it with a liver-directed DNL inhibition that you do not really see with semaglutide is helpful and potentially additive or synergistic. This is a hypothesis that could potentially be tested as well. Next slide, please. This is looking at data in a subset of patients who were on stable GLP-1 receptor analogs at baseline in the phase IIb study. To the left, I'm showing you data that 42% of those patients had resolution of NASH without worsening of fibrosis versus 0% on placebo. To the right, I'm showing you 42% had one-stage improvement in fibrosis versus 0% on placebo. Next slide, please. The mechanism of action that supports combination therapy and potential opportunities is listed here as well. If you look at Denifanstat, it is a fatty acid synthase inhibitor, and we've known based upon our previous study that it inhibits de novo lipogenesis. Resmetirom, a clinically effective treatment that is now in clinic for treatment of patients with moderate or advanced fibrosis due to MASH and used in clinical practice today, is a thyroid hormone beta receptor agonist and an oral therapy. There's a potential advantage for a combination approach that one could consider as a plausible mechanism of action for synergistic effects.
Denifanstat has a complementary mechanism, and DNL inhibition that we see with Denifanstat could work in concert with the increase in beta oxidation that we see with thyroid hormone beta receptor agonist. You could see there is a potential synergistic mechanism that one could exploit, and this could lead to potentially greater improvements in histologic response. That is the hypothesis that will be tested if we were to apply a combination approach in patients with more advanced disease. Next slide, please. This is looking at potential benefits of combination therapy in advanced MASH patients. A combination could potentially be useful in patients who have stage IV fibrosis or more advanced disease. As we previously discussed, Denifanstat decreases de novo lipogenesis. It has an impact on decreasing stellate cell activation, potential improvements in lipotoxicity, and reduction in liver fat. Resmetirom is already clinically proven and has been used in clinical practice for improvement in MASH and MASH-related fibrosis. Its mechanism of action is increasing beta oxidation in the mitochondria and improving mitochondrial function. It also reduces liver fat, lipotoxicity, and has also been shown to improve fibrosis in patients with biopsy-proven MASH. You could potentially see a synergistic effect with combining these two agents in the setting of a clinical trial and see what the results of that experiment might be. Both drugs are oral and once daily available. Therefore, I think this is a possibility that one could definitely consider in patients who have more advanced disease, such as stage III advanced fibrosis and stage IV fibrosis. Next slide, please. Now I'll pass it back to Tara for the next speaker. Thank you.
Eduardo Martins here. Thank you, Dr. Loomba, for this great presentation. What I would like to do over the next few minutes is to discuss the potential clinical development program for Denifanstat and Resmetirom combination. Next slide, please. Given the data we just discussed with Dr. Loomba, we believe that testing a combination of Denifanstat and Resmetirom is relatively de-risked, and there is no adverse safety signal. If there is no adverse safety signal, we could rapidly advance to the dose-finding stage of development. I'll now talk about our near-term and longer-term plans for assessing this combination. The first step would be to run the phase I PK study that we described earlier. The purpose of this study is to measure pharmacokinetics and assess any potential drug-drug interactions. We also want to assess the tolerability of this combination, which has not been tested together. Lastly, we would like to do some work around optimizing the dose levels with each individual compound so that we could advance several doses of the combination into a proof of concept dose-finding trial. The timing of this phase I trial initiation is in the second half of this year, actually next month. Because this is a PK in-safety trial, we anticipate data relatively quickly in the first half of 2026. These data would represent a milestone for the company if the combination is well tolerated because we already know that both individual compounds, Denifanstat and Resmetirom, have demonstrated efficacy in MASH patients. From there, we would expect to begin to work on a phase II trial of the combination in F4 MASH patients, cirrhotic patients. Currently, we expect to target at least 52 weeks of combination treatment with the primary endpoint of liver biopsy.
We would also be able to have an earlier signal of potential benefits by assessing non-invasive biomarkers such as tripalmitin, for example, in patients to evaluate target engagement and treatment response. We would like to provide a timeline for this program after evaluating the phase I results and contingent on discussions with regulatory authorities. Next slide, please. Now, what is the attractiveness of the Denifanstat-Resmetirom combination? We believe that pursuing the development of this fixed-dose combination could offer an important treatment option for patients as well as potentially generating significant value for Sagimet Biosciences investors. First, Denifanstat is a very attractive compound on its own with a unique mechanism of action that targets the three key drivers of MASH: liver fat or steatosis, fibrosis, and inflammation. Strong clinical data presented thus far where the Denifanstat has, in addition, met both primary endpoints in a phase IIb trial with significant reductions in fibrosis. What I mean is we have strong clinical data on combinations, and we have met endpoints, primary and key other endpoints in a phase IIb trial with importantly significant reductions in fibrosis, as Dr. Loomba mentioned. Also, as discussed by Dr. Loomba, preclinical and clinical data show that the combination of a FASN inhibitor and a GLP-1 had a synergistic effect on MASH histology. With regards to the combination with Resmetirom, our preclinical work in the combination of a FASN inhibitor and Resmetirom also demonstrated a synergistic effect. These preclinical data from two different mouse models, the Gubra GAN diet MASH model and the LDL receptor knockout MASH model, show that the combination reduced liver fat and reduced the size of lipid droplets down to lean basal levels similar to mice on a normal chow diet. This is not typically seen, but speaks to the complementary mechanisms of action. The combination of a late-stage fat synthesis inhibitor with an FDA-approved fat oxidizer has the potential to improve outcomes of disease in the most advanced F4 patients who are underserved by current treatment regimens. On a related note, we have applied for a patent for Denifanstat-Resmetirom combination. A patent of the combination, if granted, could protect the fixed-dose combination until 2044 with potential extension to 2048, which creates significant runway for the drug to generate future cash flows.
Lastly, we would expect to develop an oral once daily drug, which is convenient for patients to encourage good adherence in the chronic use setting. With respect to the next steps, we will begin our phase I PK trial of the combination treatment in the second half of 2025 with a data readout expected in 2026. If results are encouraging, we will explore advancing the program into the next stages of development. Thus, our plan provides for prudent deployment of capital to run a small trial that will provide a rapid path to a go/no-go decision. We have sufficient cash runway to deliver these top-line data, and we are extremely enthusiastic about this program, which offers the opportunity to deliver a highly differentiated compound into a large and competitive market. Operator, I would like now to pass on to open for the Q&A.
Great. Thank you, Eduardo. At this time, we will be conducting a question-and-answer session with our speakers. Please hold for a brief moment while we pull for questions. Our first question comes from Dominic Risso at Piper Sandler. Please go ahead, Dominic.
Hi, this is Dominic on for Yasmin Rahimi. Thank you for taking our questions, and thank you for a great event. Our question, we were just wondering how you're thinking about NITs use in the trial and histological response and how that will be assessed in a future combination trial. I guess also, how do companies run registrational studies in combo, or is it sufficient to prove if each one gets approved? Are you able to, I guess, prove the combination? Thank you. Yeah.
Thanks, Dominic. Rohit, maybe you want to tackle the NIT part of the question and what the expectations might be from that. Eduardo, maybe you can chime in on the regulatory path forward on the fixed-dose combo.
Yeah. Dominic, I think great question. In terms of the NITs that one could look at, one would be a synergism in terms of MRI-PDFF improvements that one could see. We could also do a base estimate on the ALT and AST slopes, and those might be important. In a six-month time period, we can also look at something that we've developed called a MASH resolution index that looks at baseline AST, delta MRI-PDFF, and delta ALT. In addition, I think one could also look at responses to some of the complementary mechanisms. Particularly, we could look at tripalmitin. If we see improvements related to tripalmitin, that might be useful as well. If we see further improvements with the combination approaches, then I think some of the other biomarkers such as ProC3 might be important. Potentially, one could look at ELF as well. I think that would be on the biomarker side for a short-term study as is currently being planned. If you were to look at a large phase III program in a stage IV population, I think that would be potentially based on stiffness improvements such as FibroScan and some of these scores that we've developed for FibroScan-based liver stiffness measurements. One could definitely look at MRI-based measures as well, potentially even look at corrected T1 approaches on MRI and MR elastography. One could also look at ELF and a combination of liver stiffness plus ELF improvements. In the next several months, there will be new data coming out from other trials that will help shape this area even better, particularly in the setting of large registrational trials in stage IV. I think for this early phase trial, what I mentioned should cover all NIT-based approaches. Thank you.
Thank you, Dr. Loomba. With regards to the next steps and what this trial is intended to show, of course, this is a drug-drug interaction PK study. The participants are healthy volunteers. What we want to show is that the pharmacokinetic profiles of each drug are not impacted when both are combined. Based on the different ways the drugs are metabolized, it is possible that this will not happen. Now, a PK drug-drug interaction study is the first step when testing a new combination. If the study is successful, if we show that there are no drug-drug interactions at all to be of concern, we will therefore intend to continue on to a biopsy study, a phase II biopsy study. All this is, of course, dependent upon discussions with the regulatory authorities, as with any study in clinical development, any program for whatever disease we can think of. Now, since both drugs are administered once daily, both drugs being oral, a combination is highly interesting, and we are very encouraged by that. What the next steps will look like, I listed those, I alluded to those in broad terms, but we will wait for the results to assess that. With regards to non-invasive tests in this population, we will be testing some exploratory biomarkers just to see if there are any changes. However, I want to remind you all that this is a healthy volunteer population. Thank you.
Great. Thank you so much.
Thanks for the questions, Dominic. Our next question comes from Nat Charoensook at Leerink Partners. Please go ahead, Nat.
Hi, this is Nat Charoensook on for Tom Smith. Thank you for taking our question. So we have a couple of questions for management and Dr. Loomba. First question, what's your thought on prioritization between a phase III monotherapy program and a new combination program? Are you expecting to get a phase I combo result prior to starting a phase III program? How do you expect to obtain the Resmetirom drug supply? Do you plan to purchase the commercial Rezdiffra? A question for Dr. Loomba, how do you think about patient selection between Denifanstat monotherapy, Rezdiffra monotherapy, and a combo of Denifanstat and Rezdiffra? Thank you.
Thanks, Nat. Maybe Rohit, maybe you want to go ahead and address the second part, and then we can go ahead and discuss the how.
Yeah, that is pretty simple. I think it will all depend on the next stage of development in terms of the trial and the results. If you end up going with a phase III program with the monotherapy in stage II and stage III, then that would be the patient population. For stage IV, if one goes for registration with a combination approach, then of course, you would focus on patients with stage IV disease. To me, it's pretty simple. It depends on what patient population that you choose to document in your phase III program, the clinical improvements that you will see in that patient population. Based upon that is what we will take on to clinical sort of medicine in terms of the clinic. To me, I think it all depends on what proof we show at the end of the day in the population of interest.
Thanks, Rohit. Nat, I think to answer your question about prioritizing the phase III monotherapy versus moving forward with the combo, I think it really comes down to what we've consistently communicated over the past year plus. That is that we did not want to begin the phase III study with Denifanstat as monotherapy in F2-F3s without adequate funding to be able to finish the trial. We remain committed to the space and to develop Denifanstat in these patients. We feel the best way to do that at this point, utilizing the cash that we have to be able to get to meaningful endpoints, as both Rohit and Eduardo had discussed thoroughly, to be able to get to phase IIb readout at 52 weeks with a combination drug that could be highly and should be highly attractive to not only the clinical community, but the financial one as well. I think that is our best approach right now. We're confident that it will be a positive relationship with the medications and will demonstrate an incremental benefit, certainly based on the preclinical data that we've shown to date, an incremental benefit over perhaps either medication alone. There's a strong rationale for taking it forward in this fashion, and that's what we plan to do. In terms of how we're going to procure resveratrol, it is obviously commercially available, and we can do so for the PK study.
Got it. Thank you so much.
Thanks for the questions, Nat. Our next question comes from Nicole Martucci at Cowen. Please go ahead, Nicole.
Hi, everyone. Thank you. This is Nicole on for Ritu-Beral. Just a question for Dr. Loomba. Can you maybe go into a little bit more detail on the synergistic effects? Is that driven by the increase that you see with the FASN when you're inhibiting or, sorry, when you're activating THR-beta? Just how much does FASN increase when resveratrol is in a patient? Thank you.
Yeah, no, great question, Nicole. If you look at the de novo lipogenesis pathway, there are four key enzymes. With Denifanstat being a FASN inhibitor, we'll inhibit fatty acid synthase. When you block that downstream of it, the accumulation is a substrate for beta oxidation. It will basically get into the mitochondria and then get oxidized. I think it will probably really improve the efficiency of improvements in both DNL at the same time improving beta oxidation. You can say that you are blocking a synthesis of fatty acid at the same time you are burning it. When the block happens, I think rather than having just compensatory increase, the addition of resveratrol is going to really rev up mitochondrial efficiency. I think it should have a potential synergistic mechanism based upon my understanding. Of course, that needs to be proven in a clinical trial. Hope that helps.
Great. Thanks for the questions, Nicole. Our next question comes from Jasmine Ee at UBS. Please go ahead, Jasmine.
Hey, this is Jasmine on for Ellie. Thank you for taking our question. Thank you for hosting this. Two kind of related ones. There seems to be a pretty wide range of disease severity across the spectrum of F4 patients. It seems like that might impact treatment effects. What do you think the characteristics of the F4 population are that you would be targeting to enroll in a phase II? Specifically, in those F4 more advanced patients that have less liver fat content and more fibrosis, how do Denny and resveratrol mechanisms work in that context? How do you anticipate the combination would play out there? Thank you.
Rohit, I think we'll let you tackle that one.
Sure. I think you're right. Based upon the data that we've seen across the board, those who have higher liver fat content in the setting of cirrhosis probably have more compensated NASH cirrhosis. Those are the patients who are more likely to have a histologic response. If we are showing one-stage improvement in fibrosis such as that you saw with the SIMMETRY program with FRXAFERMIN just a few months ago, you would want to enroll those patients. As done in SIMMETRY, there were about 20% of patients who had less liver fat. Those patients also saw improvements. I think we would probably be thinking along the same lines that you probably want to have an oversampling of patients who have more than five percent or eight percent fat on the liver based upon MRI-PDFF or other measures, and then include a subset of patients also with the lower liver fat, thinking that you would power mainly on those with higher liver fat, but still include a population so you can really assess what happens in the totality of the population. There is really good data that just came out from Rezdiffra, where Rezdiffra's efficacy is good irrespective of the baseline MRI-PDFF. I think it is encouraging that those with compensated disease, these mechanisms are still active, and targeting hepatocytes would still lead to improvements over a reasonable period of time. I think that is something that we could assess. Hopefully, I was able to tackle your question.
Yeah, absolutely. Very helpful. Just one follow-up, if I could. Just on timelines, right? Because we do anticipate seeing outcomes data from Resmetirom in a couple of years. Just how is that going to impact your strategy? How do you envision that playing out in terms of your timelines?
Yeah, I think the strategy question would be for David.
Yeah, thanks, Rohit. Look, Jasmine, I think that we are all encouraged by the data that Madrigal presented most recently at EASL in this population, which is highly suggestive that they may reach a positive effect in F4s. Certainly, based on our data to date, we anticipate that the combination of the two would have a rather strong synergistic effect, not just a simple additive effect, but one that could translate into a potentially much greater outcome for patients. Look, I hope that their data does continue to be positive. It only supports, frankly, the combination of the two molecules. I just want to point out, I think one of the questions was asked earlier about the path forward from a regulatory perspective and what needs to be accomplished. I want to make sure it's clear that our pursuit of a combined fixed-dose combination can be done independently of anything that we might pursue as a monotherapy with Denifanstat, meaning that the pharmaceutical industry has numerous examples of fixed-dose combinations coming forward that have been approved in lieu of either drug being used as monotherapy. A fixed-dose combination regulatory pathway is not contingent upon whether or not we move Denifanstat forward as a monotherapy. I think as Eduardo and Rohit have eloquently explained, particularly with Rezdiffra being approved on the market, that being able to combine it with a fat synthesis inhibitor, a potent antifibrotic like Denifanstat, is a highly attractive proposition.
Awesome. Thank you. Thank you both.
Thanks for the questions, Jasmine. Our next question comes from Jay Olson at Oppenheimer. Please go ahead, Jay.
Hey, Professor Loomba. It's great to see you again. Thanks to you and the Sagimet team for providing this update. And thanks for taking our questions. We have three questions. The first one is, besides a clean PK profile and lack of any drug-drug interactions, are there other metrics that you'll be watching for in phase I for the Deni plus resmetirom combination study?
Thanks, Jay. Pleasure seeing you. Of course, we will be looking at safety. That's a very important component, actually, of any clinical trial, as we all know. We will, as I mentioned, look at some biomarkers, soluble biomarkers, some of which we actually have already discussed at previous studies in MASH to see if anything changes. However, again, those are healthy volunteers, and one has to take that into account when assessing response. Since we do have the ability to assess different biomarkers, we will take advantage of that opportunity in an exploratory fashion.
Okay. Great. Thank you. Our second question is about when you advance the combination of Denny plus the thyroid beta agonist into clinical development, what is the likelihood of conducting a non-invasive efficacy trial with no biopsies? Also, would you use a factorial design so you can see the relative efficacy contribution for the combination versus each of the single agents?
Thank you. The simple answer is all that depends upon regulatory discussions. The agency has indicated, and it is still in their guidance, that they want to see biopsy. We have seen this more recently, as Rohit mentioned, with the FGF21 studies in cirrhosis, the registration trials. We all want a non-invasive measurement across our clinical trials, but that depends on conversations, and that depends also on gaining information. Remember, the agency has information beyond what all of us have since they look at every single trial, and that division is composed of very experienced hepatologists who are always thinking ahead and trying to see what is best for the patients in addition to what can bring drugs to the market faster and in a safe and effective way.
Okay. Sounds good. Our third question is, can you please compare the pros and cons of combining Denny with an oral GLP-1 versus combining Denny with a thyroid beta agonist? Would you consider Denny plus GLP-1 combination as more appropriate for an F2, F3 population versus maybe Denny plus thyroid beta in an F4 population? Are there other ways to think about how to compare these two potential combinations?
That's a very good question. Rohit showed our data on GLP-1s, as in patients stable on a GLP-1 and denifanstat from our phase IIb trial. As we saw, the combination was only effective in patients receiving Denny. Patients receiving placebo did not show an effect. That is consistent with what we saw in our preclinical data that, again, Rohit presented today. Now, there are some challenges in a de novo combination with the GLPs or in the case of an oral, a fixed dose combination. That has to do mostly with tolerability of a GLP. We know that many patients, after about one year, they drop off of a GLP because of tolerability issues. We are learning new things every day. For instance, now recently discussed real-life data showing that bone loss also happens with GLPs. Now, back to the tolerability, GI being the most important, one of the approaches that is being used in the real world is up titration over a period of time. Sometimes some advisors tell us up to a year or so. As you may imagine, that makes a fixed dose combination impossible. What do we expect? One, if our program is successful, to be able to bring a fixed dose combination with Resmetirom for MASH. Two, many patients with MASH who are overweight, obese, or have type two diabetes will already be on a GLP-1. All things being equal, we may reproduce the pre-existing data with Denifanstat and GLP-1s and perhaps increase the efficacy now with a fixed dose combination.
Great. That is super helpful. Thank you for the comprehensive explanation. It is great to see you guys. Thanks for taking all the questions.
Thank you.
Rohit, I just want to—I'm sorry, Tara. Just wanted to offer Rohit the chance to provide his thoughts on the combination of a GLP-1 with Denifanstat as well.
Yeah, I think it would be really good to see that play out. I would think that with Denifanstat having a direct mechanism of action in the hepatocyte with the GLP-1 analogs leading to improvement in weight loss, I think it could be attractive. I do think that we would have—it could have a potential role in boosting fibrosis improvement and then also getting the weight component and improvement in body weight and diabetes status with GLP introduction.
Great. Our next question comes from Tolani Uthman at Goldman Sachs. Please go ahead, Tolani.
Hi, team. This is Tolani on for Andrea. Thanks for taking our questions today. Two from us. The first one on the preclinical mouse model data that you had referenced earlier. Since that was based on a combination of a surrogate FASN inhibitor alongside resveratrol, are there any thoughts you could share as to how similar that surrogate inhibitor is to denifanstat with respect to PK, PD, and formulation? Are there any differences between the two that might impact the results of the phase I trial?
Thank you. The simple answer is no. It's a FASN inhibitor just like denifanstat. Why do we use it in mice? Mainly to do with the PK across different species. In mice, the short denifanstat is metabolized very, very, very fast, which makes experiment very difficult. 3664, on the other hand, has a PK in the animals exactly or very similar to denifanstat in humans. Long story short, it is a perfect surrogate for denifanstat that addresses the different PK characteristics seen in two different species, in other words, us and mice.
Okay. That's helpful. Thank you so much. The second question, what types of bridging studies would be necessary as you move from studying the two separate tablets of Denifanstat and resmetirom into creating the co-formulation?
Those would be your typical CMC studies that we have seen across the industry for many indications, all the way to very large ones like hypercholesterolemia. You want to make sure that they are chemically compatible, which, both being small molecules, they probably would be, needs to be tested, of course, but nothing different to what has been done and continues to be done across the industry across multiple different diseases.
Got it. Thank you.
Thanks for the questions, Jasmine. Our next question comes from Jon Wolleben at JMP. Please go ahead, John.
Hey, thanks for taking the questions. One for the team and then maybe one for Dr. Loomba. Can you tell us what dose ranges you plan on testing here for both compounds and how you landed on those ranges?
Sure. Resmetirom has been approved with two different doses, 80 and 100 milligrams based on body weight. Of course, what we will do is follow the package insert. In the healthy volunteers in the phase I, again, I always like to remind repeatedly, those are healthy volunteers. Nevertheless, we may have healthy volunteers with different weight ranges. We will follow the package insert. Denifanstat, the doses that will be explored will be different ones up to the 50 milligrams that we tested and that we found to have been successful in the FASCINATE-2 phase IIb trial.
Helpful. When we think about cirrhotic clinical trials, how much confidence do we have that liver biopsies will translate to clinical outcomes? Do we still expect that FDA will require clinical outcomes for approval, or do you think that there's going to be a sea change between now and when you guys might be at that point in development?
Sure. I'm going to make a few comments, but then I would like also Rohit as the top clinician to add to that. I think we will learn more as the trials progress across different drugs for MASH. However, in clinical liver diseases across the spectrum, good examples being hepatitis C, hepatitis B, alcoholic liver disease, hemochromatosis, we know that removing the injury improves histology, which then is associated with improved outcomes. This is a broad explanation that remains to be determined, but I'm confident that this will be shown with different drugs, assuming they are successful in the biopsy endpoint. Let me pass on to Rohit, who knows way more about this than I ever will.
Good question. I think it depends on what happens over the next several months and years in terms of the stage four biopsy reads and the safety of the interventions. I think if you look at it from FDA perspective, why does the current guidance that was written many years ago talk for stage four fibrosis only for long-term clinical outcomes? That was really at the time they were worried about safety. Now with the data from SIMMETRY and FGF21 and other trials, I think, and also we have good safety data on resveratrol, I think FDA is thinking about, looks like many of these drugs could work in the setting of cirrhosis. Why not give an opportunity that those drugs could get into patients in a conditional approval manner? That is where I think it is coming, where if you showed one-stage improvement in fibrosis, you would have a chance in play. It all depends on risk-benefit and the safety of the medication in stage four population. It is possible for certain programs, it would win for certain programs. If the liver safety is an issue, then it would be different. I think in general, one-stage improvement in fibrosis, the setting of cirrhosis, would be a good landmark to get to a shelf-board edge or a conditional approval, which still showing long-term clinical outcomes for a full approval. I think that pathway will remain open, in my opinion, for drugs that have a good safety profile from a liver safety viewpoint, which I think a lot of our drugs currently have. This should be the paradigm in the next several months, two years.
Got it. Thanks for taking the questions.
Thanks for the questions, Jon. Our final question comes from Debanjana Chatterjee at Jones. Please go ahead.
Hi. Thanks for taking my question. This is for Dr. Loomba. Given that FGF21 analogs are also advancing for this indication, could you maybe speak to the positioning of FGF21 compared to Denifanstat in F4 patients? Also, maybe any kind of safety profile that you think how Denifanstat can be differentiated. For example, it does not cause bone loss as FGF21 does. Looking forward to hearing more of your thoughts.
I think this is a great question, but potentially we'll have to wait for the data to look at the efficacy and what is the treatment effect delta that we see. Based upon that, we can make an informed decision about positioning. I think right now it's about setting up the trial and getting to the experiment. Once we see the results, then I think we can compare. Right now, we have results on SIMMETRY, but with the Denifanstat and resmetirom combination or Denifanstat by itself in stage four, we don't have data. I think it'll be premature to comment as to how we will position it. I think it's a great question. Thank you.
Thanks.
Great. Thanks for the question. I'll now turn it back over to Dave for closing remarks.
Thank you, everybody, for taking the time to participate in our call today. We greatly appreciate it. We look forward to updating you as we move these programs forward. We're very excited about the prospects of what we're about to engage in and the likelihood of a very positive outcome. We look forward to sharing that as we work through this. Again, thank you for taking the time today.