Good morning, and welcome to the 89bio key opinion leader webinar on the opportunity of pegozafermin and the overview of the advanced MASH and compensated cirrhosis landscape. At this time, 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 or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded, and a replay will be made available on the 89bio website following the conclusion of the event. I'd now like to turn the call over to your host for today's webinar, 89bio's Chief Executive Officer, Rohan Palekar. Please go ahead, Rohan. Thank you, Tara. It is my pleasure to be speaking with all of you at our KOL event today at what is an exciting time for 89bio. Before we begin, I'd like to remind you that certain statements in this presentation may be forward-looking, and I invite you to visit our website to review our SEC filings and to read about the risks associated with these statements. Today, we are pleased to welcome expert hepatologist, Dr. Arun Sanyal, Director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University. He will discuss the treatment considerations for metabolic dysfunction-associated steatohepatitis, or MASH, in both the pre-cirrhotic and compensated cirrhotic patients. Dr. Hank Mansbach, our Chief Medical Officer, will then discuss our recently initiated phase III ENLIGHTEN- Cirrhosis Trial, and we will conclude with an overview of pegozafermin's commercial opportunities before we open the call for questions. For those who might be new to the 89bio story, we are a late-stage clinical company based in San Francisco, focused on liver and cardiometabolic health. Our lead program, pegozafermin, is a specifically engineered glycoPEGylated analog of FGF21, which has the potential to transform the treatment landscape in these diseases. This is based on the unique mechanism of action of FGF21 and the promising clinical data we have generated in MASH and severe hypertriglyceridemia, or SHTG. FGF21 is a hormone that has broad metabolic benefits, regulating energy and lipid metabolism, in addition to improving insulin sensitivity. Additionally, it has direct anti-fibrotic effects on the liver. A challenge with drugs targeting FGF21 has been the very short half-life in its native state. To address this, we employ a unique technology called glycoPEGylation, which extends the half-life while preserving the hormone's potency against all the key FGFR receptors, as seen on the table at the right. This balance allows us to deliver the drug weekly or biweekly while delivering strong efficacy. Our approach to extending FGF21's half-life sets pegozafermin apart from other FGF drugs in development. And the structural differences may also explain why pegozafermin has a more favorable tolerability profile than some of the other drugs targeting FGF21 in development. Based on the encouraging data generated to date, we believe pegozafermin is well positioned to be a leading and potentially best-in-class FGF21 analog for advanced MASH and SHTG. It strikes the right balance between sustained efficacy, favorable tolerability, and dosing convenience. Specifically, it has shown robust effects on key efficacy measures, such as fibrosis in the case of MASH and triglyceride reduction in the case of SHTG, while also offering other broad metabolic benefits that are important in treating these patients. In chronic asymptomatic conditions like MASH, patient compliance and persistency is influenced by tolerability and dosing convenience. We believe our drug profile, with its every two-week dosing regimen and liquid pre-filled syringe for convenient self-administration, offer a competitive advantage. Furthermore, the liquid formulation could allow, down the road, for a co-formulation with other liquid biologic agents, like a GLP-1. As we presented this slide, there exists meaningful clinical and commercial benefits in both the indications we are pursuing. Both are large markets, and we believe pegozafermin has the potential to address the high unmet needs of patients seeking better therapies. To highlight some of these, we have shown benefit on top of other therapies, specifically GLP-1 therapies in MASH, and the existing standard of care, like fish oils and statins in SHTG. This is important given that we expect the drugs will often be used in combinations in these indications. From a business perspective, there are significant synergies across the program. For example, we expect to be able to leverage the safety database from one indication to the other. And finally, developing pegozafermin in both indications provides us with diversification with three phase III studies across the two indications. As you see on this slide, we are currently now in three phase III studies. The ENLIGHTEN- Fibrosis phase III trial, which was initiated in March. And we have received very positive initial responses from the sites. On Tuesday this week, we announced the initiation of the ENLIGHTEN-Cirrhosis trial, our phase III study in F4 patients, making pegozafermin the first FGF21 to enter phase III development in the F4 population. Both MASH studies have dual opportunities for regulatory approval, including paths for accelerated approval based on histology. Finally, our phase III study in SHTG is enrolling well, and we expect to report top-line results in 2025. We're excited about the transformative potential of pegozafermin in both these indications and look forward to providing updates on our progress. Before I turn it over to Dr. Sanyal, I first want to thank him for his time today and briefly recap his impressive background. I know Arun does not need an introduction, but for those who are not familiar with Dr. Sanyal, he's the Professor of Medicine, Physiology, and Molecular Pathology in the Department of GI at Virginia Commonwealth University Medical Center in Richmond. At VCU, he's currently the director of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health. He also serves as the chairman of the NIH NASH Clinical Research Network, the NIMBLE Consortium, and the Liver Forum for NASH and Fibrosis, and previously served as the president of the American Association for the Study of Liver Diseases, or AASLD. He has authored over 450 articles in leading publications such as Nature Medicine, New England Journal, and The Lancet. We're thrilled to have the chance to hear the expert insights of Dr. Sanyal. With that, I'll hand it over to you, Arun, to kick us off. Please go ahead. Thank you. Thank you. That's a very kind introduction. It's a great pleasure to be with you today. What I would like to do is sort of talk through where we are in the landscape of therapeutics for NASH and how pegozafermin is really an important advancement within this space. May I have the next slide, please? So just to set the stage, I think it's important to remember that the disease we now refer to as metabolic dysfunction-associated steatotic liver disease, and that was previously called non-alcoholic fatty liver disease, really one and the same, is a progressive disease that was described by pathologists, where one could start with just having steatosis, or a fatty liver, or a more aggressive form called steatohepatitis, where you had this, very specific lesion called hepatocellular ballooning, as shown on the slide, that would injure the liver cells and lead to an inflammatory scarring reaction that would eventually culminate in cirrhosis, which you see on the right-hand side, where you have islands of liver cells completely encircled by scar tissue. Next slide, please. So there has been an incredible amount of work on trying to treat, this progressive cascade of, types within the MASLD spectrum, with the goal of reducing the burden of disease. And if you look at the burden of disease, one can think about it in sort of a pyramidal form, where at the base you have people with fatty liver or, minimal fibrosis. Then you have what we call at-risk NASH, which is NASH with high activity and Stage II or greater fibrosis, which then leads to advanced fibrosis, which is bridging fibrosis and cirrhosis. And eventually, at the top are people with cirrhosis who are closest to liver outcomes. So I'll focus my presentation on really asking three questions: Will a wipeout of steatotic liver disease at the base prevent progression and thereby reduce the influx of people who will have significant liver disease? For those who are in the middle, do we now have tools to reduce disease activity and fibrosis, and how does pegozafermin fit in here? And then eventually, what do we do with cirrhosis? Next slide, please. This next slide. So tackling the first question, which is really starting at the base, or what I like to call bottom-up therapy, there are now increasing amount of data to suggest that the portfolio of molecules that we have are becoming better and better at wiping out the steatosis. So what you see on this slide are data from a triple agonist, which is a GLP, glucagon, and GIP triple agonist called retatrutide, and these are data that were presented in ADA. We hope they'll come out in pre- full publication form very soon. And what you see here is that by week 24, 86% of patients, and by week 48, 93% of patients no longer have any hepatic steatosis, as measured by PDFF. And this is accompanied by normalization of liver enzymes and a variety of biomarkers. So the question then is: If you treat people early, people who are just obese, can you reduce the progression into more advanced disease? So I think those are the kind of data we're looking for. Remember that GLPs have tolerability issues, and about 20%-30% are off therapy within a few months after starting therapy due to tolerability, and there will still be issues of access, so there will continue to be people who will progress to more advanced disease. Now, so that raises another question, which is: Can you actually address everything with just weight loss, which is a major mechanism of action of the GLP anchor therapies? Next slide, please. So these are data with semaglutide, which is a pure GLP-1. And of course, here what you see are in F2, F3 treatments that, you do get, while it was good at improving steatohepatitis, there's no clear signal for improvement or reversal. And certainly in the F4 population also, there was no benefit in terms of fibrosis regression. So GLP-1 alone, at least with the products that we have here, probably not sufficient by itself. Next slide. Even if you look at bariatric surgery, something that produces the sort of most significant weight loss, if you look, that on the left-hand side, you get a lot of improvement in disease activity. But if you look on the right, at the top in the black bars are the people with advanced fibrosis, F4 and F3s. And so you do have some improvement up to F3, but it's hard to shift the needle on the cirrhotic patients. And these are really a long-term data with five years of follow-up on these patients with biopsy. So that sets the stage to say, "Okay, but you do need something more than just weight loss, and what could those things be?" Next slide. So that brings us to the middle sector, where we have people who have already started scarring down their liver, where we not only need to reduce activity, but we also need to reduce fibrosis. And the question at hand is: What will it take to get hepatitis C treatment-like responses? We need to understand disease heterogeneity, treatment response heterogeneity. We need to understand if drivers of disease progression differ from patient to patient, how to move closer to precision medicine, and what are regression drivers, and can we leverage those? Next slide. So this provides a general framework for how we think about therapeutics today. If you look at fibrosis staging, why fibrosis? Because it's the best prognostic biomarker. So if you go from the F1 all the way to F4, you can see there's a spectrum of risk related to progression, liver events, and even cardiovascular events. So in the middle, the goals of therapy are outlined, where very early on, you want to resolve the steatohepatitis because it's minimal fibrosis, things should cool down. But progressively, as you move towards cirrhosis, you need to see antifibrotic benefit. And so the primary therapeutic interventions, you know, in the very early stages, could be primarily metabolically oriented. But the further you get towards cirrhosis, and albeit, remember that those are the people at greatest need because they are closest to outcomes, that you do need both metabolic and antifibrotic benefits. Next slide. So this table summarizes where we are with the top-line sort of classes of agents that are in advanced phase trials or have been conditionally approved, such as thyroid beta receptors. And what you see here are, you know, an ideal therapy should reduce weight, improve atherogenic risk profile, reduce MACE, stabilize GFR, improve glycemic control, reduce disease activity and fibrosis. So you can see over here with pan-PPARs, while many of these things are good, it does lead to some weight gain, and we really don't have long-term MACE data here. And we also don't have data around the GFR. The thyroid beta receptors recently have been approved. They are neutral with respect to weight. They do improve atherogenic dyslipidemia. We don't have long-term hard outcomes data yet, but they do improve histology with a moderate effect size. And then, what you see on the right-hand side. Hold on for a second here. Let me move the other GLP-1s, where, again, you know, we just reviewed what their profile looks like. So coming to FGF21 in the middle, it does cause some weight loss. There's improvement in atherogenic risk profile. We don't have long-term cardiovascular outcome data. In some, the data on glycemic control are mixed because, you know, some of the data that were neutral were with first-generation FGF21s. With more recent ones, there is a signal that even this may be improved. And certainly, as you saw from the presentations around pegozafermin and even efruxifermin, that there's evidence for improved liver disease activity and fibrosis. Next slide. So what are these FGF21s? These are a class of molecules. It's a hormone. It belongs to the endocrine class of FGFs that bind to these receptors called FGF receptors, along with a co-receptor called beta-klotho. There are different types of FGF receptors. There's 1c, 2c, 3c, and FGF4. FGF21 binds to one, two and three, whereas FGF19 also binds to FGF receptor 4. FGF21 does not bind to FGF receptor four. So FGF21, based on individual FGF21 analogs, have differential binding to these different receptors and different degree of penetration into the CNS, and also target adipose tissue and liver... and lead to weight loss, thermogenesis, insulin sensitization, decreased hepatic lipids, and all of these are considered to be beneficial. The FGF21s also have some anti-fibrotic benefits that have also been proposed. Next slide. So talking of fibrosis, in the phase 2 study, which was a 24-week study, you can see on the left that there was a significant improvement, a placebo-corrected improvement, with pegozafermin at 30 and 44 milligrams that reached statistical significance. And similarly, you are seeing NASH resolution improvement at all of these doses. So it has improved both activity and fibrosis. Next slide. Now, when you put this in the comparative landscape and you look at placebo-corrected, the reason why placebo-corrected, because, you know, each study employs a little bit different approach to assessment of histology. There are different time frames, et cetera, et cetera, which make it very hard to compare them exactly head-to-head. So looking at placebo-corrected response rates, you can see over here that the two FGF21s, the 89bio, they have somewhat better effects compared to Ocaliva, which is FXR agonist of obeticholic acid, Rezdiffra and Inventiva. Inventiva did have also fibrosis improvement and activity improvement, but the FGF21 seem to be sort of leading that race in terms of improving both activity and fibrosis. Next slide. Eventually, there may be a need for combination therapies, and the way at least I think about it, and I can tell you that there isn't any uniform consensus about the best way to approach this, is if you think about disease activity and disease stage, you can divide this into four quadrants. When you have low activity and low fibrosis, you may not even need therapeutic drug intervention, and this could be managed with lifestyle. If you have high activity and low fibrosis, a metabolically targeted therapy may be sufficient. It's really those with high activity and fibrosis, who are ideally candidates for combination therapies. But we need to really, as we develop those therapeutics, also be mindful of what are you going to do after you've started this dual therapy? Because if a patient improves fibrosis, but not the activity, how will you deal with them? If they improve activity but not the fibrosis, how will you deal with them? If you improve both, can you reduce the dose and just have a maintenance program? So I think there are a lot of things that have to be thought through as we think about combination therapies, but these are all good problems to have because we have an increasingly potent portfolio of molecules that we can play with here. Next slide. In addition to the histology, you can see here that with pegozafermin, you have additional benefits in liver enzymes. ELF score, which is increasingly being considered a biomarker for treatment response. And here you see improvement in the FAST, which is the FibroScan and AST combined data showing improvement in this as well. Next slide. So this, I think, sets the stage to say that, yes, there are a lot of good molecules. We know Rezdiffra has been approved, but behind it are coming GLPs, GLP co-agonists, and also now FGF21s. And the two leading molecules that are in phase 3 are the Akero efruxifermin and pegozafermin. So people who have the highest need are those who are cirrhotic. So let's now think about some treatment considerations in those with- Next slide. So coming back to our little pyramid, this is cirrhosis, is where I think the final therapeutic battle will be fought. Next slide. So we've made progress with many things, but I think moving on to the F4, the first thing to point out, not only is there a significant step up in clinical risk when you go from lower degrees of fibrosis to F3, but there's a big step up again when you actually get to stage four. As you can see, all-cause mortality, liver-related death, hepatic decompensation, MELD scores, increase and even development. So in this particular study, the hepatocellular carcinoma rates were higher in bridging fibrosis than cirrhosis. But this is a little bit artifactual, I think, because of the small number of HCC cases. There was a little imbalance, with more cases in bridging fibrosis. I don't think... I wouldn't pay too much attention to the HCC part of this, but the rest of it is pretty robust. Next slide. So when we think about F4 studies, it has been a little bit of a graveyard, and because I think we have taken a rather simplistic approach, the way we attack the pre-cirrhotic stages and just apply them to stage four, hoping for some magical resolution. But as you progress from stage three into stage four, the biology of disease changes quite dramatically. We really need to think about this as a continuum, because, you know, a proportion of people with stage three have already become stage four. You don't know it because you're just getting a small liver biopsy. So as you move through from early stage three with increasing fibrosis, you have increasing nodularity, your hepatic venous pressure gradient starts increasing, and then eventually you start losing some liver function. At the same time, there are systemic things that occur in this population that you do not see in pre-cirrhotic patients, and these include vasodilation, activation of the renin-angiotensin system, sodium retention, bacterial translocation, systemic inflammation, sarcopenia, worsening metabolic inflexibility, and neurocognitive decline. And it's really a combination of all of these that feed into this decompensation probability, that as you get to stage four and progressive portal hypertension as measured by hepatic venous pressure gradient, you start having an increased risk of decompensation. So it is extremely important when we think about F4 studies in the compensated patients, we need to identify where they are in this spectrum, because as you can see, even under conditions of compensated cirrhosis, this covers a lot of ground because you can have an F4 that looks more like an F3, and you can have an F4 who's on the verge of decompensation. And the amount of biology that's going on can vary considerably from one patient to the next. So picking the right patient is extremely important and has to be linked to the mechanism of action of your drug. Next slide. So when we think about the patient, the next thing is the right target. So then the target could include cirrhosis, it could impact systemic effects and the comorbidity profile. So agents that are targeting just disease activity alone or fibrosis may or may not be sufficient. You also need to understand how, depending on where you are picking the patient in that pathophysiologic cascade, whether you need to attack some of the systemic effects that lead to portal hypertension. And so, again, leads to the idea of possible combination therapies as you get close with more portal hypertension, more vasodilation, etc. And then, of course, there's the comorbidity profiles that is still in play. So again, picking the patient, very important. And for a drug like pegozafermin, picking patients who have developed fibrosis and early portal hypertension seems to be the best sort of profile for this type of patient, rather than someone who is already sliding into the scope. I mean, maybe it will work in that population, but I think it makes more sense based on the data available, to take people who are cirrhotic, compensated with some portal hypertension. Next slide. And so this, of course, raises the question, why do I say that? Well, we know there are direct anti-liver fibrotic benefits and metabolic benefits. It suppresses Kupffer cell and stellate cell activation, reduces pro-fibrotic signaling, and continues to suppress the metabolic insult. So if you pick the patient before decompensation-related cirrhosis, disease-agnostic, cirrhosis-related decompensation, driving pathophysiologic events are becoming the major driver of disease progression, then it fits into the FGF 21 paradigm. And more robust and consistent fibrosis regression data in advanced fibrosis patients and even in the cirrhotic patients, that we have data so far, all seem to fit in. Talking of cirrhosis, next slide. In the stage two studies, there's a subset of people who actually had cirrhosis, and whereas you can see, almost half of them showed fibrosis improvement by a stage or more compared to none in the placebo arm, although the numbers are very small and there is a caveat around overinterpretation. So when you look on the right, you see all the other parameters also improved in this population. So all of these suggest that this is not a random event, it is not false discovery, that this, there may be real biology over here. All of which gives us sort of relative confidence that if there is a molecule to take forward in the cirrhosis population, then FGF21 makes sense. Next slide. Of course, we've previously shown that if you reduce the fibrosis stage, it does translate into less clinical outcomes. This is shown in the study from 2022, where we looked at a number of these trials. These were part of the Gilead selonsertib and simtuzumab data, where if you look at those who had cirrhosis, and this is almost 1,000 patients with cirrhosis, when you look at the 176 who had less than stage four on the second biopsy, you can see almost an 85% reduction in likelihood of having a clinical outcome in this population. Looking at it again on the right-hand side, using a modified Ishak fibrosis stage, the effect is even further magnified. Next slide. This brings us back where, you know, where we think that eventually the two approaches would be based on where you start. Depending on cirrhotic patients, you have to prevent decompensation, death, reverse cirrhosis. For those with stage in the middle, you got to stop progression to cirrhosis and ideally reverse fibrosis and treat NASH and reduce the fibrosis. And then, of course, for people at the very bottom, if you can effectively improve their metabolic status, you may prevent them from progressing. And of course, lifestyle intervention is for everybody. Next slide, please. So with that, you know, I'll stop, and I'll turn it back to Rohan to walk you through the next set of data and slides. Thank you very much, Dr. Sanyal. Thank you for that fantastic overview of the treatment considerations in non-cirrhotic and cirrhotic patients with MASH. I now want to illustrate how we are incorporating some of these considerations into the design of the ENLIGHTEN-CIRRHOSIS study, a recently initiated phase III study in MASH patients with compensated cirrhosis, also known as F4. This slide provides an overview of the ENLIGHTEN-CIRRHOSIS study design. As mentioned, it is the first FGF21 analog to enter a phase III trial in patients with compensated cirrhosis. This is a randomized double-blind trial comparing pegozafermin 30 milligrams every week versus placebo in approximately 760 patients. All the patients will have a baseline biopsy, and a pre-specified subset will also undergo a follow-up biopsy at 24 months for the primary endpoint, evaluating fibrosis regression from F4 to an earlier stage. As Dr. Sanyal mentioned, fibrosis regression could convey substantial benefit by reducing risk of subsequent liver-related outcomes. We picked 24 months for the follow-up biopsy after extensive review of prior trials, consultations with experts, including Dr. Sanyal, and with regulators. These data are intended to support accelerated approval in the F4 patient population. We will follow all the patients in the study for clinical outcomes. As we heard from Dr. Sanyal, the primary long-term treatment goal in cirrhosis is prevention of decompensation and or death from liver failure. The clinical outcome endpoint is intended to support full approval of pegozafermin in this population. This is an event-driven endpoint, and we expect it will read out after the histology endpoint. Go ahead. We believe pegozafermin is positioned for success due to the design of the ENLIGHTEN-Cirrhosis study and the ability of pegozafermin to show a treatment benefit. For the histological endpoint, our confidence is based on the mechanism of action of pegozafermin, as reviewed just in this presentation, and the robust anti-fibrotic effects we observed on histology and non-invasive tests in the phase II ENLIVEN study across F2, F3 patients, as well as the small cohort of F4 patients. For the histology cohort, we have a pre-specified selection of less advanced F4 patients, since, as Dr. Sanyal explained, they are more likely to show regression of fibrosis. At 24 months, this will allow pegozafermin sufficient time to work through the scarring that has accumulated as the patient's disease has progressed over a long stretch of time, and also to potentially reduce the noise in the placebo group from biopsy variability. We have a robust statistical plan that is well powered to detect a clinically meaningful treatment delta. We will be following all the patients enrolled for clinical outcomes. Based on pegozafermin's clinical profile, we're confident in its potential to delay or halt progression relative to placebo treatment. The clinical outcome events in cirrhosis trials include liver transplant, death, as well as evidence of major liver related outcomes. These include ascites, varices, and hepatic encephalopathy, amongst other end- endpoints, all of which can occur as cirrhosis progresses towards liver failure. We were pleased to align with FDA on some modifications to the original guidance endpoint definitions. These modifications will allow us to detect events earlier, which should help the trial reach the final number of events more quickly and therefore potentially accelerate our timeline to outcomes readout. We have a rigorous process for event ascertainment, including adjudication committees, detailed charters, and central reading to ensure that the events are well characterized and well described. As mentioned, our trial is well powered to detect a clinically meaningful hazard ratio, and we have built in opportunities to make adjustments if needed, given outcome data in MASH cirrhosis is limited at the current time. In conclusion, we're confident in our phase III trial design for F4 and in pegozafermin's ability to potentially hit on both histology and on outcomes. I'll now turn it back over to Rohan for some additional comments. Thanks, Hank. As we advance the program towards one day, hopefully potential commercialization, I'd like to spend some time talking about our perspective on the market opportunity for pegozafermin. Over the past few years, we've conducted extensive market research amongst physicians to understand treatment goals, the market evolution, and perceptions on our product profile. In a recent survey amongst hepatologists and gastroenterologists, they identified the primary criteria for selecting a drug for advanced MASH patients is the ability of the drug to reverse fibrosis. They also emphasized the importance of combinability with other drugs, which underscores Dr. Sanyal's earlier comments about potential combination therapies. And finally, they highlighted that a drug's tolerability was crucial, given the chronic nature of MASH treatment. And so when you think about the multiple profiles or the profiles of multiple drugs, either approved or in development for NASH, the physicians believe that the FGF21 class, including pegozafermin, could offer the greatest promise due to its strong anti-fibrotic benefits, its potential in cirrhotic patients, and its broad metabolic benefits. When comparing pegozafermin's profile to others within the class in this research, physicians highlighted the superior benefit risk profile based on the fibrosis data and superior tolerability. Furthermore, the convenience of every two-week dosing, which could be a meaningful benefit for patients, would drive their prescribing behavior with the product to be commercialized one day. And I'd like to share our perspective on the market and projected growth over the coming decade. As we and others have suggested, GLP-based therapies will certainly have a role in the NASH treatment paradigm. However, we firmly believe that there remains a significant opportunity for therapies that offer a stronger anti-fibrotic effect than these therapies. So when you think about the pyramid Dr. Sanyal shared, we're talking more about those top two parts of the pyramid. On this chart, we have plotted in the blue line the projected MASH prevalence in F2, F3 patients based on the 2018 publication in Hepatology by Estes et al. Of the about 13.5 million patients shown on this chart by 2035, roughly 6 million of these patients are expected to have F3 disease. If one were to assume that GLP-1 therapies were increasingly adopted in patients with MASH, we would expect that some patients would not progress to F 2 and F 3, and some may see a reversal of their fibrosis, thereby reducing the prevalence of patients looking for additional therapies. We show this as a range with a purple dotted line and the range bars around it, yielding an approximately 20% decrease by 2035 when compared to the projections in the Hepatology paper. Now, while the prevalence of eligible patients could decrease, we expect actually the absolute number of patients eligible for treatment would actually increase based on increased diagnosis rates. Currently, the diagnosis rate remains very low. It's well below 10%, which is not surprising given that we had the first approved therapy only a couple of months ago. However, with the approval of new effective therapies, the diagnosis rate is expected to increase, and this is consistent with what's been observed in other categories, including in hepatology, what happened with the HCV category. So we expect that within a decade, the diagnosis rate could get close to 20% of the prevalent population, resulting in approximately 1.8 million patients eligible for therapies, which represents about a 12% CAGR over this diagnosed time period. We project that approximately 40%-45% of these patients could be F3 patients, representing a very large market for effective and potent anti-fibrotic therapies like pegozafermin. Using a similar logic for the F4 patient population, we see a similar trend with one key difference. Given the GLP-1s have not demonstrated a benefit in this patient population, as in the chart which aren't shared, and that the progression to F4 is a long process, the intermediate-term effect or impact of GLP-1 therapies on the F4 market is likely to be more muted. Further, given that the severity and complications of the disease state, we expect a higher diagnosis rate in F4 patients than in the F2, F3 patients. So when we put this together, we estimate that there could be roughly approximately 800,000 patients with compensated cirrhosis who could be eligible for effective new therapies by the end of this time period. Pegozafermin and FGF21 class have shown compelling data in this patient population, and we believe one day we could dominate this market segment. Now, as part of the recent work we did, we conducted some additional work with a leading consulting firm and sought feedback from physicians on their treatment algorithm for MASH patients who could be candidates for or have had GLP-1 therapies in the past, whether it's for their diabetes or obesity. The objective of this work was to identify patients who could be potential patients to be put on pegozafermin. Broadly speaking, there were three groups identified by the physicians based on their prior experience with GLP-1 therapies. In the first bucket, we have patients who are already on existing GLP-1 therapies, and upon a MASH diagnosis, if their fibrosis is limited, physicians are likely to continue them on the GLP-1 therapy. However, if they have advanced fibrosis based on non-invasive tests, what physicians told us is they will add a MASH-specific therapy in addition to the existing GLP-1 therapy. In the next group, we have patients who were on GLP-1 therapies but have discontinued the therapy. Now, if these patients have discontinued for a lack of efficacy or tolerability concerns, physicians would be inclined to put them on an effective MASH therapy like pegozafermin. And then finally, there will be a bucket of patients who are GLP-1 naive patients. If these patients do not have diabetes or obesity, which would most likely be lean NASH, physicians view pegozafermin and like therapies as the preferred option. In In patients who would be eligible for GLP-1s based on their underlying disease, the utilization of pegozafermin and/or MASH-specific therapies would be driven by the nature of their fibrosis stage. But in summary, what you can see here is we expect physicians to prescribe a MASH-specific therapy in most cases, unless the patient has a limited degree of fibrosis. Finally, we asked physicians how they would allocate shares in the future across the key drugs based on their product profiles. At its peak in the F3 market, we expect that the FGF21 class to garner approximately 45% of the market, with pegozafermin getting close to 30% based on a superior tolerability profile and dosing convenience. Importantly, what they told us is that about half this usage is expected to be in combination with GLP-1 based therapies, and the balance is monotherapies. Not surprisingly, GLP-1 therapies are expected to be used extensively, with roughly about 65% of these patients receiving the drug, but most of them getting a MASH-specific add-on to their GLP-1 therapy. When we turn to the F4 patient market share, we see that the FGF21s take a greater share of the market relative to metabolic drugs based on the potential efficacy they've shown. Pegozafermin could get a roughly about a 35% market share of treated patients at its peak, with the class garnering about 60% of this market. Given the limited benefit of GLP-1s in this patient population, one sees a lower share than what we saw in the F2, F3 population, and it's more likely to be used to treat their underlying disease, like diabetes, obesity, versus as a MASH therapy to address their cirrhosis. In summary, we think pegozafermin is uniquely positioned for success across key several areas. First, the strong reversal of fibrosis data, together with the pleiotropic metabolic benefits, offer a meaningful and differentiated profile, meaningful and differentiated profile for patients with advanced NASH. Next, pegozafermin boasts a best-in-class tolerability profile within the FGF 21 category, and the convenient every two-week injections and the liquid formulation make it easier for patients to adhere to their treatment regimen and the ability to be co-formulated. Despite the expanding use of GLP-1 therapies, the MASH market is expected to continue to grow as you think about the number of patients eligible for treatment. And we believe we could have a unique positioning, especially in the advanced patients and compensated patients, compensated cirrhotic patient group, and capture a significant market share there. Then finally, we have multiple shots on goal for success with phase 3 studies in the pre-cirrhotic population, in the compensated cirrhotic MASH population, and in SHTG. Each one of these programs represent a significant opportunity to bring this promising therapy to market. Before we conclude today's call, I'd like to extend my gratitude to Arun, my fellow 89bio teammates, to the investigators for their tremendous commitment, and to our shareholders for their continued support. Most importantly, we send our sincere appreciation from everyone at 89bio to the patients and the families for participating in our clinical development program for pegozafermin. This concludes today's prepared remarks. Operator, we may now open the line for Q&A. Great, thank you, Rohan. So at this time, we will be conducting a question and answer session with our speakers. As a reminder to our audience on the webcast, 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. And to our analysts that are on the line with us, please use the Raise Hand feature to indicate you have a question. Please hold for a brief moment. So our first question comes from Steve Seedhouse at Raymond James. Please go ahead, Steve. Great. Good morning, everyone. Thanks for hosting the event. I wanted to start maybe asking Dr. Sanyal if he's still around for Q&A. Actually, maybe I should confirm if he's able to take questions first. Yeah, Steve, he will be available for questions. Okay. Okay, great. Dr. Sanyal, so it sounds like you were consulted on the two -year time point for the histologic assessment in the cirrhosis study. Obviously, that's a key time point. There's a follow-up analysis of an efruxifermin study coming next year, and obviously, the interim analysis of this pivotal pegozafermin study. Can you just maybe elaborate on your thinking around that time point, how you assessed it in terms of, you know, likelihood, you know, we'll be able to establish reversal of cirrhosis at a time point, at that time point, and just your experience managing these patients? Do you think that's ideal and likely to yield positive results? Yeah, I think the rate of events, if you take an unselected population of patients with cirrhosis, the rate of events is in the 3%-4% per year across multiple etiologies. Now, remember, many of those studies just take... When you just go out and capture people who have compensated cirrhosis, you really don't know when they started. And so it's a mixed bag of people who developed cirrhosis relatively recently, versus some who've had cirrhosis for a period of time... So depending on where you are in the natural history of the study, if you're starting with stage three, progressing into cirrhosis and then into their rates of events are relatively low. And this is what we've seen, and, you know, you will see there'll be some data shown at DDW in a few days also to support that. So, that's why I think it is important not to go too early because your rate of events might be a little lower. The reason I think a lot of people initially got excited that we could do these studies early is when we did the original simtuzumab and the selonsertib trials, there weren't that many competitive, competing trials for the cirrhotic population. So people who had cirrhotic patients sitting in their clinic encouraged them to join those trials, and two-thirds of the people in the simtuzumab trial already had clinically significant portal hypertension. So I think goes back to identifying the right population. What we do know confidently is that FGF 21 will reduce activity and fibrosis, and the fibrosis improvement potentially all the way into that stage three, stage four interface. We don't really have a lot of data in the portal hypertension space, so you don't want to do a trial where somebody's about to fall off the cliff, but you want to catch them when they're in the stage three, stage four transition, or stage four portal hypertension transition, but not probably a whole lot further beyond that. So for these reasons, I think the two-year timeframe makes sense rather than going for a shorter timeframe. And of course, we'd have to review how many events are occurring and, you know, as we get into those trials. And where we think we can really shift the needle is actually reverse the fibrosis. Now, the fibrosis reversal data was done at one year, but I think if we go to two years, everybody wants to know also that the results are durable. I think, it sort of, you know, meets both of those, both showing, having a high likelihood of being able to show the benefit and also being able to show durability of response. So for those reasons, I think that's sort of why we landed where we landed, time-wise. Great. Thanks. Steve, I might add one comment. The last part, which Arun said, this was an important consideration even in our discussion with the agency, that two years is probably the sweet spot around where you want to show a durable response, you know? And that's an important thing from a regulatory perspective also. A couple more, if I could. Just, Dr. Sanyal again, now that we've, you know, can see the FDA review materials and the details in the package insert for Rezdiffra, curious how you would compare or contrast the safety tolerability profile you see emerging for FGF 21 class, efimosfermin in particular, compared to Rezdiffra. So the first caveat is Rezdiffra is actually quite, quite a well-tolerated drug with a very minimal side effect profile for the majority of patients. There are some minor GI-type disturbances, which are largely manageable. One little red flag that's actually in, noted in the label as well, is the single patient who developed a significant elevation in liver numbers. Now, this is a patient who had other autoimmune-type features, probably what might not have been the optimal candidate for the, you know, to start with. But, personally, I think, you know, if a patient has a high ANA and has steatohepatitis, I would be very cautious in that population, follow them more closely, maybe simply till we know more and there are more people treated. Remember, you know, the Rezdiffra, all of the data, it's a first-in-class type molecule, so the data are all what we have from the clinical trials. And once, you know, there's larger use, we will have a larger database to be able to say that was a nothing burger or whether there's something really there. The FGF 21's, so far from a liver safety point of view, no signal that I am aware of. You know, the main tolerability issues are some GI-type tolerability issues, but you don't really have people stopping therapy right and left because of tolerability issues. So by and large, I think it's a quite a tolerable, you know, drug class of molecules, and the weekly injections seem to be more or less acceptable to patients. Especially those I've found in my experience, that the more fibrosis there is, the greater is the acceptance of an injectable molecule. Last question for the management team and Dr. Sanyal as well, if you want to opine, just given your involvement in the drug development landscape here. Obviously, with Rezdiffra, indicated now for NASH, without really an explicit requirement for biopsy and maybe you know, maybe semaglutide as well down the road, it's an interesting dynamic as you're running clinical trials in NASH, where, of course, there's paired biopsies as part of the protocols. How are you anticipating being able to manage that and find patients as readily as has been achieved in the past? And could you just comment on that dynamic going forward and your confidence in being able to manage it? Thanks so much. So there are a lot of questions packed in that, but I'll answer, try and answer two, and then turn it over to the 89bio team. One, that highlights the importance for doing concomitant NIT assessments in the context of these trials. So that we can say these are the NITs, you know, that identified the population, and these are the NITs. This is how you would identify response versus non-response, durability of response, criteria, et cetera. And there are some documents in the works. I think AASLD is working on a document to sort of address this with Rezdiffra. And I think that'll create a framework of how this would be approached when subsequent drugs are approved. The second part of this is, of course, linked to, you know, a recruitment into trials. If once Rezdiffra is widely available and being prescribed, it may impact the recruitment into trials for non-cirrhotic trials, potentially, and I think there was going to have to be some people are going to have to adjust to that piece. But it's important to note that it is not approved for patients with cirrhosis. So certainly for the cirrhotic population, that should not be an issue. Hey, Hank, you want to comment a little bit on how we are thinking about it from an execution perspective? Sure. Thanks for the question, Steve. So as Dr. Sanyal mentioned, you know, as the landscape for the non-cirrhotic patients, you know, thankfully, is improving because there will be an available therapy. It's not yet widely available, and there's a choice for physicians to make as to whether to put their patient on a commercially available product or potentially put them in a trial where they have access to a medicine like pegozafermin that may have a stronger anti-fibrotic effect. In terms of how we're thinking about it, one is, you know, we've been getting very good feedback from investigators who obviously are aware, you know, in the US, investigators are aware of Rezdiffra availability or increasing availability. These investigators are still very interested in putting patients into trials because, again, they have access to pegozafermin, which may have a better impact for their disease state. Second, Rezdiffra, while it's becoming available in the U.S., is not available outside the U.S. And from a global trials perspective, you know, this is a global trial, and we will, you know, we'll be starting up sites in many different countries in order to, you know, in order to get the trial recruited on in an appropriate timeframe. And those patients in other countries, as of yet, don't have access to Rezdiffra. I think the final thing is that there's just, as was pointed out in the epidemiology, there are enormous numbers, unfortunately, of patients with MASH, who can qualify for these trials, some of whom may want to go on Rezdiff, but many of whom may want access to a trial with, again, with, access to potentially to pegozafermin. Let me just pass it back over to Rohan to see if there's other points to be made here. Yeah, that's good. Maybe we can take the next question. Thank you. Great. Thank you for the question, Steve. To our analysts on the line, we kindly ask that you limit yourself to one question and one follow-up due to time. So our next question comes from Lisa Bayko at Evercore. Please go ahead, Lisa. Hi, thanks for taking the question. I was wondering if you could circle back to the initial, you know, data for pegozafermin and particularly the placebo rate. And that's been something I think it's always kind of been curious, and people scratch their heads about that. Now that you've taken time to kind of look through the data more, can you kind of offer some explanations of why the placebo rate was particularly low? I mean, in a lot of ways, it's a good thing. It just sort of deviates from some of the other studies. So, that's my first question. Hank? Sure, Lisa. So as we've been pointing out, ever since the ENLIVEN data first came out in March of 2023, the placebo rate is low in our ENLIVEN trial, and that's likely due to the methodology we use for reading slides. So we use this three-panel consensus method with essentially an algorithmic approach, where there's no conversation between the pathologists to, you know, to align their reads. So it's all aligned through the algorithmic approach as full consensus mode or median. What we've also been pointing out is that if you look at the REGENERATE trial from Intercept, when they reread their study again, using a three-panel consensus, which was requested by FDA prior to their resubmission of their NDA, that three-panel consensus read also came out with very low placebo rates. And this is, you know, I think this and that was in a much larger population, a global study, different pathologists, we understand, than read our study. So I think this is coming down to the three-panel methodology. So what we've been understanding as we've talked to other, you know, and just been, you know, hearing through the environment, is that this approach that, you know, that we used in ENLIVEN, is being picked up by other, sponsors. And again, placebo rate in MASH trials in the past was highly variable and was one of those factors that you just couldn't, you didn't know where you're gonna net out, and obviously, that has a significant impact on, potential for observing a treatment response. So we now have our study, we have the Intercept study, using this three-panel approach, showing very low placebo rates. That's probably likely to be the real, you know, closer to the ground truth. So if that provides some level of reproducibility, it also creates a nice way for our trial, which we're using it again in our studies, and maybe other people to be able to better isolate treatment difference. Okay, great. Thank you. And then, just curious, and maybe this is best directed for Dr. Sanyal, but how are you thinking about the kind of emerging fibrosis data? And I think we're going to get some updates at EASL from some of the weight loss medicines, and I'm thinking in particular of survodutide, which will have, it has both, you know, GLP and also a glucagon component. And there, it seems like it may offer both a fibrosis benefit as well as weight loss. And so when those kind of compounds, if they do get introduced, how are you thinking about how that changes sort of the need for NASH-specific therapies? Thanks, Lisa. I'm going to ask Hank to answer that. So we just got a message. Dr. Sanyal had to drop off. There was some- Okay. Emergency he has to deal with. But, Hank, maybe you can talk a little bit about kind of, you know, what's been with the glucagon therapies and what we've heard from the KOLs as that ties to MASH therapies, you know? Sure. So I mean, we first of all, we need to actually see the actual data, which is expected to be presented at EASL for survodutide. There are a number of compounds in development that have the GLP-1 glucagon approach. There, you know, there is the glucagon does add a significant benefit from a liver fat reduction standpoint. We don't yet know until we see their data, what exactly the fibrosis benefit truly is going to be. So there may, there, you know, there may continue to be evidence that FGF21 analogs like pegozafermin continue to show a greater degree of fibrosis improvement. We'll see how that data plays out. I think more importantly, with the glucagon addition comes a host of cons, potential adverse events that are going to be potentially challenging to manage. So if you look at some of the other data from the BI compound, as well as with other of the GLP-1 glucagon agents, there's a GI profile, but then also importantly, there's a cardiac profile that's going to be very relevant in the NASH population. So I think, you know, to net out here, these are agents that we just need to [audio distortion] we will keep an eye on. They are likely, in the end, going to be still used early, as Dr. Sanyal mentioned. You know, because again, the initial treatment goals are going to be—for those patients—for diabetes and obesity. Whether they are actually beneficial in NASH, I think still, you know, will remain to be seen, and it's not clear that, what, you know, what these companies are planning to do, whether they truly are planning to go in with these dual and triple agonists into phase III programs, in MASH. So let's see what the data shows, and then we'll be able to provide some additional insight. Thank you. Thanks for the questions, Lisa. Our next question comes from Thomas Smith at Leerink. Please go ahead, Thomas. Hey, guys. Good morning. Thanks for putting together this event. Thanks for taking the questions. I believe Dr. Sanyal is going to end up presenting the final results from the REGENERATE trial for OCA at EASL, and then obviously, we'll have the longer-term data for efruxifermin in compensated cirrhotics early next year. I was just wondering if you could comment and maybe talk about your potential learnings from these data sets with respect to event rates. You alluded to an ability to make some adjustments to your phase III studies. Can you just expand on those comments and talk about potential modifications you could make to incorporate the learnings into ENLIGHTEN-Fibrosis and ENLIGHTEN-Cirrhosis? Hank? Sure. So, I mean, we're looking forward to seeing the REGENERATE data as well. We are hopeful that they're going to present their clinical outcome data. That I think has been essentially a missing and critical piece in the understanding of how patients progress in a clinical trial setting in MASH. And, you know, the REGENERATE trial was a large trial with a long period of follow-up. My understanding is that we are expecting to see some of the outcome data. I think it's also going to be important with REGENERATE to know what you know, that trial enrolled F1, a lot of F1 patients, so the event rates there are going to probably be almost zero. There's also a good chunk of F2 patients. Again, whether they get to events by the end of that trial, I think is going to be an important comparison consideration. For our study, we are emphasizing F3 patients, so this is ENLIGHTEN-Fibrosis, because one, that's the treatment population we think where pegozafermin is most likely to be used in the non-cirrhotic setting. And secondly, because our ENLIGHTEN-Fibrosis trial is continuing on through outcomes. We'll see what the event rates are in that context, and then we may have some opportunity to think about whether we've sized the trial correctly and whether the event estimates that we have to start with are going to be on target or not. In terms of the [audio distortion] so that's for REGENERATE. So I think those are really critical data for the field. They're also, you know, any correlations with NITs are going to be very useful. So that's a very important data set, and hopefully, there'll be an actual publication or multiple publications, not just a presentation. The Akero, efruxifermin, F4 data, you know, which is, at 96 weeks, apparently, you know, is expected to come out in first quarter next year. Also an important data set. We don't know how many patients are still retained in the trial. Hopefully, enough to get an estimate of treatment effect. Again, the, that will be very useful as a marker for both placebo effect, in that, you know, at two years, and potential treatment delta. You know, we've made estimates for our, you know, based on, on our best judgment from the existing data with, you know, with pegozafermin and efruxifermin and other compounds. But, you know, we need to. You know, the more data we have, we can think again about whether our, our assumptions are on target or whether we need to make some, some adjustments. That's how I would think about this, Steve. So Tom- Or Tom, sorry. Two other things I would add. One is in the cirrhosis trial, we have already baked in an ability to re-estimate the sample size as the trial progresses, and we see how the events are accruing. You do this pretty often, right? Because there's not a lot of history in event-based outcome trials in F4. I think the other thing from the efruxifermin trial, I think will be helpful if they share the data, was to understand which type of patients had seen the regression of fibrosis. Assuming that they see a good regression of fibrosis, so it'll give us a sense if there is a difference in certain types of baselines of patients. So I think these are both important data sets, and the timing is really good because we've just initiated these trials, and it gives us some flexibility, you know, to make adjustments if needed. Got it. That makes sense. Very, very helpful. And just one follow-up, if I could, just as we look forward to seeing the detailed long-term follow-up data from ENLIVEN at EASL, what are, I guess, some of the new analyses and data sets we should be watching for with that presentation? Hank? Yeah, Tom, I think we will share that when we get to the, you know, when we get to the meeting. We've disclosed a fair amount of information already. There are some interesting new things that we will be able to talk about, but I think we need to hold off until we actually do the presentation. Got it. All right, guys. Thanks for taking the questions. Thanks for the questions, Tom. So our next question comes from Kristen Kluska at Cantor Fitzgerald. Please go ahead, Kristen. Hi, everyone. Thanks for hosting this event for us. Really appreciate it. So I wanted to talk about the F4 patient population and the sweet spot that was laid out in terms of best patient targeting. Do we have a sense of what% or patient number that looks like of the total F4 population? And then of the data that you have presented so far in the F4 patients, do you believe that this essentially fits that window, again, to help with the greatest probability of success? Thank you. Hank? Yeah. So the data that we presented from the F4 patients in ENLIVEN, those are patients that are early in their compensated cirrhosis progression, if you will. And, you know, we obviously saw a very nice number of those patients have fibrosis regression. So that's the target group, which are patients that have less advanced F4 disease, because those are, as Dr. Sanyal mentioned, and, you know, as we've looked at the literature, those are the patients that have the best opportunity for fibrosis regression. We have, you know, ways in which we can identify those, you know, through non-invasive tests and other means to help identify what will be the histology cohort for the F4 study. In terms of the numbers of those people within the F4 spectrum, there are more people than the earlier side of it than there are that are more advanced. So just like within NASH, where you start, you know, there's more F1s than there are F4s, there's more early F4 than there is late F4. So we think this will be a good group of patients to that we'll be able to find relatively easily and enroll for clinical trials. Hey, Kristen, just so to build on what Hank said at the end. So if you go to the Estes paper, I believe it's north of 80% of the cirrhotics are compensated cirrhotics with a higher percentage in the earlier stages. So it's a pretty high percentage. Got it. Thank you very much again. Thanks for the questions, Kristen. Our next question comes from Ellie Merle at UBS. Please go ahead, Ellie. Yeah, thanks so much for taking the question. Just regarding the recent manufacturing deal that you did with WuXi, can you walk us through the rationale here, and also how you're thinking about the latest provisions in the BIOSECURE Act, with respect to the grandfathering through 2032, and any long-term implications this might have for you? Thanks. Sure, Ellie. So the reason for doing the deal is we were focused on making sure that by the time we are ready to file, assuming that we have positive clinical data, we also have a commercial scale manufacturing setup, such that were we to get approval, we have enough material available to support the commercial needs. So that was the driving, you know, factor behind all of this. Because it kind of would be a shame to have good data, get a file, and we don't have large-scale commercial manufacturing ready. So we have been working with this vendor for nearly two years to scale up the manufacturing. So currently, we have what I'm going to call mid-scale size manufacturing, which is like a 3,000-liter reactor.... and really for commercial scale, given the size of the market potential, you're looking at 20,000- liter reactors and 30,000-liter reactors. Having worked with the vendor for a long time, we were actually technically able to scale up the fermentation process of the vendor. So that was important, and then the second one was from a timing perspective. The vendor already has an existing reactor of that scale, so we knew we could actually get it done in timing to support the filing. So the decision criteria was, we put the criteria as the most important is, what's the technological risk? Which we got a check mark. What is the timeline risk? Where we have a check mark, and it met the needs. And balancing it a little bit with the geopolitical risk, because I don't want to suggest that that was not an important consideration. Needless to say, it's also much cheaper to make materials in China than in other parts of the world, and the quotes. It was a competitive bidding process. The quotes we got from other vendors were significantly, significantly higher. We are obviously monitoring what's happening with the BioSecure Act. As you saw last week, you know, now they're talking about they're gonna grandfather contracts till 2032, which gives us a lot of flexibility, because in addition to now having got this one done, we continue to look at backups and alternative manufacturing facilities outside of China for something to really go wrong. But we feel really good that based on the positive data we have, the positive regulatory outcome we had, it was time to invest in manufacturing to make sure we can support commercial scale. Great, thanks. Thanks for the questions, Ellie. Our next question comes from Justin Zelin at BTIG. Please go ahead, Justin. Thanks for taking the questions. Probably for Hank, you know, now that incretins and, and now Rezdiffra are commercially available, can you talk about the dynamic with patients being on these therapies in your trials, ensuring balance between arms and any expectation on the percentage of patients who will be on these therapies in the studies? Thank you. Sure, Justin. So we are a couple of things. So for Rezdiffra, we are excluding those patients from entry into our studies because there's just not enough information about the potential role of pegozafermin in patients on a new therapy like Rezdiffra. For incretins that are already approved, those are considered background medicines, and patients need to be stable for six months prior to entry into one of the studies. And that's not a high bar because many of these patients have been on these therapies for a long period of time. I think the fact that we can find a ton of patients that are on stable incretins again speaks to the fact that the incretins are not preventing ultimately the progression of MASH into the later stages. So for GLP-1 therapies in the, in the fibrosis, in the, in this ENLIVEN fibrosis study, we are stratifying by GLP-1 use, so yes or no, in order to, to, manage any imbalances you know, any challenges or imbalances from, patients coming into the study on those therapies, and if they do, in, in the end, have some impact on the disease process. The, use of GLP-1s is far more extensive at the moment in the U.S. than in other countries. As I mentioned earlier, it's a global study. We're expecting a high, you know, some high-ish proportion of patients in the U.S. will be on GLP-1 background therapies. In ENLIVEN, it was already, you know, 20-some%, but it'll be less, you know, for the overall study. So hopefully that helps you, with that context. Thanks for taking the question. I know we are pretty much a little over time. I know... Can we have, like, two last two questions from the last two people? Maybe one question each, just in the interest of time. We appreciate everyone staying longer than what we had scheduled the meeting. Yep, that sounds great. So thanks for the questions, Justin. Our next question comes from Thomas Yip at H.C. Wainwright. Please go ahead, Thomas. Hi. Thank you, everyone. Thank you so much for taking the questions, asking questions for Ed. So, as Dr. Sanyal pointed out earlier, that it could be challenging to track fibrosis progression, especially from F3 to F4. What do you envision as the best practice for F3 patients, and what are some emerging technology that can help track fibrosis progression? Thank you. I think... So the only way to definitively define F3 and F4 is histology. So, but that's not, you know, so biopsy is not, is not, is not gonna be commonly done, and, and you can see in the Rezdiffra label, it's not even required. So it's gonna be non-invasive testing, and the most commonly available non-invasive tests are ALT, AST, the FIB-4, which uses those two, plus platelet count and age, and then also, FibroScan, or, you know, liver stiffness through VCTE. So it's gonna be some combination of those that is gonna help define the boundaries between F3 and F4, but it won't be precise, because you need histology to be precise. All right, great. So thanks for the questions, Thomas. Our final question comes from Joe Kim at RBC. Please go ahead, Joe. Hi, this is Joe, and for Brian, thank you for hosting this helpful event and taking my question as well. So based on your AASLD and regulatory discussions, can you talk more about some of the key events that occur earlier on in patients with decompensated liver? How quickly these events may occur with the targeted F4 patients for enrollment and how much you know can the timing of the occurrence may vary in different individuals? Thank you. Frank? So if you [audio distortion] Yeah, so let's take ascites as an example. So that's a complication where patients accumulate fluid in their belly and is a known complication of progressive liver disease. You know, it doesn't become massive ascites with subsequent complications immediately. It accumulates over time, and there are points along the way at which there are important time points at which physicians intervene, and these are clearly illustrated in the guidance for management of patients with cirrhotic disease. So that's an example of a way in which we can utilize the progressive nature of cirrhosis and the clinical treatment practice that's already well known to define earlier time points. Thank you. And if there's time for one more follow-up question. How meaningful can every other week dosing drive the compliance over every week dosing? I believe you're testing both every other week dosing, as well as every week dosing for fibrosis versus every week dosing for cirrhosis. Just wanted to see what the rationale behind it was. Thank you. So the rationale was in a less severe patient population, the incentive to be compliant is lower. If you are cirrhotic, you know you're going to take your drug because you don't want downstream complications. So there, compliance, whether it's a weekly, every two weeks, might not make that much difference. But for the more asymptomatic, like advanced population, it's important. And when you look at other therapeutic areas we have looked at, it does make a big difference between a weekly and every two weeks. In fact, some of the leading drugs, leading biologic agents, have been a every two-week dosing regimen. And in our market research, over 60% of patients prefer the every two weeks to a weekly dose, other things being equal. So we think it's a very meaningful difference, and it's important to drive compliance and persistency. Makes sense. Thank you. Great. Thank you for the questions, Joe. At this time, I'll turn it back over to Rohan for closing remarks. Cool. Thanks, everyone, for joining our call today. We appreciate you staying longer than we had scheduled, but we really appreciate the questions. At this point, we are at the end of our session, and you may now disconnect.