Hi, everyone. Good morning. I'm Eliana Merle, one of the biotech analysts here at UBS. Very happy to have Altimmune here with us today at the UBS Obesity Day. Joining us from Altimmune is Vipin Garg, Chief Executive Officer, and Scott Harris, Chief Medical Officer. And joining me from the UBS side is my colleague, Elliott Bosco. With that being said, thank you guys so much for joining us. And if any of you on the line would like us to ask any specific questions, feel free to shoot us an email, and we will do our best to include it. With that being said, I'll turn it over to you, Vipin. Maybe just for the investors on the line that are newer to Altimmune, can you please sort of introduce the company and provide a brief background on your pipeline and programs? Absolutely. Well, thank you for inviting us, Eliana. Pleasure to be here. So Altimmune is developing a GLP-1 glucagon dual receptor agonist for obesity and for MASH. We have completed a Phase II program in obesity, and we'll talk more about the data that we have generated. We're also in the process of completing enrollment in a Phase IIb MASH trial, and we expect to have data from that in the first quarter of 2025. As you know, the obesity landscape is changing. It's evolving, it's developing. The first wave of drugs for obesity were all GLP-1s or GLP-1 GIPs. Basically, the mechanism of action there is appetite suppression. By adding glucagon, what we are doing is adding another component to the to weight loss, which is energy expenditure, so not only appetite suppression, but combined with energy expenditure. In particular, we are also transitioning or increasing fat burn. That has many benefits, as we'll talk more about that. Glucagon receptors are found in the liver. Liver is the center for fat metabolism, so we think there's some significant benefits that glucagon brings. Many of the patients... In fact, only about 20% of the patients with obesity have diabetes. Up to 70% have dyslipidemia or lipid-related disorders, including NASH and MASH, the, you know, high liver fat content. And so it's really important to treat that directly in addition to people losing weight, and that's where we think glucagon can play an important role. Absolutely. Before we jump into the specifics around obesity and MASH, maybe just high level from a competitive standpoint, how are you thinking about the other GLP-1 glucagon agonists being developed, such as mazdutide and survodutide? How should investors compare and contrast your data to these programs? Scott, you want to take that? Sure, Eliana. So the really differentiating feature of our molecule is the glucagon. As Vipin mentioned, it has great, great benefits in obesity, including greater fat burn, greater fat burn within the liver, and also because essentially a shift to a ketogenic diet, a preservation of lean body mass. And we think that this all plays out over time, not only for acute weight loss, but more importantly, weight management and the long-term safety of weight management, particularly maintenance of body composition. Our molecules are differentiated by the amount of glucagon. The other molecules that you mentioned, Eliana, are biased towards GLP-1. Particularly, survodutide has an 8-to-1 ratio. We're 1-to-1. So believing in glucagon and its benefits, we have more glucagon in our molecule than the other compounds, and that differentiates in terms of the effects on all of the parameters that I mentioned before, the liver fat, the better effects on the lipids, and the better effects on body composition. And also, potentially, the ability to maintain weight over time. If you're actually changing the metabolic tone of the patient, the ability to sustain weight loss, even after drug is stopped or there are drug holidays, could be better with glucagon than with compounds that don't have it. As we saw in our Phase II study, which I know that we'll discuss in a minute, we saw at the end of 48 weeks, continued rapid weight loss, meaning that patients were continuing over the course of time to drop their body weight, and we think that this is a glucagon property. Mm-hmm. Absolutely. And a common investor question that we get, from the glucagon side is, you know, around safety and tolerability, particularly for some of the potential changes in heart rate and risk of arrhythmia. I guess, what is your view on the safety tolerability of the class and how your molecule compares to some of the other data sets that have been reported? Sure. So with all of the other glucagon molecules, they are seeing increases in heart rate, in the range of about eight-12 beats per minute, before the next dose is given, so this is trough increases. They're not actually reporting the heart rate increases that occur right after the dose. We know with one compound in particular, retatrutide, that when they gave a single dose of drug, the mean increase in heart rate was 30 beats per minute, and I stress that's mean, so you can see the range is actually much higher. Now, with that drug, they're seeing a 14% rate of arrhythmias, and they're not insignificant. They're seeing right bundle branch block, intraventricular conduction delay. They're seeing, ventricular ectopy, and these are all of great concerns.... When you go into a vulnerable population with cardiac disease, which describes a large percentage of the obesity population, especially over the age of 50. Now, with our compound, with our glucagon, we are not seeing those increases. We're reporting at the end of dosing, where the other companies are reporting eight-12 beats per minute increases, we're seeing two-three beats per minute. We're seeing a rate of arrhythmias that's less in the pemvidutide group than in the placebo group. And across the board, we've seen in all of our studies that we're maintaining the kind of heart rate increases, minimal increases, that you see with drugs like tirzepatide and semaglutide in the range of two-three beats per minute. We believe this differentiation is pharmacokinetic. Our drug is designed to enter the bloodstream slowly. It avoids these surges in concentrations that are associated with these heart rate increases and other effects. Circle back to retatrutide, their peak concentration is achieved at about 14 hours, about 5 times faster than our compound, and we think that with that surge of a heart rate increase, that it's accounting for the arrhythmias that are being seen in the trial. But we've been extremely pleased with the safety profile of our compound. Across multiple studies, no significant or clinically meaningful increases in heart rate, no arrhythmias, good control of blood sugar, no off-target effects. Mm-hmm. That's, that's helpful context. In terms of us assessing the potential for differentiation based on the safety and, you know, less decrease or less of an increase in the heart rate relative to some of the other glucagon-containing compounds, how should we think about, you know, the threshold for which an increase in heart rate is too much when we're assessing the competitive landscape? It's a difficult one. We know that with some of the earlier GLP-1s that were approved, the daily dose compounds, like liraglutide, exenatide, they were seeing increases, mean increases of about 7 beats per minute. So is there a number where the FDA pushes back and said, "That's it?" Well, we don't know. We haven't had that discussion with the agency. We don't expect to, because we don't think that characterizes our drug, and we're not aware of what discussions may or may not have taken place with other sponsors. I think what you really look at are the clinical manifestations of them. When you start seeing arrhythmias, you're really concerned that the drug is being dosed in the no-fly zone. So you might be very impressed with the weight loss, but would you give it to somebody who's 50 years old with a known cardiac disease? It makes that kind of drug more of a niche product for younger people who have a low risk of, of arrhythmias and, poor outcomes. Now, our drug is oriented towards successful weight loss and weight management, particularly in vulnerable populations. As you can see, we have a superb potential to impact cardiac events, lowering of serum lipids. We saw a 21% reduction in LDL cholesterol in individuals who came in the study with elevated levels. We're seeing class-leading effects in liver fat, and those are known to be association, with heart disease as well. And as we'll present at the ADA meeting coming up, we have a very impactful effect in a series of lipids through lipidomic profiling, and they're known to be inflammatory to the heart. Ceramides, diacylglycerides that are associated with increased cardiac risk. So painting the picture of a drug for maintenance of a management and maintenance of weight loss, as well as the induction of weight loss. You look at the population in need, which is the obese patient who has risk, which characterizes what insurance companies really want to pay for. We're sitting in a great position in terms of meaningfully impacting that population, especially when we're gonna conduct cardiac outcome trials. Mm-hmm. Absolutely. Maybe let's talk about some of your data. Can you talk about the Phase II MOMENTUM study and the 48-week data that you've shared to date? Sure. So MOMENTUM was a study of 300 subjects. We looked at three doses of pemvidutide and placebo, and we treated people through for 48 weeks. And at the 2.4 milligram dose, at the end of 48-week dosing, we saw a 15.6% weight loss. But more important, there was every evidence that weight loss was continuing in a very fast fashion going forward, such that if we had conducted the trial after 72 weeks, which was the tirzepatide time point, we would have had comparable levels of weight loss. That's very potent weight loss. Interestingly, at a dose that we did not titrate at all, which is the 1.2 milligram dose, we still saw a 10% weight loss. Again, no dose titration, a safety profile very similar to placebo, meaning in primary care, that medication could be dosed straight up, no titration, you know, no callbacks to the patients for reapproval for titration to higher doses. We saw some people in that cohort losing 25%, body weight, and we think that's really a superb option for primary care going forward. Now, in addition to that, we saw the great effects on lipids. We saw nice effects on liver fat that we talked about before. And an extremely important attribute that we demonstrate in our trial is pemvidutide appears to prevent the loss of lean mass that we've seen with other GLP-1 agents. So just to review that very quickly—with semaglutide in at least two trials, they've seen a loss of lean mass relative to total weight loss of 40%. That's a lot higher than you get with natural diet and exercise, where you're typically in the range of about 25%, and that's been the goal, is to be at least in that range over time, particularly in elderly people who come into the study already with sarcopenia. And there are many obese people who have something called sarcopenic obesity, meaning because of their obesity and their insulin resistance, they don't have enough insulin response to maintain their muscle mass, and despite being overweight, for their body weight, they have much lower lean mass than they should. So consequently, it's really important in that vulnerable population to preserve lean mass. We believe that the mechanism represents what I talked about before, which is essentially giving patients a ketogenic diet. As you know, it's used by athletes to increase athletic performance. We think that glucagon causes a fundamental shift away from burning carbohydrate, and the substrate for carbohydrate is amino acids. In fasting, they come to the liver, and they're manufactured into glucose and carbohydrates, the shift from that access to burning from fat, and we think that's the basic mechanism of preserving lean mass. It's extremely important because in several studies, including the prescribing information from semaglutide, which I, as I mentioned before, had an excessive rate of lean loss, they're seeing a higher rate of bone fractures, especially pelvic fractures, in the elderly and in women. So this is extremely important for time. You know, right now, it's been kind of like how much weight loss you have in a year? Well, that's really good. But recognize that in the future, the primary market for treat-- using obesity drugs is going to be long-term treatment. It's going to be maintenance. The shift, we believe, over the course of time, is going to occur from this focus, intense focus on how much weight do you have over a year, to how much weight loss do you manage and maintain over the course of several years, and do you maintain it safely without the side effects of that weight loss? We think regarding that and our cardiac profile, that we're really in a superb position. Maybe can you elaborate a little bit more on the mechanism behind why you think you have a favorable profile in terms of preserving lean body mass, and maybe a little bit more in terms of how you think this compares with some of the, you know, other, you know, novel incretins in development? Right. So, again, we believe that the preservation of lean mass here is basically cutting the cord on the dependency of muscle to provide carbohydrate as substrate for the manufacture of glucose and carbohydrate for energy burn, and shifting that to the burn and the extraction from lipids to burn. We saw in prior studies that we have a higher rate of ketone body production, which is what you would see in a ketogenic diet, about a 6-fold increase, and also a shutdown of de novo gluconeogenesis in the liver. This is a fundamental property of glucagon that you don't see with other incretins. Compounds such as semaglutide, which is GLP-1 monotherapy, and tirzepatide, which combine GLP-1 with GIP, and even amylin, work by suppressing appetite. So they cut the flow of lipids to the liver. They have no direct effects on the liver, and they have no direct effects on metabolism per se, with glucagon fundamentally changes that. So in terms of what's really meaningfully impacting the obese patient, is it simply dieting, or is it shifting the metabolism to a state that will sustain them much better for healthy weight loss? Thanks, Scott. And just one more, I guess, to piggyback on the, you know, the topic of lean mass. Beyond some of the novel incretins, how are you thinking about lean mass preserving agents like the anti-myostatin agents that are in development? And, you know, how might that be, you know, compatible with pemvidutide in the future? Well, you know, Elliott, it's, it's just really a fascinating area, and we just don't have the information on the synergy between these compounds. We think that with a compound like semaglutide, you just cannot treat and, and sustain that lean loss, and that you'd really feel obliged to combine with one of these anti-myostatin or other mechanism agents to preserve lean mass. We've always argued that, pemvidutide is combination therapy within the molecule, right? It gives you gluca- GLP-1 plus glucagon. Within the molecule, it also gives you lean mass preservation. So in terms of treating with one new chemical entity, one premium-priced, molecule, versus two, and, you know, combining agents is always complicated from a regulatory point of view, from a reimbursement point of view. We think that we can hit it with one agent alone. Great. Thank you. You've said that you're expecting to have your end-of-Phase II meeting with the FDA in the third quarter. What are you hoping to come away from this meeting with? ... Well, thanks, Eliana. It's gonna be tremendously value-enhancing for the company, because we're gonna have confirmation from the agency on the value that we bring to the table. So we plan to come in with studies that bring out the properties that we've talked about. The lipid reductions in patients with hyperlipidemia, the reduction in liver fats, liver fat in patients who have high liver fat at baseline, preserving body composition, particularly in a vulnerable population like the elderly. So what we want our program to do is really stand out in terms of what glucagon can do, and it will be designed specifically to bring out those attributes. We're really looking forward to getting in front of the agency and getting confirmation on those plans going forward, because we think this will be tremendously value-enhancing to get that confirmation from the agency. As we mentioned before, in previous press releases and calls, we plan to have that meeting late in the third quarter of this year, and we're on track to do that. We're really looking forward to having that meeting and getting the agency's feedback. We really think it's gonna be a tremendous value enhancer and stake in the ground for the compound. Yeah, I just wanted to add that, as you know, most of the obesity programs require fairly large patient enrollment, mainly from a safety perspective. So it really gives us the opportunity to further subdivide that. So we'll have that patient population for safety anyway. We may as well enhance some of the features of the molecule and hopefully try to get them on the label. And as you can see here, because of the glucagon, it gives us a unique opportunity to perhaps study patient populations that have not been studied at up to this point and really enhance and get those on the label. Mm-hmm. Like, what specific populations, or how will this differ from maybe the standard overweight or obese population enrolled in the obesity studies? Sure. So we've talked a lot, lot about... Yeah, Scott, why don't you go through that? Okay, sure. And Vipin, you can supplement. So, you know, without giving specific details about the program, which we can't share right now, we can paint a picture of where we think we're gonna take the compound in terms of the populations. So, a hyperlipidemic population with obesity, that's not been studied yet by other companies. A program with high liver fat, that's gonna be extremely differentiating. And also to focus on elderly people who are at greater risk of sarcopenia and lean loss. So you can see how we can enrich our program to really bring out those attributes, which are gonna really highlight what glucagon can do for those populations. Now, not specifically enrich within that Phase III program, but in an outcomes trial, you can see that with the lipid reduction that we have, especially the reduction in liver fat, and as we'll present at ADA, the reductions in inflammatory lipids, the diacylglycerides, the ceramides, sphingolipids, a variety of lipids that are known, aside from LDL cholesterol, to be associated with cardiovascular morbidity. You can see we're really in a superb position here to have a successful outcomes trial. So we're trying to mold this compound into not only reduction of lipids, reduction of liver fat, obviously we have our MASH program as well, preservation of lean mass, but really a great, if not ideal, compound for the people with cardiac risk, and that would come out in an outcomes trial. Mm-hmm. Absolutely. How are you thinking about the potential dose selection and also the potential titration regimen, and how this might differ versus some of the other titration regimens that have been studied in the space? Right. So as we mentioned before, that 1.2 milligram dose stands out among all of the GLP-1 agents as a dose you can give without titrating to it. You know, all the other doses, you have to have a dose before to get up there, and that's a potent dose that can be used in primary care. Now, in terms of the other regimens, you know, we're taking a look at that right now. We're very happy with what we've seen before. You know, we've been very aggressive with the compound in terms of dosing. We did not allow dose reduction in our trial, other compounds did. We are allowing that going forward, and that's gonna have a major impact. Whether we extend a titration out is a discussion we'll have with the agency. I want to emphasize that we're very happy with what we have right now. Yeah, I would just add that our plan is to actually have all three doses moving forward into Phase III and get them approved separately. So if you think of a scenario where a patient comes to a doctor, they can easily start the patient at 1.2 milligram dose, see how the patient does, increase that to 1.8 if they need more, more weight loss, and they go all the way to 2.4. So if you think about it, if you've got all three of these dosage approved, you really have a natural titration built in there for the doctor if they want to do that. They can start pretty much every patient at 1.2 milligram, which is an active dose, effective dose, and many patients may not need a higher dose. And then you go to the higher dose, that automatically feels like titration, go to 1.8, and then eventually to 2.4. Thank you for that. So just going back to ADA, you had mentioned sort of some of the cardiometabolic profile data that you'd share. Anything else new that we should be expecting or looking for with your presentation? Well, I can't get into specific details because of embargo, but you know, we're gonna be presenting our MOMENTUM data. Dr. Louis Aronne, who is the lead investigator, will be presenting that. That'll be a podium presentation. And then we have the lipidomics presentation, which was selected as one of the seven presidential plenary abstracts. So we're gonna be on stage and very, very visible with very prestigious presentations confirmation at our meeting. We'll also have, as you know, presentations at the upcoming EASL meeting, and we've submitted our body composition data to a meeting later in the year. And we suspect that we'll be able to discuss the information in greater detail at that time. Great, thank you. And just, we were talking about the different dose titration schemes. You've also, I think, in the past, mentioned developing an oral formulation. And so can you talk more about how that sits as a priority for you, given where you're at? I mean, obviously, that's, that's an important milestone, and, and, and having an oral option is very important down the line. That is a priority. We are making good progress on that, and, we'll share more details as they become available, in the second half of this year. But our goal is to continue with the, developing an oral formulation of pemvidutide. This is not a small molecule. As you know, we're working with a dual agonist. It's virtually impossible to come up with a small molecule substitute that can do the same thing, but you can do formulations of the existing peptide and, and get enough bioavailability, so, to, to use them orally. We don't believe oral is, you know, at least in terms of peptide therapeutics, we don't believe oral is going to substitute for injectables, but it really gives an option, additional option to patients, and really expands the market for those who simply would not take an injectable. As you know, as we've already seen with Ozempic versus Rybelsus. You know, when Rybelsus came on the market, it really didn't replace Ozempic, but it expanded or actually increased the market size. That's... Yeah, that's a good point. And I guess you brought up the point about, you know, peptide versus small molecule. So how are you, how are you thinking about manufacturing going forward? You've seen, you know, peers invest heavily in manufacturing, and so just what are your thoughts on that? So we are working; at the moment, we are working with a world-class manufacturer of peptides that's actually making peptides for others, you know, that are on the market. So really, it's a multinational company. We've not disclosed the name. They have plenty of capacity to provide us material for Phase III and initial launch of the drug. But what's happening in this space is that the market is changing. There are people making significant investment in manufacturing capacity, so we think it's going to be there in the next few years by the time we are ready to hit the market. So from that perspective, the timing is going to be very good for us. So we're, you know, we're working with multiple vendors in establishing those relationships. So we believe there would be capacity as we need it. We, you know, hopefully will have a partner by that time, who's also willing to make an investment in manufacturing capacity, you know. But again, we have time to get to that, get to that step. I guess. Oh, yeah. Go ahead, Elliott. Yeah, I mean, you brought up partnership. I guess, can you, you know, elaborate on your thoughts there, potential timing? Yeah, so we've been very clear that our goal is to have a partner on board before we start Phase III obesity program. So we're making progress. We're moving forward with, you know, our end of Phase II meeting. All of that information would be helpful, and the partnering efforts are continuing. That's all I can share at this point. As more information becomes available, clearly, we'll talk about it. Before we move to NASH, I think, you know, we talked about some of the efficacy comparisons and safety in terms of arrhythmias and potential blood pressure or heart rate increases. But can you talk a little bit about, from a tolerability perspective, maybe how you see yourself fitting into the landscape, since this certainly has been a big focus of the space? We're very happy with the tolerability compound profile that we're having right now. It's very typical of a Phase II tolerability profile, where you push the dose of the drug as much as you can to see what kind of efficacy you could have and the kind of safety and tolerability that you have. Typically, adverse event dropout rates, Phase II are in the range of 20%-30%. Tirzepatide was 25% in Phase II, semaglutide was 30%. We actually saw recent data on another GLP/glucagon, where their adverse event dropout rate in the first 24 weeks of dosing was 31%. So we were at 19%. Now, in contrast to all those other drugs, we didn't use dose titration. So had we used dose titration, you can imagine what our adverse event dropouts would have been. In addition, we didn't use dose reduction. You know, in the other programs, 30% of subjects are either reducing their dose or not getting to the target dose. So within a protocol, which is rigid, when you say you have to increase it and not allow drop-downs in dose, to have a 19% adverse event dropout rate is very remarkable. So what also characterizes all of these programs and going from Phase II to Phase III, is that the adverse event profile gets better. The adverse event discontinuations drop to single digits, the rates of these GI events go down, and that's because we all make adjustments based on what we've observed in Phase II going into Phase III, and that's the purpose of Phase II: to really push and test your drug, to see what you can get, and then use the information that you've gotten to make adjustments. So one thing that we've done in all of our program is that we're now all going to allow dose reduction. Whether we make changes in the titration regimen is something that we'll discuss with the agency. But you can see here that we have great optionality for bringing our tolerability profile in line with tirzepatide and semaglutide, and perhaps even getting better than that. Mm-hmm. I would just emphasize that pemvidutide is the only drug where at least two doses, the low and the mid dose, we've given it without titration and are showing similar results than anybody else. So, and 2.4 milligram has very limited dose titration. So we feel that pemvidutide is, from an incretin perspective, the best-tolerated drug out there. And there's, as Scott said, there's so much optionality. If we want to improve it further, we can certainly do that. Mm, do you think- You see the other compound... In terms of the optionality, other compounds are already dose reducing and titrating up to 20 weeks. In fact, one compound is now dose titrating to 32 weeks. So those compounds have already exercised whatever options they have. We have two options in front of us for improving tolerability, and we have great confidence that the superior tolerability of pemvidutide will show in later phase trials. What do you think is driving this? Is this the more stable PK and I guess lower Cmax, or is this due to the balanced agonism of GLP-1 and glucagon, or a mix of both? How are you thinking about the driver here? We think it's predominantly the PK, where we avoid the peak concentrations that have been associated with these side effects. But also, these side effects are driven by GLP-1, not glucagon, so when you give glucagon, it is GLP-1 sparing. So it is, in fact, a combination of both, but we think the primary driver is the PK. Mm-hmm. We think that also what's driving the preventing the increases in heart rate that's being seen with other compounds. Mm-hmm. Interesting. All right, let's talk about NASH. What do you view as the rationale for your compound in NASH, and maybe how this might compare to some of the others in the landscape, such as, you know, FGF21s? Well, I mean, the first thing that differentiates is that we have weight loss. So MASH is disease of obese individuals, and in fact, up until the time they develop cirrhosis, they die more of the cardiovascular complications or the malignancies, malignancy being, a complication of obesity, than they do the MASH. So with the FGF21s or resmetirom, they're not getting any weight loss. In fact, with the PPAR gamma, which is in, Inventiva's compound, they're actually getting weight gain, and that's known to happen with PPARs. So the first thing we bring to the table is not only the effects on MASH, but the effects on obesity. And in fact, that's played out well on our studies because our studies have recruited extremely well. And the reason is that subjects are saying, "I want to lose weight." So MASH is a silent disease. If you approach them and say, "Do you want to be in a study for a silent disease?" The enthusiasm may be tempered, but if you say, "You want to lose weight," they, they rush, they rush to the office to line up and get in line. So we think that actually represents the commercial potential of the compound, that these compounds, pemvidutide in particular, will be preferred over the other compounds that you mentioned. But, you know, more importantly, we're seeing very potent effects in liver fat, and liver fat is the primary driver of the disease. It drives inflammation and it drives fibrosis. And in all of the studies, including the resmetirom studies, the Madrigal studies, and also the FGF21 studies, it's been shown repeatedly that the one factor that drives improvement across all the parameters, MASH activity, and fibrosis improvement, is the reduction of liver fat. So when you look at our reduction in liver fat, it's extremely potent. It's in the best-in-class. It's 76% at 24 weeks. But it's not only potent, we're seeing it rapidly. We've reported out similar effects at just 12 weeks, and in fact, we haven't released the numbers, but we're seeing even similar effects at just 6 weeks. So potent reduction in liver fat, rapid reduction in liver fat. We're also seeing this accompanied by best-in-class reduction in liver inflammation through the reduction of transaminases like ALT and also an MRI-based technique called corrected T1 imaging. So, you know, based on all of that, plus some additional data, and that data is that we have data in a preclinical model that pemvidutide actually has direct anti-fibrotic effects that are independent of the fat effects that I just mentioned, Eliana. So combined all of that, we have confidence in our ability to see rapid effects on MASH resolution and also fibrosis improvement. Our trial is designed to read out at 24 weeks. We have a great deal of enthusiasm and confidence in hitting that based on the data that we have, and that would be the first incretin to read out at 24 weeks. And that will distinguish from all the other compounds in the class based on its efficacy. To be able, with an incretin, not to go a year, year and a half, but to see it at 24 weeks, we think will be a very firm forward statement about the potency of our compound compared to others. Mm-hmm. Yeah, we're certainly eager to see the histology data in the first quarter next year. Maybe just to ask a high level, a really obvious question, but what's your expectation in terms of the effect size that you'll see? Maybe just starting with fibrosis and how we should think about that. And, like, relative to others in the class. I mean, you mentioned, you know, the deep liver fat reductions and some potential independent effects on inflammation. How do you think this will stack up to what we've seen, say, with the FGF-21s? Well, we think it's going to be as good, if not better. I think numbers are a little hard to bring out in a discussion like this. We have taken a look at this in terms of our estimated effect and powered the study appropriately. We also are running a somewhat larger trial than the other companies. Akero study was about 45 per arm. 89bio was in the low 60s, I believe it was about 62, and we're 76. So we are not only confident about our ability to read out at that 24-week mark, we're adding power to the study in order to better assure that effect taking place. We point out that with resmetirom, the treatment effect is only about 12%-15% for fibrosis. 25% is an absolute amount. That means 75% of people aren't getting better. We think there's tremendous room for improvement, and we think that by having potent effects in MASH, plus the effects on body weight, that we're really gonna stand out here in terms of patient and physician preference, for the treatment of this condition. Mm-hmm. How are you thinking about your effects on MASH resolution relative to fibrosis in the context of the space? Do you expect to be maybe more potent on MASH resolution and, you know, fibrosis benefits might take more time to see? How are you thinking about what we could see on fibrosis at 24 weeks? You know, I mean, typically, MASH resolution is a lower hurdle than fibrosis, right? Right. MASH resolution occurs quicker. Fibrosis may take longer. Correct. So that, that's why a lot of the incretins are reading out at a longer time. But the FGF21s did have success at 24 weeks. The Inventiva PPAR gamma compound did have success at 24 weeks. We have better liver fat reduction than any of those three compounds. We also have direct effects on fibrosis, and we have better anti-inflammatory activity. So we believe that based on their success at 24 weeks, we can hit it as well. But you are correct, it's easier to hit MASH resolution than fibrosis improvement, especially at an earlier time point. But we feel very good about it, and we think our study is adequately powered in order to achieve statistical significance on both of those endpoints. Mm-hmm. What is the methodology for the readers and the? Are you using a consensus method in how you're doing that? Sure. We use a consensus method for adjudication, like other sponsors. I think importantly, what we've learned, coming in a little bit later than some of the other sponsors in this space, and your development's been going on in MASH about 5, 6, 7 years, is that it's very important to give the pathologist a very clear definition of what you're looking for. And we learned this in the 89bio studies, where they got their placebo response rate down to single digits. So give them very clear instruction of what's a ballooned hepatocyte. What is the difference between stage 2 and stage 3 fibrosis, for example. And if you give that, the placebo response rate comes down. So the adjudication is important. We've learned from the consensus read from the other companies, but even more importantly, we've learned how to direct the pathologist in order to give us the most accurate read. Mm-hmm. You mentioned having direct anti-fibrotic mechanism as well as direct anti-inflammatory mechanisms. Can you elaborate on that? Yeah. So this data will be presented at a meeting later in the year, but in all of the other studies from other companies that have looked at the effects of the drug and fibrosis, they've been in obese models. So if the animal is losing liver fat, you cannot distinguish that effect on fibrosis, because the reduction of liver fat itself will have a positive effect on fibrosis. But we used a carbon tetrachloride model, which is known to produce fibrosis. These are animals that are normal weight, have normal liver fat, and we showed that in that fibrotic model, with only two weeks of dosing, we were able to have a significant effect on fibrosis. So it's rapid, and it's direct, because there was no fat involved in that model. Now, it makes sense because glucagon is known to be anti-inflammatory in the liver. You may or may not know that, when livers are transported for liver transplantation from a donor to a recipient, as the liver is being transported, it's packed in glucagon, and it's because it prevents inflammation and the production of free radicals that lead to liver destruction. And we think that process is in play here in the prevention of fibrosis. But it is a direct glucagon effect on the fibrotic mechanism. Mm-hmm. An investor question that I got for Akero and 89bio is, if you guys are successful in the first quarter in F2, F3, what this might mean for your potential to compete in F4, where we're also getting longer-term F4 data from Akero in the first quarter of next year as well. How are you thinking about your program and the potential? Does it make sense in F4, and how would you think about the approach there? Right. So, when the data with the GLP-1s came out, it was very concerning to the FGF21s as to whether they could compete in the early stages of NASH, right? So what we are seeing with some of the earlier reports in the GLP-1s, like semaglutide, is really good effects in weight, body weight, liver fat, but not really great effects in fibrosis. So when scientists, experts, and investors started looking at that, they're saying, "Okay, the FGF21s will be used to treat F1, F2, F3, but when you get to advanced F3 or F4, you're gonna have to use an FGF21 or, or even resmetirom. They have no effects on, on, on body weight per se." Now, we're seeing with some recent data with glucagon, there are effects in fibrosis. We're seeing that in the survodutide data, which we presented as EASL as well. We believe we can do better 'cause we have more glucagon in our molecule than survodutide. So to answer your question, in the initial segmentation of the market, Eliana, the easiest approach would be, well, the GLP-1s are gonna be used for F1 and F2 and maybe some F3, but when you get to more advanced fibrosis, you need an FGF21 or resmetirom. With our data that we expect to show next quarter and the anti-fibrotic effects, we think that we can cover F1, F2, F3, and also F4. 'Cause unlike the other GLP-1s, we're gonna have potently antifibrotic effects. So the bottom line is that we think we can cover all stages of NASH, and that would also include cirrhosis. So, our studies right now do include cirrhotics, but clearly, that's something within our range and our vision, going forward as we plan out Phase III. At EASL, there's been a lot of conversation around the presentations from tirzepatide, and survodutide, and MASH. What are you looking for in these presentations, and, you know, how might this inform how you're thinking about your competitive positioning? Well, we're, we're gonna be very interested to see the data. Obviously, with tirzepatide, they didn't hit their fibrosis endpoint based on the absence of glucagon. That, and what we've said about the space so far, that would make sense. They would seem to be more positioned in early NASH. With survodutide, we think it's affirmation of the glucagon mechanism. The problem with survodutide is its tolerability. It's, it's just not well-tolerated. We're seeing the highest adverse event dropout rates with survodutide of any program, whether it's obesity or NASH. It was reported earlier this week at DDW when they did a 24-week interim analysis, they had a 31% adverse event discontinuation rate in just the first 24 weeks. That would be the highest reported of any drug in either obesity and NASH. And also, NASH patients tend to tolerate these drugs better than general obesity. Patients with disease tend to tolerate adverse events better than those without it in the general obesity population. That 31% in a more tolerant population in just 24 weeks is pretty concerning. So, you know, we applaud any effects they get in fibrosis. We think it will really be a good sign for our compound and our ability to success, but we think we clearly differentiate from survodutide in tolerability. Mm-hmm. In terms of the development path forward, how are you thinking about the degree of, you know... Is there a certain level of efficacy you'd wanna see to have a competitive profile going forward, and how you're thinking about prioritizing between obesity relative to NASH? Vipin, do you wanna take that? Yeah, absolutely. Well, look, our plan is to move both of these programs in parallel. As you can see, we have very compelling data in obesity, so we, we certainly have a drug for obesity, and we have very compelling data for na- for MASH. In fact, when we had first in-licensed pemvidutide, the main focus at that time was MASH or, or NASH, and, so that, you know, clearly, the, the drug has panned out, from that perspective as well. MASH is an indication that we can take forward on our own. We've said for obesity, we'll, we'll need a partner. So I think, time will tell where we end up as, as these discussions continue, and we'll make a decision. But we have a drug that's active. We think it's very safe and effective, and there are multiple paths forward to take this drug into Phase III programs. Mm-hmm. Absolutely. And last question, just in terms of thinking about the commercial landscape, there's a lot of conversation about combinations. Now, I know you emphasized that your program essentially is its own combination, but how would you think about how your profile in NASH might compare to, say, a combination of GLP-1 plus Rezdiffra or GLP-1 plus an FGF21? We think we're really in a very good position from that perspective. If you want to treat NASH, early NASH, early F 1, F 2, with, with an incretin, we have that. We have the weight loss drug. So we bring that to the table, but in addition, we're the only incretin that also has this direct effect on the liver. So we are really combining the two mechanisms, one being the weight loss and the other one having a direct, liver fat reduction, and on top of that, fibrosis. So doesn't matter how you want to enter the market or how you want to treat the patient, why wouldn't you want to treat a patient with a drug that has both of these things combined in one as opposed to having to do combination therapy? Mm-hmm. Makes sense. Well, I think we're a little bit over time, but thank you both so much for joining us. We're looking forward to seeing these updates and data readouts. And thanks for those on the line for joining us.