All right, good morning, everyone. Welcome to the next session here at the 2025 Jefferies Healthcare Conference. I am absolutely pleased to have here with us today the CEO of Akero, Andrew Cheng. As many of you know, Akero has had a phenomenal last couple of years, obviously with recent positive F4 cirrhosis data, among other things, and executing on a phase III program. I might as well just say, speculated as a potential M&A candidate in Bloomberg. That's all public. Would love to give an opportunity for Andrew to maybe just talk a little bit about where Akero is right now in 2025 in terms of executing on the phase III program, and obviously an update since your cirrhosis data. Have you talked with the FDA? Tell us a little bit about what you're working on this year. Yes. So thanks, Mike. You know, since January, we've had a little bit of the wind at our backs. We had very exciting times. We had a late-breaker presentation last month at EASL and simultaneously a New England Journal publication talking about the SYMMETRY data. I think we're, as Mike mentioned, we're in the middle of phase III. We've already completed enrollment on the first of our phase III programs, the SYNCHRONY Real-World, which is a non-invasive study. We've guided that it will read out in the first half of 2026. We also have the SYNCHRONY Histology Study, which is the F2, F3 study, which is the rate limiting step towards pre-cirrhotic filing, and that will read out in the first half of 2027. We have the F4 study, what we call SYNCHRONY Outcomes, and that is enrolling. The first patient was just enrolled last September, September of 2024. We haven't given any guidance to that. We want to have a little more enrollment under our belt before we give you some suggestions about where that would be. That's fantastic. There are a number of phase III programs obviously ongoing. Before I get into those phase III, maybe you could just revisit the particular wind in your sails, which was the positive phase II F4 cirrhosis data, which happened earlier this year. You could summarize what, briefly, what was so important about that data because that supports your phase III. Maybe you could summarize the data and, importantly, have you engaged with the FDA on that data. Has there been any meetings or what interactions at all have you had with the FDA on that data? Sure. On a top level, we're the first company ever to demonstrate statistically significant improvement in one-stage improvement of fibrosis in patients who are cirrhotic. That has been something that has been a little part of medical dogma. There are a number of people who believe that cirrhosis was irreversible in this population. Largely it was until January 27th because no one had really been able to convincingly demonstrate that, primarily because whether it's the mechanism or the duration of the study, it was pretty uniform. We're thrilled to have been the first to show that. The second thing about that is it's consistent with what we know about efruxifermin. That is, in both pre-cirrhotic and cirrhotic populations, longer dosing is essential to its mechanism of action. We saw both the effect size increase from 20% to 52% in pre-cirrhotics. That's one-stage improvement of fibrosis without worsening of NASH, minus placebo, placebo-adjusted. The same thing is true that we saw in SYMMETRY. We weren't stat-sig, as we all know, in October of 2023, but at the 96-week time point, we were. The effect size grew from just 10% to 25%. Really, it's, and what that, there are important implications for that when we think about what that means for our outcome study. Mike asked about the FDA. We haven't had, we're still working on our background. We haven't had any direct FDA feedback on SYMMETRY yet. You know, I'm familiar with the pre-NDA meetings, different types of meetings. I mean, in this case, it was an important clinical trial readout. I don't know, is that required? I mean, you request a meeting because you want to talk with them about it. You request a meeting because you also want to look at your phase III and perhaps adjust your phase III or make agreements on the protocol so that the phase IIIs read out on a certain number of patients in F4 based on the strong data that you had in the phase II. For the audience, you know, you are running phase III, but you have not given the details as to how many patients it will read out on for the primary endpoint. The data that you saw in this F4 on January 27th may help inform that. What is the basis of a meeting request? What do you want to talk with the FDA about? What do you expect could come out of a meeting? Yeah. In terms of informing the FDA, the FDA will receive the data from the study via when we write a clinical study report, which is under construction, we'll have that. In terms of the type of question, we probably have a very narrow question. That is a type D meeting where we're just asking for a limited subset of data. As a reminder, we've already had end-of-phase II meetings, our formal end-of-phase II meeting when we had our F2, F3 data earlier. You know, they've reviewed the protocol, so we don't have protocol concerns. You're right in terms of the way this study is designed, the Synchrony Histology Study and the Synchrony Outcome Study, there are two cohorts in each of those studies, much like what we saw with the Madrigal approval. Although there are 1,600 patients in the F2, F3 study, we do not need biopsy data on 1,600 patients in order to file for the primary endpoint. Similarly, we have that biopsy subset in the Synchrony Outcomes Study. All patients are participating in outcomes, but only a subset will get the second paired biopsy. The breakdown of that group is, and the sample size is shifting a little bit in light of the increased efficacy that we saw. Where we have landed on that, we are not quite sure yet. We are still, there is some internal debate because the effect size grew to much greater than what we saw week- 36. So. Right. So look, for those that are following this, the results that happened on January 27th were certainly above our expectations. I'm not sure if they're above your expectations. Perhaps you always assumed it was going to be positive, but they were definitely a positive surprise for everyone to see the results. Wall Street saw for the first time a randomized statistically significant, now you're under the bright lights of the F4 cirrhosis and that you have that data in hand. One thing is like, hey, could you talk with the FDA about that? I can't recall if you have breakthrough on which population. You have breakthrough therapy. We have Breakthrough Therapy Designation across both pre-cirrhotic and cirrhotic patients. Okay. So you have breakthrough designation on F2, F3, and F4. Mm-hmm. Okay. So you have Breakthrough Therapy Designation. This data came out and you could say, hey, is there any chance that we could file for accelerated approval based on this result, which no one has ever seen? You said it was, I can't remember the term you used, but it has never been seen before. Correct. Could you file that to FDA? You know, we think the chance of that is extremely low in terms of given the past comments they've had and the fact that the current guidance doesn't support histology in cirrhotic patients. That being said, we do intend on sharing the data with them and that's a potential topic. Again, we think that it's low likelihood. Okay. I think we mostly agree with that. I think people are like, oh my gosh, that could be a huge positive upside surprise if that happens. What needs to happen? Because I'm actually, oh, I'm surprised. I mean, now we're into June. The data was January 27. Are you wrapping up a report and then you just have to submit that and request a meeting? I think even when we saw you last at our last conference in March, you were still working on that. Now we're in June. Yeah, absolutely. Exactly. I think that's the easiest way is to file this clinical study report. That's what we're working towards rather than a specific request because the question will be, let's see all the data. Okay. All right. To be clear, if these results are positive, you meet with the FDA. Again, one of the things to agree on, which Wall Street is looking for, is to try and understand in the F4 study, if I may again focus on this opportunity, that the phase III is running. Technically speaking, which is kind of crazy, is that the FDA guidance documents and perhaps what you've agreed on is the primary endpoint in F4 is outcomes. Yes. We have, that is the, that's how we've designed the study because that's consistent with guidance. Think about that. That's like a multi-year outcome to determine clinical outcomes, which is ascites and decompensation and all these things, which take many years. Another company, Madrigal, has also run an outcome study and that could be years. You just enrolled the First patient in September. Again, while there's no guidance on the result of that, obviously anyone logical could see it could be years to get that result. Therefore, one of the things that we're looking forward to is this idea that perhaps there will be an analysis on just fibrosis at a two-year endpoint rather than have to wait years for the outcome. The timing of that two-year result, which could be like 2027, will be based on how many patients to do that analysis on. The analysis is that the results are so strong, maybe you need fewer people to hit the two- years so that it could read out earlier. If that is, maybe you could talk to the FDA. Given that the study, to get to my question, given that the study is 1,400 patients or whatever you said the number was, could an analysis on fibrosis read out? Is that an interim? Do you use alpha spend on that? Is that definitely something that could happen? Yeah. The answer to your question is you've described the situation we're in very accurately. That is that what was once thought to be the sample size may not be as big. We're trying to decide how much to change it. It's a discussion with the agency. One of the nice things about SYMMETRY is oftentimes people who sit in this chair and have jobs like I do ask you to read through to something. The difference is that we just gave you 96 results. The endpoints read 96. The dose is exactly the same, 50 mg we're studying, 50 mg in phase III. The patient population is exactly the same. In terms of what you could see, I think we think SYMMETRY is a pretty good representation because there's so much overlap between what we've seen in phase IIb and what we're seeing in phase III. So the phase II SYMMETRY, is that the name? Correct. How many patients was that? So 183 people. 183. So roughly 60-ish per arm. Okay. It was placebo versus 28 versus 50. Phase III is 1,150, only 50 mg being studied, not the lower dose. So roughly 575 per- arm. Only a subset of those will be receiving the two-year biopsy. Right. Think about that. So 183 versus 1,500, it's like eight times larger, something like that. And you just said we hit statistically significant on 180 patients. Obviously eight times larger is going to be totally easy. You would, we do not want to replicate exactly at 180, but if we like doubled the study, you'd probably feel pretty good on that. You know, phase III, sometimes there are surprises, but we feel very good the fact that the sample size is what it is and that the endpoints and the dose are very similar in the population. Just to be clear, the primary endpoint of the study though is outcomes. Is a secondary endpoint fibrosis? Like looking at that cut, go ahead. Yeah. So what you described is accurate is that the overall for all patients, the endpoint is outcomes. Yes. For the subset of patients that will get a two-year biopsy, that biopsy endpoint is primary. Therefore, there's some splitting of alpha, as you referred to. There's some splitting of alpha for that. Okay. Right. Okay. We will get to that time point. Jefferies believes if it was hundreds of patients that could read out after enrollment of perhaps a year, that a two-year endpoint could read out in like 2027 plus, but that's an estimate. That would be a huge event. You are trying to get agreement with the FDA on what that number would be because you have to agree on a protocol is why. Exactly. We have a protocol agreement already in place, but if the number of patients in the cohort one were to change, I think again, we'd have to discuss it with them. Okay. Good. How does that, so we look forward to that result in a couple of years, a few years. How does that change versus F2, F3? If I could focus on something that could seem to be much more sooner, you are also in phase III studies for F2, F3. You know, Madrigal is approved there and you're coming quickly behind. In F2, F3, there are two phase III studies. One is an open label observation study that you've already completed enrollment on. I was surprised because I'm not really paying attention to this, that it could read out in first half 2026. Correct. Okay. So there's a phase III study reading out in first half 2026. It's not a randomized placebo controlled, but it's a study. And then the placebo controlled portion is finishing. Can you walk through those two? Yeah. Tell us what is, what would we learn about a phase III coming in first half 2026? Just to clarify, that study, which we call SYNCHRONY Real-World, is placebo controlled. It's 50 mg versus placebo, randomized two to one. The patients, it's roughly 600 plus patients. What we'll be learning about that is they're all biopsy confirmed with F1 to F4 NASH and they're being treated with EFX for a year. We're following them non-invasively. In the way, that's the reason it's called Real-World, because that's how in most clinics they don't use biopsy as an endpoint. They're following these patients just as we're doing this study. It helps the safety database, but it also provides some insight into the variety of non-invasive markers and how patients could be treated with this non-biopsy data. What, when this reads out in first half 2026, based on what, some 12-month endpoint? 52 weeks, yeah. Okay. Primary endpoint is safety? Correct. Safety and tolerability, but there'll also be non-invasive efficacy measures. Like a key secondary endpoint is what, FibroScan or what are the points? FibroScan, ELFScore. The kind of things that recall that last November at AASLD, we had a presentation looking at the correlation between 30% decrease in FibroScan versus ELFScore change of 0.5 versus one stage improvement of fibrosis. There was quite a bit of correlation, although imperfect, not perfect correlation between the patients who had all three of those markers. Only 40% of those patients in the study had all three of those changes, yet we saw 75% one stage improvement of fibrosis. The non-invasives still have a little bit of ways to go. What would we learn in this readout in first half 2026? I mean, I guess it would be, well, just a bigger version of the phase II F2, F3 readout that happened at a year, which was striking data at that time too. Yeah. I think. Which would be basically the same, except we won't have an F fibrosis reversal endpoint. Correct. It would be non-invasives. We'll have 600 people or 300 people on EFX for a year, which recall that the F2, F3 phase IIb study HARMONY was three doses and it only enrolled 120 people, roughly 40 per- arm. Now you have a much bigger sample size. It gives us much more insight about this overall safety profile of the compound and gives us some insight into how patients might be treated in the clinic and what sort of changes to that we could observe non-invasively. We and Wall Street believe that you will show strong efficacy on those non-invasives. One thing to, you know, be clear about is that there is, and you would expect in this study, there would be some changes in bone mineral density, right? I think here too. What is the response to what you would expect on bone mineral density in a 52-week study in this Real World study? How should we think about the importance of that given, you know, we do not want to make people's bone mineral density go down? Recall that we looked at 48- weeks in HARMONY and that we saw no statistical difference between active or placebo at 48- weeks in the F2, F3 population. At 96-- weeks, we did see a statistical difference in the pre-cirrhotic population, about a 3% decrease over that time. In a larger study, what could we see? I, you know, could we see something that's statistically significant? We could. Oh, that's right. In both F4 and maybe in F4, F2, did we not see it at one point? We did. We didn't. In the cirrhotic population, having more advanced disease, we saw a change that was statistically significant at week- 36 and week- 96. In the pre-cirrhotic population, we didn't see it at one year, but we saw it at two years. Is there any biological reason for that or just powering of the page? I don't know. It's hard to, I don't have a good answer for that. Why the one year we didn't see it in pre-cirrhotics, we did see it nine months. I think mostly the history of the patient. I think the conclusion is there's some change. Even though it was not stat-sig in the F2, F3, there is some decrease in bone mineral density. It just was not stat-sig. Here now we've got a lot of patients, we could see it. If it's a couple%, does that matter? Are these people better controlled on calcium or vitamin D or whatever it is? Like how do we think about that? Yeah. What we would say is that in the past, we allowed people who weren't taking calcium, had low vitamin D, into the study. In Synchrony, we are asking patients to have a normal vitamin D at screening. They're all taking supplementation. We're pushing for people who come in as osteopenic to be referred and seen and treated. As you may recall from the SYMMETRY data, 40% of the patients in active and placebo were osteopenic at baseline. Yet during the course of the study, only 3% of the patients on the active arm who saw a decrease were being treated at all. This is old medicine. The agents treated, such as the bisphosphonates or the RANK ligands, these are not new drugs. The ability to treat these things and adhere to standard of care exists. We are being more aggressive in encouraging our sites to have these patients treated. Just to be clear, it's definitely plausible because there's more criteria in the protocol that we don't see as much of an impact because there's other protocols to help mitigate that. Yeah. There are approved therapies and many of whom are generic. Okay. All right. So that comes out. And then just in terms of the second study that's coming, which is a randomized controlled placebo-controlled study with a fibrosis endpoint this time, where are you in terms of enrollment? There is no, well, actually there is formal guidance for readout first half 2027. Correct. Right. We're tracking. Yeah. That guidance was given a while ago. Are you tracking ahead? How is enrollment going on your first major randomized controlled phase III study? We're doing well. I would say overall we're tracking about where we want to be. Have there been some changes? As you can imagine, if you're the first drug to show an improvement in cirrhotics, even though that's not exactly what the F, F3 study shows in pre-cirrhotic, it generally there's a little bit of a benefit in the sense that physicians feel, well, this is a pretty effective drug if it does that. It sort of distinguishes the compound from other competitors. There's much more competition in the F2, F3 space, not only from compounds in phase III, but also in compounds that are in earlier stages of development. It's a much more competitive field, but having that F4 data has helped us. You feel like there's been a very clear sense of, I don't want to say pickup, but a very clear delineation between, hey, Akero is the guy that's got this strong F4 data and therefore it's been, you know, not too difficult to enroll your phase III and you're right on track in terms of enrolling that globally. Exactly. The guidance I can reiterate is that we expect something in the first half of 2027. Being an analyst, you could like do reverse math, which is okay, therefore you would complete enrollment by first half 2026 for a readout in first half 2027 because it is a one-year study. Appreciating there is some time to clean up the data and all that kind of stuff. Do you think it is possible that you could complete enrollment in calendar 2025 rather than first half 2026? It is a possibility. It is possible. We're not guiding towards that. We just have to wait and see. We still have a little bit of ways to go. We're sticking with our guidance that we'll read out in the first half of 2027. Okay. So we'll track that, but it's not out of the question that enrollment could complete later this year. Yeah. When we complete enrollment for what we call cohort one in the Synchrony Histology, which is the one that will read out in first half of 2027, we'll announce that. We'll make an announcement. Okay. All right. So we'll pay attention to that. Definitely if you do the math, the phase III data on this is not that far around the corner if you do the math on time. Okay. Now when you put all that together, you did mention that there are a bunch of other competitor players out there. Madrigal is approved and on the market in F2, F3. On one side, they're trying to say that, hey, some of our F4 cohort data looks very similar to your data when it comes to some of the, I guess, non-invasive, I guess it was FibroScan data. Yep. They say that their improvement in liver stiffness looks like yours and therefore that they're going to have positive F4 data too. How should we interpret or would we expect that a Madrigal could show an F4 because they're also running their F4 study? Yeah. You know, Madrigal's compound resmetirom is a good drug. Could they show a benefit in F4? Certainly it's possible. You know, that's why they're doing the study. At the same time, just as they're the first drug to get approved and they have what they have in their label, there are other compounds behind it that have perhaps a differentiated one stage improvement of fibrosis that may still also be true for outcomes. They may show a benefit, but there may be other drugs that come later that show a different benefit, maybe larger. Maybe larger. Okay. Okay. By the way, one of the things I thought was also important for the audience is that your endpoints, certainly for the F2, F3 study that we just talked about, that endpoint is actually not just fibrosis. I believe that is fibrosis and MASH resolution. You have to have both. Is that correct? That is different than others. Correct. The FDA in the F2, F3 population allows you to have two endpoints for approval. You could either have one stage improvement of fibrosis without worsening of NASH, MASH, or you could have MASH resolution without worsening of fibrosis. Those are the two choices. In Europe, they require an and, not an or. Companies have approached this different ways, recognizing those two things are essentially the combination. We chose to use the and, even though the substrates are, it's hard to imagine that you would, if you do the and, that you do not succeed on both as well. The reason we chose the both is because of our data from HARMONY, which shows that roughly we have about a 5x response rate over placebo, roughly 35% versus 7% for the combined endpoint. As you can imagine, powering studies with low placebo rates is very helpful. That is the driver for us to choose that. Yeah. That is why it is definitely highly likely that it will be a win. Your point is that that actually changes again what the number is, because by the way, for your F2, `F3, you have not disclosed a number of patients that this readout is coming on. I do not even know if that has changed since the F4 data. How has that disclosed the number? Yeah. It's a competitive field. There's some people who look to see what we're doing and, you know, for strategic reasons, we haven't disclosed it. When it comes, when we complete the enrollment, we'll announce it. It's on hundreds of patients. Yes. It's on hundreds of patients. Of course. That will read out. Enrollment will happen and then we'll have the readout then. First half 2027 is the guidance. Jefferies thinks it could be a little earlier. In terms of the competitive landscape, this is also important and quite timely. While Madrigal is out there building a market, doing quite well and is running an F4 study, there are a couple other FGF21 right in the mix too. 89-bio is, I think, trying to enroll their phase III right there with you too. Comment on that. Where are they? Are they enrolling at same sites? How do you feel versus that? Boston Therapeutics was another FGF21 company. They just got acquired, but I think they were trying to enroll too. Comment on the landscape of FGF21. Novo has an FGF21. They have not read out their data yet. There's a couple of them. How should we digest the fact that there's three to four FGF21? I think that it's when you have an impressive mechanism and others want to be in on that space. I think the FGF21s are looking like they're going to be major players in the NASH landscape. It is always good when larger players like Novo, obviously they're very much a metabolic and diabetes company, have an asset. We're waiting those results. As you said, the clinicaltrials.gov said it was supposed to be Q4 of 2024. You know, now we're in the second quarter, near the end of the second quarter. We haven't heard those results. We don't know. That study is a very complicated multi-arm study, not just looking at FGF21. It's placebo control, looking at SEMA plus SEMA alone, SEMA plus FGF21, SEMA plus CAGRI, their amylin asset. It's multiple tiered. It includes patients F1 to F4. We're eager for the results. Novo is in their last call as well. I believe they are pushing forward in NASH because they're filing SEMA. Correct. So I mean, they're filing SEMA in NASH and they are planning to invest in the space. We'll see what happens with their FGF21, but they are definitely pushing forward and want to push that. Now, you know, they're going to try and grow the market with SEMA. I assume they want revenues. GSK just acquired Boston Therapeutics for 1.2 billion, I think like a month ago or whatever the date was. Now Pharma is now following this space. What happened there with GSK? GSK bought a NASH. They bought an FGF21. They bought Boston. I think it's great because oftentimes I've had to address the question from some analysts, not you, but others, and some investors who have asked, why is there no large Pharma involvement in NASH? Now you just highlighted two things. The first of which is that Novo's coming. There's no Pharma larger than Novo, just about, unless Lilly. Number two, there's been an M&A transaction in the space. Those are two questions I no longer have to answer from investors and analysts. The first of which is, I think it's fantastic that Novo's coming because it shows that it's a large Pharma market. Novo's got a great drug. They showed data last AASLD and they have a roughly about a 14.5% effect size. It was just also published in The New England about a week before our data. It will be great for the field because you can imagine how effective they will be in increasing disease awareness and creating, you know, more excitement about the field. GSK is now going to try and play in the space and you think that other Pharma companies as well are catching on. I know that obviously we've always asked you, well, don't you guys engage in lots of BD developments and discussions as well? Now Pharma does care? You know, I think that the fact that two pharmas are involved in the NASH space, one of whom is in the FGF21, is fantastic. So I think we look forward to continuing to grow in this field. There's no question, however, that in terms of the Novo drug and/or the now GSK drug, we're ahead of both those compounds. We're in phase III. Neither of those two compounds are. You've said openly before that you are definitely in regular dialogue with Pharma. That continues. I mean, yeah, we were the only company in the midcap company to have a large pharma investment. Recall in 2022, Pfizer made an investment in the company. Oddly enough, Pfizer has sold that position, but in any case, that is different. They did very well. You know, they did. They made about double their money. In any case, thank you very much, Andrew. We continue to follow the progress and look forward to the next milestone. Thank you. Thanks again. Thank you.