All right, welcome everyone to the next session. I'm Michael Yee, a senior biotechnology analyst here at Jefferies, and I'm very pleased to introduce the next company, the CEO of Akero Therapeutics, Andrew Cheng. Andrew and his team have been executing quite well across multiple studies in NASH, or MASH, now if I may call it, and there's some very important data coming up that Wall Street is very focused on, which is randomized controlled phase 2b, two-year data in F4 cirrhosis, so we're going to talk about that, but maybe it would be great, Andrew, if you could give us a brief introduction specifically to where you are in your pipeline with your FGF21, and then we can go into some of the questions about some of these important studies coming up. Yeah, happy to do so. So we are very much in the thick of things when it comes to our phase three development program. We have two pre-cirrhotic studies in F2, F3 histology, as well as a non-invasive F1 through F3 program that's been enrolling since Q4 of 2023. And we recently just enrolled our first patient in Q3 '24 in our cirrhotic outcome study in phase three. So we're very much in the thick of things in phase three, four, NASH, MASH. Think about that. So well into phase three for F2-3, Jefferies estimates, since there's no formal guidance, I think, but data would be like 2026, yeah, for F2-3. Actually, if I could interrupt, we just did give some guidance on when we gave earnings, and that is that we announced that our SYNCHRONY Real-World, that is the non-invasive study, would be in 2026. And then our Histology F2, F3 study would be in the first half of 2027. Okay. And importantly, you have started enrolling in the phase 3 for F4 cirrhosis, yet you have a big readout of a randomized controlled phase 2. So without making too much inferences into that, because it sort of already was the plan, you've already committed to and are enrolling in a phase 3. So what gives you the confidence, if I may just start out with the F4 cirrhosis readout that's coming, which is a huge focus, obviously a huge unmet need. I assume most people in this room may know that. And the data are coming up. So can you describe the study? Describe what the initial nine-month study data showed approximately a year ago. Actually, it was October of 2023. And this readout is coming in February for two-year data. Yeah, happy to talk about the SYMMETRY study. It's a phase 2b, a randomized double-blind placebo-controlled study looking at two doses of EFX, 28 and 50 milligrams. There were 182 patients that were randomized. And in the nine-month study, which read out in October of 2023, we missed statistical significance, but we had the best results ever seen in the field for one-stage improvement of fibrosis. We had roughly 24% on the 50 milligram dose compared to 14% on placebo. And these patients are now proceeding in the intervening time. And we have announced that we'll read out in February of 2025. And that will be the 96-week results. So there'll be a second biopsy on drug. So, promising results at nine months, 24% reversal of fibrosis, 14% for placebo in the highest unmet need patients with F4 cirrhosis, best data that had been reported by anyone in F4 to date at the time. Yet the market reacted quite negatively to the results and had missed statistical significance. So what would you expect a year and a half later now, coming up in February? What would you expect to show at two years? We expect to show a trend towards an improvement in the efficacy from week 36. As a reminder, we are not fully powered for the two-year endpoint. We are fully powered for the primary endpoint. But that being said, given what we showed in the HARMONY data in pre-cirrhotic patients going from 24 to 96 weeks, we showed a broadening of response. That is, the number of patients that had one-stage improvement fibrosis at week 24 was 40% for 50 milligrams. It moved to 75% at week 96. And that was made up equally of roughly half the patients who maintained their one-stage improvement of fibrosis at week 24, plus an additional roughly half the patients who were new responders at week 96. In addition, we saw the number of patients who had a two-stage improvement of fibrosis roughly double. They were 15% at week 24, moving to 36% at 50 milligrams at week 96. So that really shows us that the response rate not only broadened with the one-stage, but also deepened at week 96. And that gives us encouragement that in a more difficult to treat population, that with a higher collagen burden, higher fibrotic burden in cirrhotics, that that two-stage improvement of fibrosis really gives us some insight as to the efficacy of the compound. Remind me in those strong results in F2-F3, because we're learning from those results and maybe trying to extrapolate what will happen in the F4 study coming up. But in the F2-F3 study that was so strong, 40% versus 20%, went to 75% versus 25%, that was also two doses, strongly statistically significant. What were the number of patients at the completer analysis in those results? Because I want to compare the numbers of patients there, which was a strong result, to what we're going to get in the F4 study coming up to right-size people's expectations and think about what the powering and what the data could look like. Yeah. So at week 24, we roughly had 113 biopsies across the three arms. And then when we got to week. So it's a little less than 40 per arm. Correct. And then when we got to week 96, we had roughly 88 biopsies. We retained roughly 77% of the biopsies from week 24 to week 96. So clearly there were some discontinuations, mostly due to administrative reasons. But recall that the phase two formulation, unlike the phase three formulation, requires weekly visits into the doctor's office to get an injection. So it was not self-administered, where it is self-administered in phase three. So it's an extra burden for patients. But in the phase twos, they're all required to be administered in the physician office. Correct. Weekly. In the phase 3, it's self-administered. Your point being that in phase 3, we would expect potentially even better compliance than we had at that point. Okay. So where I was driving at is people are trying to figure out in this upcoming result in February, which Jefferies analysts think the stock could go up 50%-100% if it's strong, but let's talk about this. 24% versus 14%. How much widening or improvement do you think you could see in the drug arm? And what do you think you would see in the placebo arm at 14%? Yeah. And what is a good result? I know you say widening, but what is good? You know, when we think about it, we think, let's go in reverse order. We think that over time, the rate of untreated patients on the placebo arm will progress more rapidly in cirrhotic patients than they will in pre-cirrhotic patients. So that the proportion of the liver that is F4 will advance meaningfully from what was seen at baseline. What I'm referring to is that when there's a patient who is F4, it doesn't mean that 100% of their liver is F4. There are pockets of F3. So when we see improvements in quotation marks, it's really essentially a false positive on the placebo arm where the physician or interventional radiologist sampled at the biopsy period a portion of the liver that was. Let me think about this. So if you're biopsying a person who's F4 in the placebo arm, there is obviously a, the way it works and defined is a certain percentage of the image is F4. Is that correct? Correct. Okay. And they're deemed to be F4 based on the image where you sampled with the needle. Correct. In this case, it was deemed that 14% of the people after nine months somehow went to F3. But maybe that's because when they sampled again, that depends where the needle kind of went. Exactly. After two years, the probability of that sampling, which would show this F3, is the same or even less. I would start with the same, but less because more of the liver over two years has progressed to F4. So the probability of hitting a cell or area that's F3 is difficult. That's what you're saying. Correct. Thank you, Mike. Okay. So minimum stays the same, but could go lower. And in the drug arm, what do you think is going on there? We think that much like what we saw in the pre-cirrhotic population, that the drug still continues to suppress new collagen synthesis, yet at the same time, the degradative process of removing collagen is still ongoing. And so we would imagine over time that the number of patients who have a one-stage improvement of fibrosis should increase. Now, I think what you're driving at is what is the magnitude of that increase? And I think that's uncertain at this point. I don't want to put a number out there because we don't have, I'm still blinded and I don't know the results. What I would say, of course, if it ultimately was a phase three, but just kind of putting it in perspective, Wall Street was sour on the result a year and a half ago because A, it didn't hit statistical significance, B, Wall Street's expectations were higher at the time point. But if you even go look at Madrigal Resdifra, that is an FDA-approved drug, just did $65 million or whatever the last quarter. So it is off to a good launch. And in a less unmet need per se population, it is a 24 versus 12 type of number. So not that far different. Now, in the upcoming study, people are concerned because Wall Street seems to love statistical significance about whether you have enough power to show statistical significance. You didn't show statistical significance at the nine-month time point. And I believe you had about 50 patients per arm. Roughly 50 patients. Correct. 153. 153 biopsies. Excellent. In the phase 2 F2-F3 that we just talked about that was so great, you had even less patients per arm. It was about 35-40 patients per arm. Is that about right at the six-month time point when you did hit a 20% delta? Correct. 35 patients, roughly in that time. Roughly. Okay, so based on that rough math, if you show a 20% delta this time around, wouldn't that be sufficient to show statistical significance? It could be. It all depends on. 50 patients falls to about 40. It's still more than the 30-something patients. Yeah, I think it depends on what the balance is. And is it conceivable? Yes. Is it something we're counting on? Probably not. I think the difference here is that the cirrhotic population has a much higher fibrotic burden. And we're also cautious after last year and also just the history of what's happened in the cirrhotic trials that things, it's been a very challenging population. So I think we're optimistic, but cautiously so. Wow. We have run some analyses. What I would say is that first, it should be said, and I think you have said that at 15% magnitude of delta, if 24 goes to like 30 and placebo is 15, 14, that's still a doubling. Although a 15% at this smaller phase 2 is not so well powered to hit statistical significance. Despite the fact that a doubling, hopefully people would see as a good result, strong result, certainly better than Madrigal's F2-F3 result, and if you power that up to a phase 3 and instead of 40 patients per arm, it was hundreds of patients per arm, like a typical phase 3. In fact, you're running the study. Correct. I think it's hundreds of patients per arm. Exactly. Our phase three study is at 1,150 patients. 1,100, and I think that's two doses. One dose. One dose. One dose. Versus placebo circling. Correct. Two or two. 500, not 40 per arm. That would be well powered, as I'm sure you've already had the protocol, to hit statistical significance on a 15% delta. We are well powered as we are in a phase three study. My point being that if we see a 15% delta, just a continued improvement, expansion on your arm, placebo kind of stays the same at 14%, could go lower, could go to 10%-14%, that a 15% plus or even 20% of it doesn't hit statistical significance is still a very strong result and is 10x powered in the phase 3. You would have great confidence that that would hit. Yeah. I think that's the beauty of this study is it reads out at two years. That is really the primary endpoint for histology in our phase three study is at two years. So it's very much a read-through in that sense for the dosing duration. The difference is obviously, as Mike pointed out, the difference in sample size. Okay. Can you talk a little bit about when this result comes out? We've talked about efficacy. You'd like to see the drug treatment arm continue to reverse fibrosis, 30% plus in SYNCHRONY. That's going to be great. If the placebo arm, you gave us some information why it could go lower. I didn't appreciate that part. That would be a great result. If it hits statistical significance, even more fantastic. What about safety? In the phase two, both results you read out, there was a signal for bone mineral density. How do you put that into context for the F2-3 patients and to whatever extent in the F4? Yeah. So just for clarity, for one, looks at the lumbar spine. In the HARMONY study, we saw roughly about a 3% decrease over two years in the lumbar spine. It was statistically significant versus placebo, but that arm increased, which was much to our surprise. But overall, for postmenopausal women, which are the most common patients in our study, they lose about 1-1.5% per bone per annum. So the overall 3% loss was somewhat consistent over that timeframe. However, your point is that when one thinks about the F4 population, how does one look at bone mineral density changes? I think one has to take a look at the risk-benefit ratio for the patients. Most of these patients have advanced disease, advanced diabetes, advanced cardiovascular disease. When our SYMMETRY study, much to a little bit of our surprise, these patients, although they may have had advanced bone disease, almost none of them were being treated for bone osteoporosis. So there are drugs available for it. They're not new drugs. Many are generic, but they weren't being utilized in this study. And that's something as we go to phase three, we're asking the patients and their physicians really adhere more to standard of care. But that being said, to answer your question is that we think that when one looks at the benefit-risk of liver cirrhosis, for which there are no approved therapies, one can think about the risk-benefit ratio slightly differently. Okay. So if we could have strong results, first again, I'll repeat, I think everyone agrees that your F2-F3 results are super strong. It will be some time to get the data. 2026, I think you said, is more the open label. Correct. Phase 3. 2H first half is the randomized study. I'm hoping you're going to beat those expectations. We'll see. But also in the F4, let's see those results. That would be huge if it's positive. I think a lot of people are trying to still figure out the market. Now, we had Madrigal that's putting up some good numbers. Maybe you could comment about what that means for people and whether that means it should be more clear that there's a market evolving and building. But there's also like a number of FGF21s that are also out there. So does that matter? Is your drug better? You've got 89. They're rolling a phase 3 now. You're not the only one. You had Boston Pharmaceuticals put out some data. It's a monthly injection, Andrew. That just came out. Press release came out. Those results looked eerily similar. Correct. And even Novo has an FGF21. Novo is like in the other room. And they've got data coming out for F2, 3, and 4 coming out. So tell me about those. We're excited overall in the FGF21 space. When you see multiple mechanisms, really seeing similar results. The Boston Pharmaceuticals results, the effect size is very similar over 24 weeks compared to ours. 45 versus 22, I believe, versus our 40 versus 21. So very, very similar, and when we think about it, we see that FGF21 has likely played an impact on patients. But it's a monthly, not a weekly. How do I digest that? I think the dose, we are yet to see the data. I think the dose is 300 milligrams that they studied once a month. I think I believe I was told by some investors that it's multiple injections because it's not just 1 mL sub- Q. So that may be slightly different. Right. 300 mgs is difficult based on most math to be able to fit into a one or two mil injection. Correct. Yeah. So I think that's when one thinks about what it means to the patient. It means perhaps multiple injections once a month versus our drug, which is once weekly. So four injections a month versus, and yet. Last time I checked, there's like 10 million people that are going to be on a weekly type drugs called GLP-1. Correct. Okay. So not a big. Yeah, we don't see that difference is a particular material. I think overall, we're excited getting back to the first part of your question about how Resdifra is doing and how the market's growing very, very well. I think there is some, prior to the approval of this drug, there are some questions among investors about how viable the NASH market is. We're seeing right now that they put up $62 million in Q2 and really exceeded expectations. Do you believe, you know, what's remarkable about this market and seeing those results from Madrigal is that in essentially every major therapeutic category, and we have a full M&A chart that goes through all of this, oncology, autoimmune, orphan, obesity, there has been multiple M&A, huge deals in every one of those spaces. Yet there's like 10 NASH companies and not one major BD transaction has occurred. What do you think is going on? What are the general conversations you think, and you've had them, I presume you have some of those conversations, and you used to be at Gilead, so you could see what is also on the other side, but what do you think is going on there? What are the data sets or things that are happening where it would require someone to go ahead and move on this, considering that there's a large focus on metabolic disease now? You know, I think it's one of those where it's always hard to know what third parties do or don't want to do. But I would just say that when drugs launch extremely well is what we're seeing from Madrigal. And you're seeing results from Novo. We haven't seen the full data presentation, but the press release looks very good. They're likely to enter the market, I would assume. I think the market is growing. I think that only increases the attractiveness of the pipeline. Now, to answer your question of why hasn't there been transaction yet, that of course is not really, I have no insight, I guess, as you pointed out, some of those companies are across the way in the other building. We should probably ask them. But I think overall, as the market improves and grows, I think it just makes the field much more attractive. I can tell you what they say. First, they say GLP-1 is going to be used in all these people. Let's start them all on a GLP-1. It's cheap. They lose massive amounts of weight. There's a cardiovascular benefit. Everyone's going to be on a GLP-1. Sema just showed some positive F2-F3 data, although not going to work in F4, again, to the importance of your data. What would you say to that? Second of all, you know, the overall diagnosis of the disease, market size? I mean, basically it's the GLP-1, to be honest, I would say. I think all of those factors are at play, and I think when one looks at the market, one can look at the diabetes market as a very good proxy. A lot of these patients are diabetic, and you see multiple agents in the field. Even though the GLP-1s are in that market, there are plenty of other agents that make an impact, so no question that drugs that have been around for a long period, like the GLP-1s, will have an outsized impact, but I don't see when one thinks about it, you talked about F4 as an area that they probably won't go into, so there's a range of possibilities for multiple agents in the market to benefit both patients and physicians. It's actually an interesting question because yes, they're being used. You might agree with me that Lilly hasn't formally committed to advancing their running phase threes. Really, I sort of stated no real plan there. I presume Novo is going to file the Sema data, which that's probably. That's what I've heard. Yes. Okay. So they would have a label for that. But overall, I would just say that most people believe that that's going to be an issue and therefore the market's crowded. Now, when the F4 data comes, if that is a strong result, do you think that that changes the mix? And you know, again, you're in discussions, presumably in general, always in BD discussions. But is that a gating step, you think, is wanting to see additional data? I think whenever there's more data, everyone likes to see, to know what the landscape is, so I think certainly the F4 data will be helpful, but at the same time, I think that there's some patients who are more advanced and some patients who are earlier stage, and even in the F2, F3 market, there's room for multiple agents. There's room for an agent like Madrigal's drug. There's room for GLP-1s. There's room for FGF21s like EFX, so I think in both stages, independent of F4, physicians and patients want to have multiple options. Well, look, if Madrigal is doing $62 million and growing, and I think safe to say well on pace to eventually be a blockbuster drug, reasonable, then that proves that there is a market despite the fact that there's GLP-1. In addition, you actually have data in combination with GLP-1. So can you speak to that? Because I guess if it's a weekly, you could get two different injections to treat two different situations. But what would you say to that? We've had a study where we looked at patients who were all taking GLP-1s for more than a year. We added on an adjusted short non-invasive study to look at tolerability, that the combination of EFX versus placebo over 12 weeks was highly beneficial for those patients, that nearly 90% of the patients normalized their liver fat. And they all had significant reductions in their hemoglobin A1C, in addition to also having significant reductions in their C-peptide, the marker of endogenous insulin production. So thereby EFX lowers insulin resistance slash increased sensitivity. So it's very much a sort of hand in glove combination with a drug that's an insulin secretagogue, which is what the GLP-1s are. So it allows that the insulin that is being secreted to be more effective. And so we've seen GLP-1 use in our own studies, 15% in the F2-F3 studies, roughly 20%. We feel that the drugs work nicely together as it is. Fantastic. Okay. So given that we're at the top of our time, looking forward to the upcoming cirrhosis data in February, looking forward to continued execution, and we will absolutely be in touch with you on this. Fantastic. Thanks for having me, Mike.