I'm very pleased to have joined me in our first slot of the afternoon session, Andrew Cheng, CEO of Akero. Thank you so much for joining us. Thank you for having us, Jason. Perfect. Maybe just to start broadly, to provide a little context for those newer to the story, can you describe the role of FGF21 in the pathogenesis of liver fibrosis? Kind of acknowledging that it is somewhat early, but what are some of the advantages the mechanism here has in the space relative to maybe others that are either shown efficacy or late stage? Yeah, so I think when one thinks about efruxifermin, it works really by two mechanisms. It is not uncommon to have drugs that remove liver fat overall, and by being anti-steatotic, then it allows the liver to heal via indirect mechanisms. Through our early stage studies, EFX does that very, very well. Fat comes off very quickly, and among the most effective agents to date, even more so than some of the GLP-1s. At the same time, it is also a direct-acting antifibrotic, which is unique. That is, that EFX works directly on the hepatic stellate cells to inhibit new collagen synthesis, which is why you have seen in multiple mechanisms, whether it is our agent, other FGF21s like 89bio, as well as Boston, you have seen impressive fibrosis responses in just 24 weeks. That is a timeframe that you have not seen other mechanisms hit their endpoints. We've seen one year for both tirzepatide and the Bi- drug, and for semaglutide in their ESSENCE study, their endpoint was 72 weeks, so 18 months. Got it. Maybe looking more inwardly at EFX, what differentiates this molecule versus other FGF21s, many of which have been discontinued? Yeah, so I think the FGF21, because it acts in the two ways that I outlined, had been really a desirable target for a number of years. Like all of drug development, it's one that early stage compounds don't always work. They don't hit the targets. We saw not that long ago a compound of FGF21 from Bristol- Myers Squibb that was discontinued. EFX in particular, Amgen, who developed and discovered this compound, also made some important modifications to it at the C-terminus. FGF21s in particular rely on a trimeric interaction. That is, the C-terminus must bind with a co-receptor called β -klotho on the cell surface, which helps to anchor it. That binding is an obligate step. If that binding is abrogated, then the molecule is untethered from the cell surface and cannot signal through the N-terminus to the FGF receptor. Amgen made some important modifications to enhance binding at that point. I think that's one of the differentiating points about EFX overall, is that in addition to its three- to four-day half-life, it's been sort of engineered for longer activity. Makes sense. Maybe just one last question on background dynamics here and tying your previous two answers together. I mean, if you think about MASH-NASH, it's been challenging to address until recently. There haven't been any approvals. At a high level, what do you think has shifted? Why should investors be confident we're kind of hitting our stride after years of setbacks? Yeah, so I think I've been at Akero six and a half years. I was employee three. It's been a bumpy course. I mean, there have been failures, as we talked about earlier. Drug development is not one that's generally littered with success after success. It's new fields and new mechanisms. It takes a while. I think the real change, the inflection point, was the March 2024 approval of Madrigal's Rezdiffra. And with that compound, it slayed multiple bear theses. Number one would be the FDA doesn't want to approve drugs. Number two, approvals will require biopsy. Not true. Number three, that they wouldn't price well. They priced where they did. Number four, they couldn't launch well. I think quarter after quarter, they've beaten expectations. A small-cap company with a single asset launching a compound, well, that has, I think, reset a lot of investors' expectations and how they look at the field. It makes sense. Good compounds are the ones that make differences in our field. Hats off to the Madrigal team. They've done very, very well. Got it. Let's dive into the Akero story a bit. I mean, obviously, the big focus, I think, for everyone is in January, you disclosed the 96-week phase II-B SYMMETRY data. 39% of patients on EFX versus 15% on placebo had one or more stage improvement in fibrosis with no MASH worsening. You talk to a lot of doctors, and they say this data is transformative. But for maybe somebody who isn't in the field, I mean, can you put this into context? What are the implications here, and why were they so surprising for many? We were talking about failure just a minute or so ago. The F4 population, Madrigal's drug is approved in the pre-cirrhotic population. We were talking earlier about the timeframe and other agents. There have been multiple agents with multiple mechanisms being successful in the recent two to three years in the pre-cirrhotic population. There has never been an agent who's demonstrated statistically significant improvement in fibrosis due to MASH. This is regardless of the company, regardless of the mechanism, regardless of the duration. Part of it goes to what we were taught in medical school. That is, that cirrhosis is irreversible. That was one of those taglines. It was true for multiple generations of physicians, and people learned that. It was true until January 27th, as you pointed out. Drugs that change medical dogma are ones that make a difference for patients and physicians. I will just highlight, the study you were referring to was just published Friday in the New England Journal of Medicine. It is those kind of studies that get to publish in that kind of journal when it is a significant medical advance. Can you put this into context for patients? What's the danger of being a cirrhotic patient, and what could an improvement of close to 40% in fibrosis mean for someone with cirrhosis? Yeah. So unfortunately, for patients who have cirrhosis due to MASH or cirrhosis due to anything, but let's just focus on MASH, the five-year mortality is 50% short of a liver transplant. Those aren't great circumstances. You can imagine you cover multiple companies, but in oncology, there are a number of diseases that have a better prognosis given the innovations in therapy. When one goes back and has when one thinks about, let's say you were F3, one stage earlier, non-cirrhotic, the duration to get to 15% mortality on a Kaplan-Meier curve that the FDA uses is 19 years. Going from F4 to F3, we haven't had drugs that do that, but one could perhaps interpret maybe not correctly, but that you gain 17 years of life. I mean, it's, or excuse me, 14 years. I did the math wrong, but it's substantial. Drugs that potentially provide mortality benefits are very meaningful. Is the implication, do you think, and granted, it might be a little speculative at this point, but for an F2, F3 patient, is there also likely to be a mortality benefit if we kind of look longer term on that Kaplan-Meier curve? Sure. I think when you're pre-cirrhotic, especially if you're F2, the goal is to not progress to F3 or later further stages of cirrhosis. The difference is if one looks at the FDA Kaplan-Meier curve that they often use in their deck, F2 and F3 are relatively close. The real challenge is when one progresses to F4 from F3, and that is, we just talked about. I think overall, halting the progression of cirrhosis and maintaining liver function is very valuable. Makes sense. There was a profound difference between looking at the data, 36 weeks versus 96 weeks. I think the first question here is, has EFX reached its maximal response, or how far out do you think before we get to that plateau? Yeah. So that's a really good, very good question. I think what the data showed from SYMMETRY is that longer dosing matters for this drug. You saw the response rate go from 24% to 39% between adding an extra nine months from week 36 to actually another 14 months, now 60 weeks. That gained quite a bit of efficacy. What you see is that that's very consistent with what we saw in the pre-cirrhotic population. In their pre-cirrhotic time point, when we first met the primary endpoint at week 24, we saw approximately a 40% one-stage improvement in fibrosis. By week 96, we saw a 75% one-stage improvement in fibrosis. Again, in both scenarios where this pre-cirrhotic is cirrhotic, obviously the magnitude of the pre-cirrhotic is greater because the fibrosis burden is lower. In terms of your question, have we reached a plateau? I don't believe so. I think the longer that we dose the patient, because the drug is effective at shutting down new collagen synthesis, but allowing resorption of the collagen burden, I think longer-term dosing will benefit patients. Makes sense. I think one question about the data, given what we know about cirrhosis, was the placebo rate high? I mean, did that surprise you? Yeah. So we saw 14% at week 36, and at week 96, we saw 15. I lost the bet internally. I was hoping, thinking that, like you did, that it'd be 10% or lower, because that's what was seen in large studies run by INTERCEPT and Gilead, that in these large phase III studies where patients, we had 900 patients, the placebo rate was about 9% or 10%. Those were single reader and done at a different time. I think at that same point, placebo increasing 1%, not much, but still increasing, speaks to the fact that the efficacy rate on the EFX arm was strong, which is why we made statistical significance in both completers analysis as well as the ITT analysis, where we treated missing data as failures. Got it. Last weekend, you presented the full data set at the AASLD conference. Curious, how was the data received? What was feedback like? What did you hear from the prescribers and the rest of the community on the ground there? Yeah. While this audience is one that obviously follows press releases and follows company releases quite closely, the scientific community, well, they treat patients. They're not so focused on what we say via press release. For them, this was the first presentation of the data. As you can imagine, the response was overwhelmingly positive. Keep in mind that for most of their careers, these physicians, or nearly all of their careers, they've unfortunately had to watch their patients succumb to the disease because there's been no effective treatment. I don't think anyone gets into medicine to watch your patients pass. I think this is something that you want, something for your patients. To have a possibility of giving them a meaningful benefit is very encouraging and motivating to them. Got it. What would you say is sort of the biggest question about the cirrhotic population at this point? I think the question really is how much of an impact this could have for patients right now. Because although liver transplant saves people's lives, I'm not sure people are eager for a liver transplant. There are, of course, too few organs to go around to begin with. I think the idea that this could improve, you asked earlier about 40% of fibrosis. Right now, the options are zero for these patients outside of liver transplant. I think a 40% one-stage improvement in fibrosis is very well received. Got it. You bring up a really good point, and I think that's a great segue to the next question here. Given that outcomes are so poor and there are limited current options, is there any sort of potential for regulators to be flexible here? That's a very, very good question, Jason. And one question I receive a lot from investors nowadays. I would say the answer is maybe. How's that for definitive? The answer is that obviously providing this kind of benefit, given the reception from physicians, has been very encouraging. The challenge is that current regulatory guidance says that there really isn't an accelerated approval pathway for in-cirrhotic patients. Now, guidances are not permanent, and they can change. I won't give too much into upcoming discussions, but it's something we want to look into. I certainly won't overpromise as to say or prejudge what the FDA may do. Got it. All right. So we've seen some of the initial cuts of the phase two data, but I'm curious, what do you think the implications of SYMMETRY are from the phase II, phaseIII patient population, especially as we think of kind of the early results from the phase II HARMONY? Fundamentally, does this give you increased confidence around SYMMETRY Histology? Oh, absolutely. So when you think about the F2, F3 population, recognize that we've chosen a primary endpoint, which is consistent with the European guidance, which is a combination of one-stage improvement in fibrosis and MASH resolution. In the United States, technically, for the pre-cirrhotic population, it's or you can achieve one or the other. Obviously, for patients, fibrosis is much more important than resolution, but we've chosen that because we want to file in Europe and the United States. That being said, when one looks at the ITT results of the two-year data, we see 35% of patients where ITT is missing data or failure have a one-stage improvement in fibrosis and MASH resolution compared to 7% on placebo. When one thinks about that, that's 5x the placebo rate. That gives us a lot of confidence that, of course, F2 studies, sometimes they're smaller, there may be some differences in efficacy, but there's a wide margin for us to be successful. We feel confident about SYMMETRY Histology as we go forward. Got it. Can you give us a sense, though, of timelines here? I mean, when do you think you'll have greater clarity into sort of the regulatory path forward, particularly as it sort of the outlook for maybe a faster pathway? Yeah. So when it comes to the pre-cirrhotic population that we were just talking about, we have regulatory clarity. Right now that we've guided that we'll have the SYMMETRY Histology results you were just asking about to file in the first half of 2027. And given that would be the same pathway that Madrigal filed on, so I think we have a trailblazer there, as we touched on earlier. We feel comfortable with that timeline. Of course, a small company, after we get the results, there's some window of time in between when we file. I think that that accelerated approval pathway is likely open to us, and it's something we'll pursue. The other pathway that for cirrhotics is a little more murkier and how we'll proceed. I think there are two companies, us and 89bio, who have phase three studies with two-year histology endpoints. I think that is something that we will be looking at as we get to that point. Our studies have started about the same time, and we look forward to having those results. Makes sense. Obviously, we've seen quite a bit of the efficacy data, but safety is coming into picture as well. Rates of decompensation were fairly low in the SYMMETRY data, but do you think we have enough of a sense there that it's not as big a risk as I think some might have initially feared? I think it's hard to say that. I'll give you an example. In the SYMMETRY population, we had two cases of ascites, one in the 28 mg dose and one in the 50 mg dose. Both of those cases were in patients who were discovered on incidental finding in the U.S. What does that mean? What it means is that when you're cirrhotic, you need to be checked for hepatocellular carcinoma every six months. That's standard of care. You're being checked by an ultrasound. When an ultrasound was given, they saw some fluid in the stomach. Basically, they call that ascites. Now, technically, that is ascites, but you're asking why am I bringing this up, because the FDA for phase three has a different definition. Incidental finding of ascites would not qualify as a clinical liver event. They would require something that requires clinical intervention in, I guess it's after lunch, I can bring this up. The treatment for ascites is paracentesis, which means that you remove the excess fluid from the distended abdomen. Neither of these patients would qualify for paracentesis, so they wouldn't have been clinical events. When one thinks about it, there is really one other event, which is hepatic encephalopathy. That patient was also a little bit atypical in the sense that they had multiple strokes, small strokes prior to entering the study at baseline. It's not clear at this period of confusion what it is the cause of, because if one looks at their profile, it's not really consistent with someone who's having hepatic decompensation. With our clinical events that have been recognized as a phase two study, I think there's some question about whether they're really clinical events. Makes sense. Maybe switching gears somewhat, Novo Nordisk is conducting a combination study of its FGF21 zalfermin with semaglutide. Obviously, there's not a lot that we know about zalfermin at this point, but maybe at a high level, does this combination make sense based on what we've seen from both mechanisms? Absolutely. Remember that when one thinks about what GLP-1s do very well, GLP-1s remove liver fat. FGF21s in our data in particular, I touched on earlier, were very effective at that. At the same time, the indirect process of steatosis, removing the fat from the liver, takes time to heal, which is why their endpoints in essence was 72 weeks. On the other hand, FGF21s are direct-acting anti-fibrotic. You can see the combination of those two mechanisms works well together. Whether it is 89bio, our data, or Boston Pharma, all with FGF21s saw impressive anti-fibrotic results within 24 weeks. At the same time, one has to think about the patients who are receiving GLP-1s, many of whom are diabetic. GLP-1s are insulin secretagogues. What that means is it forces the pancreas to try to secrete more insulin. Why is that necessary? Because many diabetics, especially type two diabetics, have a wall of insulin resistance, very high resistance, which prevents the insulin that's being secreted as working as effectively. The efruxifermin reduces, it's an insulin sensitizer. For every molecule of insulin that's secreted, it doesn't have to work as hard. In fact, in our clinical studies, we saw statistically significant reductions in C-peptide. C-peptide is the natural proteolytic byproduct of endogenous insulin secretion. What that means is that when you lower resistance, the pancreas doesn't have to work as hard, so it doesn't have to submit as much or secrete as much insulin. It's a nice sort of hand-in-glove thing, having a drug that helps the existing pancreas work better. Got it. Could you remind us, I mean, you looked at a similar sort of combination in cohort D of the phase II-b SYMMETRY. What did those patients experience appreciating that they had type two diabetes? Yeah. We had this question because we wanted to know, it's well known that the GLP-1 class has some GI side effects. We do see, most FGF21s see some degree of nausea as well as diarrhea, so GI side effects as well. If you were to dose the two drugs together, what would be the effect on tolerability? We ran a study of everyone receiving a GLP-1, whether it's semaglutide or it's Trulicity or tirzepatide, and they added 50 mg of efruxifermin or placebo for 12 weeks. What we saw on the tolerability side is really no additive tolerability. In fact, numerically, the combination arm had a little bit less diarrhea. We're not saying we're an antidiarrheal, it wasn't additive. There was slightly more nausea. At the same time, impressively, in just 12 weeks, 90% of patients on the combination arm normalized their liver fat. That speaks to what we talked about earlier. That is that GLP-1s are good at reducing liver fat, but patients after being on GLP-1s for the average time was more than a year, they still had abnormal amounts of liver fat. Within 12 weeks of adding EFX, they all, 90% of them, normalized. That is, they got to less than 5%. In addition, they had improvements in glycemic control, as we just talked about, because insulin resistance went down, and they had improvements in their lipids. Taken together, what that study cohort D showed us is that the combination of GLP-1s and efruxifermin worked very well together for multiple facets of the patient's illnesses. When you think about MASH at a high level, the pathogenesis is driven by multiple pathways. From a fundamental standpoint, is it your expectation that the treatment of MASH will be sort of a multimodal combination approach? Absolutely. Unfortunately, these patients, as you pointed out, have multiple medical problems. If you look at the SYMMETRY study, 80% of the patients were diabetic. Nearly 100% of them were obese. They had dyslipidemia. When one thinks about the challenges facing them, they are going to require multiple agents, and we would expect that that will continue. What does it take to get efruxifermin to a foundational part in this pathway? I think in our studies, we're allowing patients to take whatever is approved for the therapy, existing drugs. They're not allowed to take Rezdiffra, but I think at this point that we're excited that having multiple regimens in the therapy allows us to look at this kind of cohort D-like background therapy, plus minus efruxifermin, and you could subshoot multiple agents there. So there are a lot of built-in studies to allow us to look at the benefit of efruxifermin in combination with other agents. Got it. Again, kind of I know this is somewhat speculative, but given the totality of evidence, I mean, in what patient does it make sense to use an FGF21, and maybe what patient not so much? I think we have to look carefully, and all the FGF21s are injectables. I think for patients who are needle phobes, I think that's obviously a challenge. I think for many patients, FGF21 as a rapid-acting anti-fibrotic, I think is desirable at pretty much every stage of infection or disease. I think the challenge is that given where other agents are, I imagine that it's going to come after some of the agents that are already approved today just by virtue of not being approved at this time. Makes sense. Of course, you did allude to the fact that there are rivals within the class. I'm curious, what factors do you think are going to be key in determining kind of the market split among the FGF21s? I think this field is a data-driven field. I think as you accumulate more data to help inform how your drug will be used, the more data you have, the better your circumstance because you provide more information to physicians and patients. I think that will be the distinction. At the same time, sometimes we hear from investors, who's going to be the winner, who's not going to be the winner. Luckily, I looked at the diabetes field where there are multiple agents for multiple mechanisms and it does not prevent any individual drug from being successful. I look at the GLP-1 class between semaglutide versus tirzepatide. They're both doing very, very well. Got it. Back on the subject of efruxifermin, when you think about kind of the treatment paradigm, what does it take to move an agent like efruxifermin into the hands of your average endocrinologist or even a GP and outside your average hepatologist? Yeah, so that's a really good question. I think the challenge is that most newer drugs are used by sort of specialists. That's generally how it will start. I imagine that efruxifermin, given its activity in cirrhotic patients, will probably start with hepatologists. Over time, as more and more data gets out, there'll be some degree of GI and/or endocrine who will use it probably in the pre-cirrhotic patients before it will get to sort of broader family practice or internal medicine folks. Got it. Maybe just one more on the commercial landscape. As you think about payers, it's been interesting how welcoming they've been with the class in terms of not requiring biopsies. I'm curious, is that going to change moving forward, especially as the overall treatment armamentarium grows? How are payers going to be when a patient is on therapy for two, three, four more years? Yeah, I think that's a challenge as we see the therapy and standard of care evolving, that overall you really need to be providing value. Payers are likely going to require patients to be followed non-invasively since that's pretty much standard of care now. People do not use biopsies to follow patients given its morbidity and mortality. I think two to three years from now, they will want to see progress on some of these non-invasives in order for them to continue in supporting them. Got it. Makes sense. In the few minutes that we have left, if you could please remind us where you are with the pivotal studies that you have, SYNCHRONY Histology, Outcomes, Real-World, and then what the timelines of those look like, and then how that compares to, as we talked about earlier, kind of a potential for a shortened improvement pathway. We fully enrolled the first of our phase three studies, which we call SYNCHRONY Real-World. We announced that in January. We expect that a 52-week endpoint in a non-invasive study to read out in the first half of 2026. The SYNCHRONY Histology, which is the biopsy-driven F2-F3 study, we have not fully enrolled yet. It is still ongoing. We expect that the biopsy endpoint to read out one year in the first half of 2027. For SYNCHRONY Outcomes, the F4 compensated cirrhosis study that has a biopsy component, we just started enrolling that in September of 2024. We have not given any guidance to that. Got it. Makes sense. I guess as we kind of wind down here, as you think kind of the bigger picture, I mean, for you, I think what is the overarching question that we think we need to understand about both the class and kind of the treatment of MASH? I think the driving issue for us is to demonstrate clinical benefit in either histologic or clinical outcomes measures. I think we're well on track with our ongoing studies that are enrolling to really hit that. I look forward to, in the not too distant future, to revealing some of those results. Perfect. With that, I think we are done. Thank you so much, Andrew, for joining us on stage. Thanks again. Take care. Great.