All right, so we'll get started here. I'm Eric Joseph, Senior Biotech Analyst with JP Morgan. Our next presenting company is Akero Therapeutics, and with us to bring us through the story is CEO Andrew Cheng. There is gonna be a Q&A session after the presentation. Just raise your hand and we'll bring a mic around. And for folks tuning in via the webcast, feel free to submit questions by clicking the Ask a Question button. With that, Andrew? Thank you very much, Eric, for having us, and we're excited to be back and really to be moving into 2024. I think that, you know, 2023 was an eventful year for us, and it really set us up well for how we're gonna be moving forward. So, I have to show my safe harbor slide to please my legal counsel, but I think that's enough. And so when you think about where we are as a company, we're a clinical-stage Phase 3 company, and that's really exemplified by our press release at the end of last year when we talked about the global SYNCHRONY Phase 3 program, how we announced that we'd enrolled our first patients in both the SYNCHRONY Histology pre-cirrhotic F2, F3 group, as well as the SYNCHRONY Real-World trial that's based on non-invasive tests. Of course, we also announced that our compensated cirrhotic study, the F4 Outcomes study, we're meeting with the FDA for an end of Phase 2b meeting in the first quarter of this year. So when one thinks about that, one really looks back, what's the foundation for our Phase 3 program? It's really the 2-year Phase 2b studies that are really in circles one and two. That is the pre-cirrhotic HARMONY study in F2, F3 patients. It is a 2-year study. We also announced that we'll be providing those 96-week results in March, and I'll talk about the data underpinning that in a moment. And then we also, in 2023, in October, we announced results of our SYMMETRY study at the primary endpoint at week 36, and I'll talk about that momentarily as well. Now, one note that we're announcing at this meeting is that we'll be providing the 96-week SYMMETRY results in Q1 of 2025, so about a year from now. All right, let's move on. As a reminder for, in case there are some new investors here, that our main asset, efruxifermin, is an Amgen in-licensed and engineered asset that is a bivalent FGF 21 analog. And you can see the structure on the left-hand side of the slide. That is, that you see it has, two FGF 21s, where there's the Fc fusion protein attached to the N-terminus. And at the C-terminus, there are, important modifications that, lead to enhanced binding, most prominently by beta-klotho, that also translates to, enhanced activity, that we've demonstrated in our clinical trials. In addition, the, When one looks at some in vitro data that we've touched on in scientific meetings, the bivalent nature also leads to longer term exposure, enhanced or demonstrated by the longer dissociation or the KD from the receptor. And this is different than some of the single-chain FGF21s that we've demonstrated in vitro. So why don't we turn to HARMONY? And that is, this is the 96-week study I touched on on the first slide. As a reminder, it's a randomized, double-blind, placebo-controlled trial looking at two doses of FGF21 that is EFX 28 mg and 50 mg, in biopsy-proven F2- F3 NASH patients with a NAS score of greater than 4 and an MRI-PDFF of greater than 8%. We reported the primary endpoint results week 24 in September 2022, and the 72-week follow-up is what's ongoing, and that we'll report out the 96-week data in March of this year. As a reminder, when one looks at the endpoints, you can see that these are the FDA endpoints and the two boxes on the left that lead to registration for NASH products. You can see that the fibrosis response was statistically significant and not too different between doses, roughly a 20% effect size over placebo. The NASH resolution results at 76% are among the highest seen in a Phase 2b study, and that dwarfs the 15% response rate on the placebo arm. And lastly, the third box is there because that's the combined endpoint, and that's the endpoint we'll be taking into Phase 3 in our SYNCHRONY Histology program that I've talked about. What is the reason behind that? Why didn't we choose one or the other, which is what the FDA requires? It's because in Europe, you're required to meet both endpoints, and so this is an endpoint that meets both, fibrosis improvement and NASH resolution. And also, it's probably the most clinically relevant endpoint, because if one thinks of what you are as a patient, you want to be improving your fibrosis stage and you want to be free of NASH. You want to have NASH resolved, and so that's why we've chosen that as well. Lastly, when one looks at the 5% placebo rate, that also helps in our powering for our study. When one compares these results to some of the fibrosis, one stage improvement in fibrosis results with some of the other compounds that are in development, you can see on this slide that it compares favorably. When one thinks about the effect size seen, it's among the top seen to date in the field. It is, of course, notable that the Madrigal study is a Phase 3 trial, and it's also ITT. But when one thinks about how successful they are, I think we're encouraged that our phase 2b results were statistically significant. Lastly, we left the semaglutide study up there because it's one of the questions we often get, and I think you'd have to be living in a cave over the last year to not be aware of the GLP-1 impact in our society overall and in NASH in particular. It is notable that after 72 weeks of dosing in a fairly sizable Phase 2b, and in this trial, super Wegovy dosings was used. It was 0.2, 0.3, and 0.4, three arms for the active arms, and those doses were given daily. And so when one thinks of Wegovy at 2.4 doses, at least on the 0.4 mg, these were super Wegovy doses. Yet despite that, as well as the eighteen-month duration, there was no statistically significant difference when it came to one-stage improvement of fibrosis. Nevertheless, we look at GLP-1s as a class that really make are likely to be impactful in the NASH field. And in fact, given, you know, how it's impacted on weight loss, we wanted to understand the combination of our agent, efruxifermin, with GLP-1s, and that's what we released in June of last year. That is what we called Cohort D, which, D standing for all the patients who were diabetic, and so not very creative. But I think this study is very much a real-world study. That is that all of the patients, 100% of the patients, were receiving a GLP-1 at baseline. That is, and the average time was more than a year. And we didn't specify they could have been on any flavor of GLP-1. Some of them were on Mounjaro. But the important thing is that, when we looked at these patients, we wanted to understand what was the tolerability as well as what was the impact of adding 50 mg of efruxifermin to patients that were had been taking GLP-1 for more than a year. What we showed is that if you look at the panel on the left, is that... Well, first of all, the average baseline liver fat was roughly 11%. So recall that in most NASH trials that patients are naive to therapy, their liver fat is roughly in the upper teens, anywhere from 17 to low twenties. So even though these patients have been on a GLP-1 for more than a year, they still weren't normalized. They were at about 11%. Yet after just adding efruxifermin for 12 weeks, roughly 90% of patients normalized their liver fat. That is, they went to less than 5%, in just a short, very short period of time. The average liver fat reduction was 65%, which compares very favorably to just about any other agent in terms of liver fat reduction. Keep in mind that they were already receiving a GLP-1. And then when one looks at the percentage of patients who had a greater than 50% reduction, it's again, nearly 90% of patients achieve that, and that's consistent with the middle panel. Now, when one looks at the impact on lipids, I think it's important to recognize that in NASH patients, these are patients who the number one cause of morbidity and mortality is cardiovascular disease. You can see, consistent with previous trials with efruxifermin, whether it's in pre-cirrhotic patients in Phase 2a, Phase 2b, or in cirrhotic patients, we see a very similar statistically significant improvements in lipids in just a short period of time. Overall, we would probably summarize this as being very heart-friendly. You can pick the panel, whatever it is, it's really going in the direction you, your cardiologist would want it to go. Why don't I turn now to patients who have perhaps a more difficult time? That is the patients who are cirrhotic. Recall that in this field, there's not a single agent that's been successful in demonstrating improvements when it comes to cirrhosis. You know, unfortunately, despite the acute medical need, that's a setup that has been difficult for therapeutics. We set out with this study to look at patients who were compensated cirrhotics, Child-Pugh Class A, and they were randomized in a double-blind fashion to, again, one of two doses, 28 and 50 mg of efruxifermin. The primary endpoint differs from this study was at 36 weeks. Again, it's a 2-year study. In last October, we released the data on the primary endpoint, which was one stage improvement of fibrosis at week 36. So what we showed is that we fell short of statistical significance. Yet at the same time, as you see on the panel on the left, these are among the strongest results ever seen in NASH cirrhosis. That when one looks at it, we had roughly a 10% effect size at week 36, but keep in mind this is a 96-week study. And for the first time ever, on the panel on the far right, we demonstrated statistically significant improvements when it comes to NASH resolution. That had never been seen before for any agent, for any duration. So, and that was seen for both durations, both doses of efruxifermin. At AASLD in November, we did some additional analyses. We tried to understand the response rates a little better, and we had a subgroup of patients. That is, those patients who were either cryptogenic cirrhosis or had a greater than six months duration of dosing since they were, they found out that they were cirrhotic. And what it showed in roughly, a little more than 60%, about 60% of the patients, is that we were nearly statistically significant when it comes to the one-stage improvement of fibrosis by looking at that group of patients. And one could ask, why do we think that is? I think largely the response rate for EFX didn't change very much, especially at the 50 mg dose. But what really changed is the placebo rate, you can see on this middle panel, really dropped from 14 down to 3. And what that really tells us is that biopsy in itself, in compensated cirrhosis, and it's true in pre-cirrhotic as well, is inherently variable. That by taking patients who had a greater portion of their liver that was probably cirrhotic, that is, those that had, had known that they were cirrhotic for a longer period of time, we're able to see, sort of lower false positive rate, and that bordered on significance. So w hy am I raising this at this meeting? Is that these kind of insights and what we're able to draw from these data are help guiding us when we think about what would be, the optimal Phase 3 study in compensated cirrhotics. So I think we're, makes the basis for what I referred to earlier. We have an FDA meeting in Q this quarter, and, we'll be utilizing some of these data as well as others in how we, construct the study. One of the other questions about this is when we get this, is that people want to ask: "Okay, well, you, this looks promising, but what about the non-invasives? How did that look?" So when one looks at that trial, you can see that the non-invasives, consistent with other, pre-cirrhotic studies, but also in this study, go in the right direction. We're statistically significant for ELF score. We are for PRO-C3, a marker of new collagen synthesis, and we are for the FAST score as well. We didn't meet it for FibroScan for the Liver Score, primarily even though the magnitude of the effect is similar to what we've seen in past trials, we do have a much larger placebo rate, which we're still investigating, to better understand why it's so high in this trial compared to other studies. One of the things that's notable about this study, that gives us a lot of confidence about the activity asset, is that we saw patients who had more than one stage improvement of fibrosis in just 36 weeks. In fact, one of these patients is on this slide. So this patient had a three-stage improvement of fibrosis. That is, they went from F4 to F1 in just 36 weeks of dosing. And the background for the patient is a 69-year-old woman who had Type 2 diabetes, and they were diagnosed, about a year and a half prior to, entering the study. They weren't using a GLP-1, and they had a very small weight loss at, about just two kilos. So but you don't have to be a liver CRN, Clinical Research Network, pathologist to see that when one looks at the baseline biopsy versus now, the week 36 biopsy looks nearly normal. It's free of the purple staining that one would see, and it's consistent with high amount of bridging fibrosis. We just don't see that in this patient. So it's when we shared this at AASLD, it's a remarkable picture. But again, there are skeptics, as there always are, and they ask: "Well, what did the non-invasives look like?" So when we see on this slide, so this patient, as I mentioned, went three stages. And not only did their fibrosis stage change, but you can see that they basically normalized their liver fat as well. They went from a NAS score of 5 down to essentially 0, and they were clear across all of the parameters. The non-invasives all go in the right direction. You can pick one, whether it's transaminase or PRO-C3, ELF score, FAST score, they're all decreasing. This, taken together, is a very complete picture of very strong activity. One of the questions we've also gotten, again, about GLP-1s is: What difference does that make? Because there's a higher percentage of patients receiving GLP-1s in this study than our other studies, and could that have been, A, explained the result or been driving the results? And in this trial, in this slide, you can see that didn't really make a difference. Having GLP-1, and the groups get small, because when it's a 180-patient study gets divided up, you can see the subsets aren't enormous. But at least on the macro, you can say that it didn't matter. There's no clear benefit to having combination of GLP-1 and EFX. Their response rates and when it comes to fibrosis weren't driving the response. Looking at markers of liver health, the transaminases, you can see, consistent with previous trials, you see a very rapid and statistically significant reduction in ALT as well as AST through the 36-week period. Turning to safety at this point, we unfortunately had a patient who died during the study. This patient was receiving placebo. They died of pneumonia. We had a number of serious adverse events, more than we've seen in past trials, but none of them. Importantly, none of the events were seen to be or drug-related by the physicians in a blinded fashion. What it really speaks to is really the advanced nature and unfortunately, the number of multiple medical problems that these patients face. As a reminder, these patients who are compensated cirrhotics are not. Unfortunately, the liver disease is not their only problem. They have a number of other problems that are also advanced as well. Treatment adverse events leading to discontinuation was a little bit higher on the EFX arm, and that was largely driven by the incidence of diarrhea and was highest on the 50 mg dose. Diarrhea is a adverse event we've seen in previous studies. It's probably a GI adverse events are to be expected, not only with our asset, but other FGF 21s. Let's turn now to some other things. We saw in this trial no clinically significant changes in heart rate or diastolic blood pressure. We did see, for the first time, an increase in systolic blood pressure that was significant at week 36. This is something we've not seen in the pre-cirrhotic population and something we'll be looking at when we take a look at the 96-week data in March of this year, out of the pre-cirrhotic population. Bone mineral density. Bone mineral density has been associated with poor... Cirrhosis has been associated with poor bone health, and we did see relative reductions of about 1%, less than 1% in the spine and about 2%-3% in the hip at week 36. Keep in mind that we'll be getting additional bone data out through week 96 in this trial, and we'll have more insight as we follow that going forward. There was an imbalance in oral corticosteroids as well as other con- meds that may be associated with bone health, so we're also examining that as well. Lastly, we did see improvements when it comes to markers of liver functions, as I touched on earlier, but we also saw statistically significant improvements in platelets during this study. Consistent with what we've seen in previous studies in, when it comes to glycemic control, we've also seen improvements throughout the SYMMETRY study through week 36, whether it's hemoglobin A1c or improvements in C-peptide as well as plasma insulin. So, when one thinks about SYNCHRONY, just as a reminder, as what we released in the December press release, the SYNCHRONY Histology study in pre-cirrhotic patients is a randomized, double-blind placebo patients and approximately 1,000 patients, equally divided among the arms at 333. That study has already begun enrollment, has been enrolling for quite some time, or screening for quite some time, just enrolling in December. And then, the real-world study is a non-invasive trial that looks at just one dose of EFX 50 mg, compared to placebo, and we'll be looking at safety and tolerability over the 52-week endpoint. Finally, to conclude, when one looks at our near-term milestones, we've already touched on the SYNCHRONY Histology and Real-World enrollments in last quarter. We have an FDA meeting and a phase 2 scheduled in the first quarter of this year, as well as in March of this year, reading out the 96-week data. And we plan on initiating SYNCHRONY Outcomes, the F4 compensated cirrhotic study, in the first half of this year. And then, about this time next year, well, first quarter of next year, we will read out the two-year data on the SYNCHRONY, or excuse me, the SYMMETRY study. Maybe I'll stop here, and maybe Eric will take questions. Great. Well, thanks, Andrew. Just a reminder for those who have questions, just raise your hand, we'll bring a mic around. But, I can get started. Andrew, just, you highlighted at the top of the presentation, the 96-week readout from the HARMONY study, expected in March. I guess I'm gonna ask you to just set the stage there a little bit in terms of, you know, what really the relative importance of that readout would be relative to the 24-week efficacy readout last year and maybe just sort of what magnitude, what change in the relative rate of fibrosis improvement would be compelling, I guess, in the views of, you know, the treating physician community here? Yeah. So, that's multilayered, so let's see if I remember all of them. But let's start the last one since that's easier. So, the question really is: What sort of improvement in fibrosis rate do we expect to see after 96 weeks? That's, of course, a tough question, and one I'm just gonna dodge a little bit by just saying that we're hopeful for improvements in where we are. And in terms of what the meaningfulness of these data, I think there are two things to take away, is that recall that EFX works as a direct-acting antifibrotic, which is why we saw the rapid improvements in fibrosis. We did see it 24 weeks. But at the same time, we've seen field-leading improvements in NASH resolution, 76% after just 24 weeks. The improvements in fibrosis after achieving NASH resolution are more indirect, and the benefits take a longer time to accrue. So we would expect, and are hopeful, that we'll see some of those translate out at the 96-week timeframe, even though we didn't see that at week 24. And of course, the other component is the one of safety. So some of the things we're eager to see, what the profile looks at and how different or not different it is compared to week 24. Okay, great. Question over here. Oh, thanks. Yes. Yeah, thanks. Well, are you measuring any portal function in the longer-term studies to connect to outcomes? Uh- For example, the clearance of cholate is to calculate a disease severity for how well the liver portal system is working. We're not measuring cholate in this trial. What about imaging? We have imaging ongoing in the study. We have a sub-study looking at some imaging procedures, but in terms of specifically a portal venous gradients or hyper, we're not looking at that. Yeah. We think that the hepatic clearance of insulin is an important indicator of how poorly the liver is functioning. And fasting insulin levels, when they're high, they correlate with the type of fibrosis that leads to these outcomes and also worsening of diabetes. So that could be something to look at, the insulin clearance. Thank you. In the back? Oh, wait. Yeah, wait, wait for the microphone. Sorry if I've missed it, but, you know, in your trials, what was the average weight loss reduction associated with your product? The reason why I'm asking this is that I was very intrigued by the combination with GLP-1s. Mm-hmm. We know the GLP-1s are associated with lean mass reduction, which is bad. Do you actually have data on, you know, what your product does on lean mass as well? So we don't have data when it comes to lean mass. Your first part of the question was about the average weight loss. I think when we've seen it, it's about 2kg to 3 kg after 24 weeks, is the amount we saw in the HARMONY 24-week study, which was statistically significant. We also saw continued weight loss in the combination study with GLP-1s that we reported last June. So I think overall, and we've seen weight loss in most of our pre-cirrhotic studies. Okay, and I suppose it is excess visceral fat as opposed to subcutaneous fat. I think we can't make that assessment because we haven't measured. We haven't done a whole body DEXAs to be able to assess Okay or imaging to assess one way or the other. Thank you. Maybe just following up on that question. I'm sure there's sort of three sort of treatment profiles you might think of here, in addressing NASH, right? There's EFX alone, what the prospects of GLP use, alone, right, as monotherapy, and then just the combination of the two. Picking up a little bit on your expectation with the 96-week readout from HARMONY, that, you know, longer time on drug might actually see some NASH resolution converting into fibrosis improvement. Should we not kind of hold the similar expectation for the GLP-1 class? Obviously, you make the contrast that you're seeing, you know, obviously, you know, much greater magnitude Mm-hmm but after 12 weeks, now, with longer term, does that delta perhaps shrink? I mean, would you care to get So I think, like, we, we await the data. Yeah. I think that's the challenge. We've not seen the HARMONY and SYMMETRY studies are a little bit special in the field because they have serial biopsies. Most trials terminate after some period of time, whether it's 24 or 36 weeks. For instance, the Phase 2b trial on, with semaglutide, that ended at 72 weeks. So the ability to accurately answer your question is limited. Yeah. So but do I think that longer term dosing is likely? I think the studies from bariatric surgery will give us some insight because, again, even though there's rapid resolution of NASH, the benefit when it comes to fibrosis takes on the order of four to five years to fully accrue. So I think that's the challenge for some patients, especially those who are cirrhotic. Sorry, I just lost my train of thought for a second. I was gonna ask about from Cohort D whether there's you know any clear indication that GLP-1 might be actually additive to the activity of EFX and whether you might expect combination use of the two agents in patients that are non-diabetic to manage their NASH? So I think the takeaway from the Cohort D study is really that the ability. Your question would be best answered if everyone were on EFX, and we added either GLP-1 or placebo, and that was the converse of the study. So we can't really answer that. But when one looks at what happened in, for instance, in the SYMMETRY study, where we didn't see a difference, we're not sure that that's the case. I think one of the unique properties of EFX is really the fast-acting nature of it as an antifibrotic. And as you know well, the fields have been looking for that for quite some time. So I think we remain excited about the antifibrotic component of the EFX. Other questions? Maybe just let me ask about, Sure. the endpoint selection, primary endpoint selection for the SYNCHRONY trial using the composite endpoint, right? You mentioned that was, that's being employed to satisfy both U.S. and EU regulatory requirements. I guess from a trial design and kind of powering standpoint, I guess, can you just talk a little bit sort of the the facility to, you know, arrive at a stat sig signal Yeah. with that composite endpoint, what de-risks it from your prior studies? Yeah. I think the biggest advantage of it is that we didn't really give i f you go back to that slide, just focusing on the 50-mg arm, you really saw that the response rate for the 50 mg was 41%, which is not dissimilar than the one-stage improvement of fibrosis rate. But the biggest thing is we saw a 75% reduction in the placebo rate. And so when you have that 8x delta, eightfold delta, between the groups, it gives us a lot of confidence in terms of whether we're gonna be able to land that phase III study in a statistically significant manner. And also, you know, mostly because we think about the global nature of the disease and the ability to have one trial satisfy both EU and U.S. regulatory authorities, is really compelling for us. Assuming success there, you know, and certainly an initial label that encompasses the pre-cirrhotic population, I'm curious to get a sense of, you know, whether you might see commercial use in the cirrhotic population or really does that require a total separate study in order to support use in that setting? Yeah, so that's, you know, you're asking, is there a possibility for accelerated approval in the cirrhotic population? Current guidance says no, but I think you, you and I are both we've had a discussion where, another company in the field has managed to get FDA concurrence on that. So I think we're eager to, as we will, you can imagine that's maybe a topic during our End of Phase 2b meeting, and, if the FDA remains open to it, I think we would be hopeful to add that to our program, and it would be something where, the indication at a launch could be at F2 through F4. Like, and just, from a tolerability standpoint in the F4 population. Mm-hmm. I guess the signals around, you know, bone health, they're kind of definitely more of a focal point than that in the pre-cirrhotic or non-cirrhotic patient population. I guess, can you just talk a little about sort of the, you know, how you're continuing to monitor that? Yeah. and what sort of margins, I guess, around bone loss you'd want to be within in order to kind of have an acceptable profile in that patient population? Yeah. So I think that's a great question. It's something we're looking at, and we'll be following up at the two-year point in the trial. I think it's also just important to recognize how many approved agents there are for bone loss. Mm-hmm. At the same time, unfortunately, as I mentioned during that study, there are no approved agents for patients with cirrhosis, and recognizing that the five-year mortality for patients without liver transplant is roughly 50%, I think the medical need is quite acute in this patient population. So, that being said, safety is always paramount, but at the same time, there is a benefit-risk calculation for all patients. Any other questions? Questions from the group. Maybe just one sort of operational question as it relates to histology. I guess just how to think about accrual timelines in that registrational study and, you know, to the extent that, I mean, look, you've conducted a number of trials in this setting, and so we can kind of look back obviously at the, you know, the enrollment timelines there. I guess, should we do that basically and map that on and kind of adjust for sizing? I guess what other site expansion efforts have you undertaken to support this? So I would say that the trial is a global study. Of course, the sample size is quite a bit bigger than our Phase 2a and 2b studies, and as such, it's also the pre-cirrhotic population is very competitive. That being said, you know, in terms of mapping out when things would read out, I think we get that question quite often from analysts and investors. You can imagine since we announced our first patient was enrolled in December, we're a little bit cautious to get too ahead of our skis. As you know, we, we don't like disappointing investors or analysts, so I think we're going to not directly answer that, Eric. Understood. Let me see if any questions, other questions from the floor. Okay, great. I think we'll leave it there for time. Thanks. Thanks, Andrew. Thank you. Thanks for having me. Thanks for joining us.