Hi, my name is Dan Lundquist. Thank you very much for joining the Wednesday event. I'm the healthcare specialist here at BofA. I'm very pleased to welcome with me today, Kitty Yale, from Akero. She's the chief development officer. She does have some presentation slides, so she'll go through those. If we have some time, we have some Q&A as well. All right. Thank you, Kitty. Thank you. Good morning, everybody. As Dan said, I'm Kitty Yale, I'm the Chief Development Officer at Akero. Akero is developing efruxifermin, or for short, we just refer to it as EFX, as a potential best-in-class NASH therapy. EFX is a differentiated Fc-FGF21 fusion protein that's been engineered to mimic the balanced biological activity of native FGF21. The data I'm gonna share with you today is from our Phase 2a program. We're pleased that some of the data that we generated in our Phase 2 program is some of the strongest efficacy data we've seen to date in a short-term NASH study. The data from those studies have allowed us to go forward and gain Fast Track designation from the FDA and then PRIME designation from the EMA. We're currently conducting two Phase 2b clinical studies. The first study is HARMONY. It's in F2/F3 patient population. The second study, SYMMETRY, is in a more advanced compensated cirrhotic F4 patient population. Both of those studies are well powered for a histology endpoint of fibrosis improvement and without worsening of NASH. The HARMONY study is actually fully enrolled, and we remain on track to actually report data in Q3 of this year. The team at Akero is experienced. We've been involved with multiple global drug approvals in various therapeutic areas, and we have a cash runway through 2023, or Q3 of 2023. Just to highlight the molecule. EFX, as I said, it's a differentiated Fc-FGF21 fusion protein. What we have is, there's three point mutations on the C-terminus of the FGF 21. What those mutations do are actually increase the binding affinity to the co-receptor beta-klotho and as well as prevent degradation. Ultimately what this does is it's increased the half-life to 3-4 days and allows us to support once-weekly subcutaneous dosing. We have balanced potency across the FGFR receptors. We have agonism against FGF receptor 1c in the adipose tissue and then the 2c and 3c that are present in the liver. What this allows us to do is actually affect the liver fat in both the liver itself, but also in those peripheral tissues. Just as a reminder, this is our Phase 2a BALANCED study. The design is pretty straightforward. It was a randomized placebo-controlled study where we compared three different doses of efruxifermin compared to placebo, and patients were randomized to receive once-weekly subcutaneous injections of either a 20, 50 or 70 milligram dose of EFX for 16 weeks. All of the patients in this study were biopsy-confirmed NASH with fibrosis stage 1 through 3. They had a NAFLD Activity Score greater than 4 and a MRI-PDFF liver fat content higher than 10%. The primary endpoint was absolute reduction in liver fat at week 12. The unique component of the study design was that we actually defined subjects who achieved a greater than 30% reduction in liver fat as responders, and then the responders went on and had end of treatment liver biopsies. The endpoints are all there on the right-hand side of the slide. You can see we had a number of secondary endpoints in terms of looking at reductions in liver injury ALT, and then all of our biopsy data and endpoints were all exploratory. Jumping straight into the data. Here I'm presenting the primary endpoint of absolute reduction in liver fat, along with the secondary endpoint of relative reduction in liver fat, both of which were highly statistically significant. What you can see is reductions in absolute liver fat ranging between 12% and 14% and the relative reductions ranging from 63%-72%. These were some of the highest liver fat reductions really seen to date in a short-term NASH study across the competitive landscape. If you look over at the tables, I think what's maybe more important is when we look at the proportion of patients achieving the fat reduction thresholds defined that 100% of the patients that were on EFX achieved the 30% liver fat reduction. Actually, when you look at the higher thresholds, it was almost half of the EFX patients reached that higher threshold of greater than 70%. When we start to look at actual normalization of liver fat, and that's what we define as when the patients have their liver fat reductions go less than 5%. Again, when we look at the two highest doses, approximately 50% of the patients reach that definition of liver fat normalization. When we look truly across the board, what was driving liver fat normalization, what you can actually see, it was often influenced by the patient's baseline liver fat. Some of the patients that didn't reach the definition of normalization were those that came into the study with the highest fat levels and just didn't reach that less than 5% in the 16 weeks of treatment duration. What was also interesting is when we correlated normalization of liver fat, it correlates very strongly with NASH resolution. There was a four-fold probability of NASH resolution in the patients whose liver fat had normalized over the treatment time. As a result, you know, we saw about 50% of the EFX patients also were achieving NASH resolution in this study. If we jump forward and look at the other histological endpoint that is part of the FDA acceptable endpoints for histology in a Phase 3 clinical study. Which is proportion of subjects who achieved a one-stage improvement in fibrosis and no worsening of NASH. Here you can see that we are presenting the EFX data on the left with the shorter treatment duration of 16 weeks. As you move across the slide, the treatment durations increase up to 72 weeks with semaglutide. What you can see really is that the EFX data stands pretty favorably across the competitive landscape here. Even with the short treatment duration of 16 weeks, with 46 and 62% of patients achieving the endpoint just after 16 weeks of therapy with EFX. We went and did a subset analysis on looking at patients who came into the study that were fibrosis stage 2 and 3, and looked again at the same endpoint fibrosis improvement. What you can actually see here is the response rate actually increases when we look at the more advanced patient population with 68% of patients achieving this 1-stage improvement in fibrosis. I think the more important point of this slide is when we look at the patients who actually had a 2-stage improvement in fibrosis. You can see here 50% of these patients achieved a two-stage improvement in fibrosis after just 16 weeks of treatment. This is really a metric that you don't see in many NASH studies. They just don't see this level of fibrosis improvement, especially not in such a short treatment time. If we look at other non-invasive markers of fibrosis, we see again statistically significant improvements. Here we're looking at the enhanced liver fibrosis score or the ELF score, as well as PRO-C3, which is a marker of collagen synthesis. What you can see if you look at the PRO-C3, you know, we see very rapid reductions in PRO-C3, really as early as week four on study, that basically are maintained out throughout our treatment course. We also see significant reductions in the ELF score at the end of the study. These are at levels that have been correlated in other data sets to a one-stage improvement in fibrosis. Really sort of supporting the histology data that I just presented. If we move on and look and think more about, you know, treating the NASH population as a sort of holistic treatment, I think you have to look at the other comorbidities of NASH. When you think about your average NASH patient, 50% of the population are diabetic. Most of these patients are overweight and have this dyslipidemia. When you look at the slide here, if you start in the middle, looking firstly at the hemoglobin A1c and the C-peptide, we see statistically and clinically relevant reductions in markers of glycemic control. You can see here with the 50 milligram dose group that we're seeing a sort of 0.4 reduction in hemoglobin A1c. If we actually do a subset analysis of this data set and just look at the patients who were diagnosed with type 2 diabetes at entry into the study, these levels actually almost double. You can see the most benefit in terms of the glycemic control in the patients that are the most uncontrolled in terms of their hemoglobin A1c. We also see nice reductions in C-peptide, which is a marker for insulin sensitization. You can see this insulin sensitizing effect of efruxifermin. If you go down to the middle bottom panel, what you can see here is overall we see really nice reductions in the overall lipoprotein profile with efruxifermin as well, with almost a 50% reduction in triglycerides. Nice increases in HDL cholesterol and decreases in non-HDL cholesterol. Then really lastly, what's also kind of encouraging is that we're seeing a trend towards weight loss in this patient population that are generally overweight. We added an expansion cohort to BALANCED, and this was an expansion into the more advanced compensated cirrhotic fibrosis stage 4 patient population, and they were all Child-Pugh A. Just to kind of give you an overview of the study design here. Again, these were all biopsy-proven F4 patients. This was done by a local pathology read. It was a randomized placebo-controlled study where patients were randomized in a 2-to-1 ratio between placebo and our 50 milligram dose group of efruxifermin. The primary endpoint in this study was actually safety and efficacy, and we were looking originally at FibroScan or transient elastography and then the fibrosis biomarkers ELF and PRO-C3 as our markers of efficacy. We actually amended the study while it was ongoing based on requests from physicians and actually a patient, and added histology to the study after it was started. We have histology data in a subset of patients. Jumping directly to that data, again, in the same format as I'd provided before, this is in fibrosis improvement of one stage, no worsening of NASH with the efruxifermin data on the left, the current competitive landscape and the increasing treatment duration as you move from left to right. You can see that again the EFX data, although a small proof of concept cohort, that we see a nice level of a third of the patients saw fibrosis reversal in this patient population, really in an area where we haven't seen much success across the competitive landscape. For us, we feel this data, although small and like I said, proof of concept, really encouraging and is what really drove us to move forward with our ongoing Phase 2b study SYMMETRY that's in this compensated cirrhotic patient population. We also in the study, I don't have the slides here today, but the fibrosis biomarkers that we evaluated, again, statistically significant changes in both PRO-C3 and ELF, as well as when you look at transient elastography in the FibroScan. Really, what does this data really present? Well, what we can see is that we're really seeing early and rapid reversal of fibrosis across sort of the NASH patient population. What this has really led us to believe is what we think is that there's a sort of two-pronged mechanism of action happening with efruxifermin. Starting in the blue, what we really describe is sort of the metabolic effect, and we believe this is an indirect anti-fibrotic mechanism where you're actually reducing the liver fat content, you're reducing the overall hepatocyte stress. Really sort of what you're doing here is removing the drivers of NASH in these patients. With time, what you really are going to see is this indirect fibrosis improvement. In the orange, we're more focused on what we believe is a direct anti-fibrotic component of this mechanism. This is where we're seeing decreases in inflammation, decreases in the collagen synthesis. This really supported, I think, just by the data I highlighted earlier. The reversal of fibrosis in the F4 patient population. The two-stage improvement in fibrosis that we see in the F2, F3 patient population and the fibrosis biomarkers that we're seeing these rapid and sustained responses. Really just to wrap up just where we are today, the data we presented is the top-line data. We have the two ongoing Phase 2b studies that I mentioned earlier, and we're excited to present the HARMONY data in Q3 of this year, which feels like it's just around the corner. Thank you. Great. Thank you very much, Kitty. Maybe just to dig in a little bit on HARMONY. Since it is a near-term readout, can you maybe just discuss a little bit more the study design and powering? Can you speak to the size and the minimal difference in reduction of fibrosis without NASH worsening that the trial's power to detect? Maybe just some. Yep. Color there. The HARMONY study is very similar in terms of the design to BALANCED in terms of it's a randomized placebo-controlled study. We're looking at two different doses of efruxifermin, the 20 and the 50 milligrams. We're looking at a fibrosis improvement, no worsening of NASH primary endpoint at week 24. The study actually continues out until week 96 for a long-term safety follow-up. We haven't actually fully disclosed the full powering publicly. What I can say is the study is very well powered to hit that endpoint. We have taken into account what I think is probably a pretty realistic placebo response rate of around 20%. We feel that, you know, we should be able to see statistical difference from there. The study was originally designed to be 40 patients per treatment group, and we over-enrolled slightly. I think we have 128 patients enrolled in that study. Maybe just switching to kind of commercial opportunity. Can you walk us through the F2, F3 population versus F4 in terms of relative market size? Kinda how to think about the stratification there. I think, you know, I'm the Chief Development Officer, so I'm gonna not give you the best financial forecast. You know, I think that obviously the F2 patient population is substantially larger than the F4 patient population. I think when we really look at efruxifermin and the data that we've generated to date, I do think that we believe that, you know, especially with a subcutaneous injection, that we're more suited to that later stage of the disease, definitely the F3, F4 patient population. Clearly, that's where there's the highest unmet medical need. I think when we also look at, you know, the size of the NASH market in general, there also is some concerns of just, you know, it's one, getting the drug approved for NASH, but two, it's about being reimbursed. When we think about payers and insurance, the F4 patient population, we believe, will definitely be prioritized in terms of the market and reimbursed appropriately so. If you think about conversations, I mean, it's obviously early to have conversations with payers, but when you have conversations with KOLs and regulators, what have they talked about as kind of the degree of benefit that they view to be clinically meaningful? I feel like, you know, in the current environment, not just in NASH, it's oftentimes a question of what is deemed to be clinically relevant, which versus what might be statistically significant. Maybe just help us frame that out. I mean, when I look at the design of our trials, we've been very focused on this fibrosis endpoint. There's two FDA acceptable histology endpoints for NASH currently. You can either aim for a NASH resolution with no worsening of fibrosis, or you could focus on fibrosis improvement, no worsening of NASH. We are obviously focused on the latter. The reason really for that is we really believe that that's where the payers are really focused. There's data really correlating that one stage improvement with fibrosis with long-term clinical outcomes. I think that's where you're going to get the payers to buy in and really look at reimbursement based on the long-term clinical outcome improvements, which is just not so clear, whether if you just achieved a NASH resolution endpoint. You had a good slide up earlier in terms of the other kinda metabolic improvements that you see across the board. Are there complementary mechanisms of action that you think that you would pair well with, considering that a lot of these patients are on background therapy for diabetes, et cetera? When we initially started our development program, and I think we were, like everybody else, very focused on looking for potential combinations. I think the data that we've seen to date with efruxifermin actually, you know, leads us to believe that, you know, it really could be a monotherapy on its own. That said, we have talked about looking at complementary mechanisms. I think you know the one area that we're trending toward weight loss. It's, you know, we're not sure, with longer treatment it may become statistically significant. Partnering with another mechanism that is, you know, driving weight loss, I think would make the most sense for us as we were moving forward. That's something that we are considering evaluating. Yeah, it's been pretty eye-opening to see some of the obesity trials recently reading out, getting on par with bariatric surgery in terms of weight loss reduction. You know, hence the question. One of the other things, you know, to think about, is just the broader opportunity, even ex-U.S. Can you maybe discuss with us kinda whether you would look to partner in certain regions, maybe if there's a combination therapy that wants to be brought forward in some of those regions? Just talk about any kind of business development conversations you've had along those lines. You know, I think as an organization, we are very open to numerous different ways of developing EFX. I think in our past lives, we have run very large global studies where we've really brought the products to the market, you know, across U.S., Europe and Asia. We do have continuing conversations, though, with potential partners in various different regions. I think it's just really. You know, as we look forward and think of just the complexity of running a large global Phase 3 program for a small biotech, that there are some advantages if we could find the right partner for certain regions in the world. We are continuing those conversations. If I look at the competitive landscape of NASH, right, it's been at various different times, a lot of companies with late-stage trials that maybe haven't panned out. Can you maybe talk us through the market development that's needed on the physician and patient side, really, to continue building out awareness of NASH as a disease? Yeah. I think it's interesting. You're absolutely right. You know, when you come into an area where there's this unmet medical need and no current products in the market, there really is going to need to be a big build-out. Having spent the majority of my career at Gilead, it is interesting. I think Gilead really did start leading the way in terms of building that market when they were running their studies with selonsertib. I do think that the market will need to be built and globally. I think, you know, the U.S. is probably further along than maybe certain other parts of the world where I think, you know, in Europe there's still concerns about, you know, whether, you know, diet and exercise should really be the formation of the treatment for NASH. I think in the U.S. now where people are really seeing the challenges with the overall metabolic dysfunction and realizing that these patients, you know, probably have spent maybe 20 years of their life with, you know, excess calories, you know, leading to a broader metabolic dysfunction that, you know, just prescribing the same advice that these patients have had for 20 years is really not gonna move forward. I think for us, we do realize that, you know, the market will need to be built. In that regard, I think we're very excited for Madrigal to read out, hopefully at the end of the year. I think it would be good for the NASH market to see success and start to build out that the market in general. I think it would always be easier not to be the first. Madrigal, I know, are doing a lot of work and also looking at partnering in terms of building the market out, you know, again, as a small biotech. Yeah. It would make sense just to kind of help broaden out the further awareness. In terms of kind of how to think about the regulatory process, I mean, there have been some moving goalposts in the past. It feels like the FDA has at least narrowed down to two endpoints to go after. Maybe kind of talk about your, the evolution of your conversations with the FDA, what gives you comfort that having chosen, you know, the endpoint that you're pursuing is the right one? Maybe just kind of give us some color there. Yeah. You know, I think the regulatory landscape has been complicated for NASH. I do think that really from the Intercept perspective, you know, there's this sense that the goalposts have moved. When you actually look at the NASH regulatory guidances, there's two different guidances. There's one in the non-cirrhotic patient population and then a separate guidance for patients with compensated cirrhosis. Those guidances really haven't been updated, and they've basically stayed constant, where the guidance allow for an accelerated Subpart H approval using histology in the F2, F3 patient population. Then you need to follow the patients out for long-term clinical outcomes. In the F4 patient population, the guidance really is that you need to just evaluate those patients for long-term clinical outcomes. I think what's changed really is since the Intercept situation, really is the guidance that the agency have given people about how to actually do that biopsy analysis. I think there was some concerns about how those reads were done. As we've been working with the regulators, we're now getting very clear guidance on exactly how that endpoint should be read. I think all companies are writing very detailed, what we call biopsy analysis plans. In those plans, really you have to talk about how you're going to use multiple histology readers. You have to bring the readers together. They're all NASH CRN trained. You train them on your protocol. You train them on how to read to consensus. Then all of our screening and end of treatment biopsies are read to consensus by two separate readers. If those two readers can't come to consensus, you bring in a third. Those biopsies are read in a sort of random fashion, so you're intermingling screening and on treatment biopsies throughout that process. I think the goal really of that process is to reduce some of the variability that we've seen in the biopsy read and to standardize that process really across companies. Okay. With that, I think it's all the time we have. Thank you very much, Kitty. Thank you. Thank you, everybody, for attending.