Okay, thanks again for joining the 40th Annual JP Morgan Healthcare Conference. I'm Eric Joseph, Senior Biotech Analyst at the firm. Our next presenting company is Akero Therapeutics, and it's my pleasure to welcome company CEO, Andrew Cheng, to talk to us a little about the company. There is a Q&A session after the presentation. Just click the icon and I'll work in the questions, where appropriate with that. Andrew, thanks again for sharing some of your time with us today. Thank you, Eric. Thank you for having us. Why don't we go ahead and get started and, let's go to the first slide and then, here's our safe harbor statement. I'm not gonna read that. I'll just let that project. Here's a snapshot of Akero. We have a FGF 21 analog, which we call efruxifermin, and based on our phase IIa data, we feel that it has the potential to be a best-in-class NASH drug. Keeping in mind that the NASH patient growth is very substantial, it's on track to reach 30 million Americans by the end of this decade. Based on our phase IIa data, we have initiated a phase IIb program, which has two trials. The HARMONY study, which is a pre-cirrhotic F2, F3 program, began enrollment about a year ago, and we're on track for results in the third quarter of this year. Based on some of the phase IIa results, we also initiated a F4 study in compensated cirrhotics, which we call SYMMETRY, and that is screening and enrolling as we speak. The totality of the phase IIa data has allowed us to earn regulatory designations of Fast Track and PRIME from the FDA and EMA respectively. Taken together, these allow enhanced regulatory interactions for compounds with unmet medical needs. In the past year, we've made substantial progress on our commercial drug product device, which we plan on utilizing in phase III. Financially, we reported at the end of last quarter that we have $215 million in cash and have reiterated that that provides a cash runway through the third quarter of next year. Why don't I talk a little bit about NASH in general? As I mentioned, that the patient growth in the United States is substantial, and this is true in most of the world. NASH is really the largest medical need for which there is no approved product. When one thinks about NASH as a liver disease, really the inciting event is excess liver fat. Fat that's deposited in the liver beyond the normal limits leads to a cascade of pathogenesis. This pathogenesis results in the ultimate deposition of collagen fibrils leading to cirrhosis. However, the question is: What is the source of the liver fat? Well, some of it is the liver, but the majority of the liver fat comes external to liver. That is peripheral fat. Adipose tissue is the largest source of liver fat. And as I touched on, the inflammatory cascade resulting in myofibroblast proliferation results in fibrosis. And ultimately, it leads to cirrhosis and unfortunately, potentially transplant and liver cancer. But NASH is much more than just a liver disease, that these patients are also afflicted with other metabolic diseases. That is that nearly all of them are overweight in the United States. Roughly 50%-60% have type 2 diabetes with elevated levels of insulin resistance, and nearly all of them have dyslipidemia. And cardiovascular mortality is the number one cause of death for NASH patients. Let's turn now to our phase IIa program. Efruxifermin was studied in a phase IIa study called the BALANCED trial, which is a randomized double-blind placebo-controlled study in pre-cirrhotic patients, fibrosis stages F1, F2, and F3. These all had biopsy-confirmed NASH at baseline, and they were dosed for 16 weeks in a dose-finding study with three doses of efruxifermin. For the purposes of this presentation, I'll only be focusing on the 28-mg and 50-mg doses. Those are the doses that we are taking forward into phase IIb. For the full details, we published the study last year in Nature Medicine, and the reference is on the slide. We also created an additional cohort, which we call cohort C. It was an expansion of the trial, which looked at compensated cirrhotics, F4, and they were also dosed for 16 weeks with just one dose, the 50-mg dose. We'll talk about that in the presentation. Why don't we turn now to some of the results. This shows liver fat as measured by MRI-PDFF, a non-invasive measure, after 12 weeks of dosing. You can see that there are statistically significant decreases in liver fat. In fact, these responses are among the best in the field, regardless of mechanism in terms of total reductions. We clearly met our primary endpoint of demonstrating significant differences. Not only were the patients did they have reductions of greater than 70% at the 50 mg dose, but quite a number of them normalized their liver fat. That is, they reduced their liver fat to less than 5% after just 16 weeks of dosing. Why don't we turn now to our liver biopsies? A subset of patients received liver biopsies. What we saw is among those who did receive them, that roughly 60% of those on the 50 mg dose had a one-stage improvement of fibrosis without worsening NASH. This is one of the FDA regulatory endpoints, the other being NASH resolution. The 28 milligram you see had over roughly 46% improvement in one stage. One of the questions has been, how does this compare with some of the other compounds at a similar stage of development? In this slide, we take a look at some of the other drugs that are being studied for NASH. These are results from phase IIb studies, whether it's for lanifibranor, resmetirom, or semaglutide. You'll note that their dosing durations were all longer than the 16 weeks that efruxifermin was studied, and yet our results compare favorably to theirs. Of course, ours was a phase IIa study, smaller patient numbers and shorter duration, but this really forms the basis of our enthusiasm for the HARMONY results, which we will reveal in the third quarter of this year. One of the questions that has been asked, though, is that we allowed patients who had F1 through F3. Could it be that the results, these results, were driven largely by the F1 patients who are at earlier stage of disease and potentially easier to treat? When we took a look at that, and these are the patients who had F2 or F3 at baseline, keep in mind that those are roughly 66% of the patients in this study overall, that we saw that on average, these F2, F3 patients had, two-thirds of them had a one-stage improvement of fibrosis. Most remarkably, that roughly half of these patients had a two-stage improvement of fibrosis. Very few companies report these data because it's quite uncommon to have a two-stage improvement of fibrosis in a relatively short period of time. We're quite encouraged by these results demonstrating the potential benefit to patients when dosing with efruxifermin. Let's turn now to some of the other parameters. As I mentioned, dyslipidemia is a problem that afflicts nearly all NASH patients. When one looks at the lipoprotein profile on this slide, taken together, we can see a rather heart-friendly approach. That is that the parameters are really going in the correct direction. We see statistically significant decreases in triglyceride as well as non-HDL cholesterol, which includes LDL, and importantly, increases in HDL, which were quite substantial. As we're all aware, finding a compound to increase HDL has been something that the industry has tried for a number of years without success. Let's turn now to glycemic control. We see after 16 weeks at the 50 mg dose, a statistically significant decline in hemoglobin A1c. So glycosylated hemoglobin as a measure of glucose has declined after 16 weeks. The mechanism by which this is achieved is a decrease in insulin resistance or an increase in sensitivity. Those measures are reported in the Nature Medicine article. As a result of the decrease in insulin resistance, the pancreas, specifically the beta islet cells, have to produce less insulin, and this is evidenced in the C-peptide. C-peptide is a degradation product of endogenously synthesized insulin. You see statistically significant declines at both the 20-mg and 50-mg doses for C-peptide. Lastly, when we look at weight, we see a roughly 2-kg decrease over 16 weeks at the 50-mg dose. Keep in mind that the baseline for these study patients is roughly 100 kg. This is about a 2% decline. This is, while certainly beneficial for patients, not weight loss is not the mechanism by behind the improvements in histology. I think this is a, you know, it's helpful for patients but not, explanatory in the way that, weight loss is important for, GLP-1s like semaglutide. Taken together, you see a profile based on our phase IIa data that's really helpful for patients. It clearly improves liver fat as well as improvements in, liver fibrosis. It also takes care of the, some of the other challenges that these patients face, whether it's, dyslipidemia or, type two diabetes and obesity. Let's turn now to those patients who have greatest medical need, that is those who have F4 cirrhosis. This slide really highlights the challenges these patients have once patients are F4, that over a five-year period, their mortality is roughly 50%, for those who don't seek liver transplant. It's the curves are quite stark when one compares them to the earlier stages of disease. As a reminder, we dosed patients with 50 mg of efruxifermin for 16 weeks in a small 30-patient cohort. What we see is that we also see important improvements in fibrosis, although numerically not as great as what we see in the pre-cirrhotic population. The 33% is quite a substantial number when one thinks about the other compounds in the field. The next slide really highlights this. Regardless of mechanism, regardless of duration, there hasn't been a lot of success in reversing fibrosis in F4 patients. These studies have been conducted over a number of years, and unfortunately, there hasn't been much of a difference between placebo regardless of the company or mechanism. These results were encouraging for us and helped us move forward and decide to advance it up into a phase IIb program. We also see, when one looks at other parameters, some similar results. That is, for the lipoprotein profile, whether it's triglycerides, HDL cholesterol, or non-HDL cholesterol, we see similar, statistically significant declines in non-HDL cholesterol and triglycerides and increases in HDL cholesterol. While not numerically exactly the same, they're certainly in the same ballpark when one looks at them, with relatively little difference. This is also true for glycemic control. One looks at hemoglobin A1c, where the numbers are exactly the same or very, very similar when one looks at C-peptide. The weight loss is also in the same zone, roughly about 2 kg, slightly more in the F4 patients. There overall, one sees a very consistent results in the efruxifermin profile when one looks at, histology changes as well as other parameters like lipoproteins and, glycemic control. When one takes this together, a very consistent response across all of these parameters, from pre-cirrhotic and cirrhotic patients really leads us to the conclusion that we're really treating the whole patient, not just the liver. Certainly the results in liver are the most important at this point since there are no approved therapies for NASH. We feel that this efruxifermin has the foundation to be a very important monotherapy for patients with NASH. At the same time, if there were to be circumstances where, efruxifermin were to be combined with other products, it would also add, to that combination regimen, which we designate as the EFX category. From the basis of these phase IIa results, as I touched on, we did advance into phase IIb studies, which are on the right-hand side of the slide. When one looks at HARMONY and SYMMETRY, both are 24-week. Both studies are ongoing, HARMONY being 24 weeks and SYMMETRY 36 weeks. Both are powered for biopsy, which is different than the phase IIa balance study, which is really powered for on a non-invasive measure of MRI-PDFF. Turning to HARMONY, this is the trial design. F2 or F3 NASH, liver fat greater than 8%, three arms, dosed for 24 weeks, and the primary endpoint is one-stage improvement of fibrosis without worsening of NASH, the FDA registration endpoint. The secondary efficacy endpoints are highlighted, NASH resolution, as well as glycemic control, lipoproteins, and weight change. This trial, although we're dosing for 24 weeks in the primary endpoint, will continue for up to two years to provide long-term safety follow-up. You'll note that the schema highlights that there will be one dose in that follow-up, but that dose will be selected at an end of phase II meeting in consultation with the FDA, and that will also be the basis for the dose we hope to use in phase III. Turning to the SYMMETRY study, which is still screening and enrolling, similarly using two doses. We're hoping for cirrhosis reversal as the primary endpoint. After 36 weeks, we're dosing longer just because treating F4 patients is so challenging. We're adding another 24 week or 12 weeks to what we did in HARMONY, and we'll have a similar consultation with the agency at that time point, hoping to select a dose for phase III as well. I mentioned early in the presentation that we'd made significant progress in the manufacturing side and looking at our drug substance or active pharmaceutical ingredient, we've partnered with Boehringer Ingelheim, and we've been able to transfer the process from Amgen to Boehringer. We have made drug substances at commercial scale. It's released for phase III, and most importantly, the comparability between the two products, the original Amgen product and the product that we've made in partnership with Boehringer Ingelheim is very similar. In addition, we're also working on a phase III drug product device combination, which has been used in the past for other approved drugs, both in the United States and Europe. It will be a 1 ml subcutaneous weekly injection, and it will be self-administered and stable at refrigerated conditions. We're very excited about the progress we've made here in the past year. Lastly, just to reiterate that, we are in a strong cash position with greater than $200 million in cash as of the last quarter. We expect this cash to keep our operating plan running into the third quarter of next year. Thank you for your attention. I'll turn it back to Eric. Thanks, Andrew, for that presentation. You're advancing two doses in the phase IIb or still evaluating two doses in the phase IIb HARMONY trial, 28 mg and 50 mg. Can you speak to the rationale to keeping the lower dose of 28 mg and whether there's a meaningful difference in tolerability profiles that you think might emerge in the readout of that study that might have at least impact commercially? Yeah. Overall, I don't think we'll see that. I think if you poll the team, I would think that we're all believing the 50 mg is the likely dose that we'll take forward for SYMMETRY even with some of the differences or lack of differences that we've seen, because we haven't seen much of a safety difference in phase IIa, numerically slightly better. Efficacy-wise, the fibrosis improvement is better at the 50 mg dose, as well as you do lose a bit of glycemic control when you move to the 28 mg. Given that half the NASH patients are diabetic, I think it's an important differentiator for EFX. Okay. You made reference to some of the competitive landscape, and with some programs you've seen really some surprises in the reproducibility of clinical data going from phase IIa to phase IIb. For potential skeptics out there, I guess what gives you confidence in the strong signal demonstrated so far in BALANCED being recapitulated in the HARMONY study? I guess as part of that, can you speak to how patients entering HARMONY compare with those evaluated in BALANCED? Sure. There's no question that NASH is for NASH companies, we're all in a little bit of a show me stage right now, given some of the results that you talked about earlier. But I think when you look at our results, in particular, the two-stage improvement in fibrosis after just 16 weeks and half of the F2, F3 patients having that really gives us confidence because that's a threshold that's not been seen by other companies. In addition, there have been one of the challenges that's been raised is some companies have reported high placebo rates. I think one of the things that we've focused on in partnering with the FDA, they've issued some new recommendations about that. We have multiple readers reading our slides, and they have to come to consensus. I think overall we're confident as we move forward with a dual reader process that we will have reproducibility of these results. Okay. Okay. In terms of asking the question about the baseline characteristics. Maybe, Kitty, do you just want to take that at a high level since we haven't fully analyzed that? Yeah. What I would say is that more or less, the entry criteria that we're using in HARMONY is very similar to what we used in BALANCED. You're really going to see a very similar demographic in terms of patient coming in. Of course, you know, in HARMONY, we're only looking at F2, F3 patients, where in BALANCED we looked at F1 to 3. The one area we really changed was we were able, based on the BALANCED data, to sort of broaden the entry criteria and to allow a broader group of patients on with type 2 diabetes and also include those patients taking or who were well controlled on insulin. Really that's just one sort of subtle change. But really more or less the patient population is very similar. Okay. Go ahead. I guess, well, yeah, you sort of anticipated my next question, which is, you know, what allowances there are for concomitant therapies to manage, you know, what's likely to be a fair amount of underlying diabetes. Similarly, are there allowances for lipid-lowering medications, or other, you know, standard of care therapy? Any expectation that that might have an impact on either tolerability or efficacy? I think we have a pretty standard requirement, I think what you'll see across NASH studies, where patients who are on either anti-diabetic weight loss or lipid-lowering meds really have to be what we define as a stable dose. That's really being on the same dose for three months prior to enrollment in this study. We do recommend that they stay on the same dose throughout the treatment period. I mean, these patients are on multiple medications. I do think, you know, when you see us moving forward into phase III, I think that requirement would really remain the same to just make sure these patients are stable. You know, we really haven't seen a major difference looking at subgroups within those patient populations. I don't think that really it's gonna be a concern for us as we move forward into phase III. Given, you know, the state of care in diabetes, you know, goes beyond insulin to include other classes of compounds, the SGLT2s and GLP-1s, some of which have kind of shown some activity in NASH. Looking at the phase III study, how do you think, you know, when thinking about what the comparator arm might comprise in terms of background therapy, how do you think about, you know, the role that anti-diabetics might play? Do you anticipate sort of regulatory requirements for patients to be on anti-diabetics beyond other than insulin? I would say we, as Kitty highlighted, we always want the best therapy for our patients. Regardless whether it's, since there's nothing approved for NASH, certainly for those diabetics as well as those patients with dyslipidemia, we want them to have. We don't wanna restrict their access to treatment. One of the ways that we address that is that we stratify by those with type 2 diabetes, so we don't have an imbalance where all the diabetics on one arm or the other. While we don't stratify by background measurements, we're hopeful that by stratifying, we'll at least minimize the differences overall. Is it theoretically possible that all the GLP-1s could end up on one arm? Yes, it is, but that's a low likelihood event overall. In terms of the powering of HARMONY, can you just speak to, you know, at its size, you know, what the minimal difference in reduction of fibrosis without NASH worsening the trial's power to detect? Yeah. I would just say overall, we're greater than 95% powered to detect between active and placebo, assuming a 20% placebo response rate. We're very comfortable when it comes to powering. This is not an underpowered study. Okay. At the sample size that we have, we're well powered. With respect to SYMMETRY, just curious to get a sense of how that trial has been accruing and whether, you know, you might be able to either here or in the near term guide when, you know, that 36-week readout might take place. Kitty, you wanna comment? Yes, Eric. We haven't said publicly when that data is going to be available, but what I can say is we started SYMMETRY last year. It's enrolling as we expected. I mean, overall, I think there is less competition, for in terms of the number of studies running in the F4 patient population. I think we'll provide guidance shortly. As part of the phase III program, well, actually, first, just thinking about the commercial opportunity here, it might be useful to have you sort of just put in context, you know, the F2, F3 population versus the F4 cirrhotics, in terms of their relative market sizing. Just from a registration standpoint, whether you'd need to pursue these populations individually or there might be a potential to pursue kind of a comprehensive integrated phase III plan that meets the whole fibrosis spectrum. I'll let Kitty sort of touch on that, just about our overall how we're approaching this. Eric, yes, we are planning a sort of integrated phase III program that really would encompass both the non-cirrhotic and cirrhotic patient populations. We are proposing currently sort of three different studies. The first study would have a histological endpoint after a year that would be predominantly F2, F3 patient population. You would combine that with a second study in the F4 patient population with long-term clinical outcomes. Our third study would be using a non-invasive strategy for both diagnosing patients and then also using a non-invasive primary endpoint. Mostly this would follow the current sort of both FDA and EMA sort of draft guidances. There are some areas that we feel that, you know, with good data from either HARMONY or SYMMETRY, where we could negotiate with the regulators to really come across with the broadest possible label we could have based on that Subpart H accelerated approval. Makes sense. Given that the phase III will be the first evaluation of the commercially intended drug product, you spoke to the demonstration of equivalency so far. I presume that's non-clinical. Any need to evaluate sort of a or demonstrate clinical equivalence in a bridging type study ahead of the start of the phase III trial? Tim, could you comment about our drugs, substance or product? Yeah. Maybe just taking a step back from that, Eric. In terms of drug substance, we're manufacturing at commercial scale. We made 6 lots in the last year. Four of those are clinical grade material that will be the basis of the drug product for phase III. Two of those have already been released for conversion to drug product. In terms of the drug product, that will be based on lyophilization of efruxifermin, and it will utilize an approved device in both Europe and the U.S. for patient self-administration, and that's the Vetter Lyo-Ject 3S dual-chamber syringe. It's a relatively straightforward concept. You freeze dry the efruxifermin in one of the chambers, and you add diluent to the other chamber, and that represents your drug product device combination. At the point of administration, it's a two-step syringe plunger mechanism. The first step mixes the diluent with the lyophile. You leave it for five minutes, and then you complete the subcutaneous administration. You know, as part of what we're required to do, in terms of demonstrating the comparability of that material, we've already had scientific advice from the Europeans in respect to the drug substance, and that guides us as to which tests we should be using. We'll go through the same exercise in the next period with relation to our drug product. At the end of that, you're pretty confident that what you've got hopefully will be the same as what you've had in the past. We would do a modest clinical bioavailability study before phase III to reassure ourselves that the exposure in phase III will look like that which we've seen in phase IIa and phase IIb. That's quite distinct from doing a bioequivalence bridging study at the end of phase III, which is a regulatory requirement if your commercial presentation is different from the one you use in phase III, but that's not our intent here. Our intent is to use our commercial presentation in phase III. Okay. That's very helpful. We've kind of spoken in the past about potential combination or the formal development of combination approaches with EFX. Has the outlook changed of late? I know this is something that you have, you know, contemplated in the past. Should we anticipate collaborative studies in the near term that might look at, you know, combination with EFX with other agents? I think now that we have a better idea of our profile after the phase IIa study, while we don't think that EFX needs to be combined with other compounds, whereas we do think that there is a potential role for some compounds that could benefit from a combination with EFX. It's something that we're looking at very closely and hope to announce in the not-too-distant future that we'll be starting probably a small clinical study. Okay, great. Well, I think that's the extent of my questions here, this morning. Andrew, Kitty, and Tim, thank you for your time. Excuse me, Tim. Thank you for your time this morning. I really appreciate it. Thanks everybody for tuning in to the presentation. Thanks again, Eric, for having us.