Hello, and welcome again to the Eighth Annual H.C. Wainwright NASH Investor Conference. My name is Ed Arce. I'm one of the senior biotech analysts here at HCW, and I'm very pleased to have our next presenting company, Akero Therapeutics, and representing Akero is Kitty Yale. She is the Chief Development Officer at Akero. Kitty, welcome. Thank you for joining us. Thank you for inviting us, Ed. It's great to be here. Absolutely. So, let's start off with perhaps just a quick snapshot of Akero and maybe what we can look for from the company over the next twelve to eighteen months. Sure. So Akero's developing efruxifermin. It's a unique bivalent FGF21 analog. We're currently enrolling, you know, a large global three-study phase III program, which crosses both the non-cirrhotic and the cirrhotic patient populations, and that's, you know, running right now. We enrolled the first patient in December of last year. Last year, I think, you know, we reported some important data for us. It was our phase II-B HARMONY study read out, and that's a non-cirrhotic study in F2, F3 patients. And really, we reported what we believe is some of the strongest fibrosis improvement data seen in that patient population in the field to date. I think in terms of near-term milestones, I think we're really looking forward to data coming up from our phase II-B SYMMETRY study for patients with compensated cirrhosis, and that week 96 readout is coming in Q1 of next year. Great. All right, so as you mentioned, your lead asset, efruxifermin or EFX- Yeah. s an FGF21 analog. Maybe you could briefly describe how that mechanism works and what are the advantages of it, relative to other FGF21-targeted agents from 89bio and Boston Pharmaceuticals? Yep. So EFX is really... We would describe it as a direct, rapid, acting anti-fibrotic agent, and I think we've seen that, you know, in the studies that we've reported out to date, you know, where we see, substantial numbers of patients achieving, fibrosis improvement as early as twenty-four weeks of treatment in the non-cirrhotic patient population. But what we do see is with longer treatment durations out to week ninety-six, that we see that broadening and deepening of, those responses. But I think it's also interesting that there's almost the dual mechanism occurring with the FGF21s, and we really describe the second part of the mechanism as being a sort of more of an indirect anti-fibrotic activity. And that's where we see, you know, large decreases in liver fat. We see reductions in hepatocyte stress. These really, you know, what we're doing with this part of the mechanism is really addressing the underlying NASH disease drivers, and that if you can remove those, ultimately, you, it leads to fibrosis improvement over time. In terms of, like, the unique aspects of efruxifermin, I think it's really around the structure. I describe it really as this unique bivalent structure on this Fc fusion protein. It really gives it four attachment points to the cellular surface, and what we really think is happening here is it contributes to stronger receptor binding, and you get slower dissociation. And this really differentiates it in terms of pharmacology, leading to sustained engagement of the receptors compared to the other FGF21s and leading to a sort of like the enhanced efficacy profile that we've seen to date. I think that really sort of explains the difference between 89bio and efruxifermin in terms of pegozafermin. I think that the other unique aspects of the Boston Pharmaceuticals compound is that their dosing strategy, you know, they're trying to do a once monthly dosing strategy, which leads to, you know, loading with higher doses, and therefore, you get very high Cmax from after your initial dose. And maybe over time, you know, your C trough, your pharmacology drops lower over your interdose interval, and so I do think the pharmacology from that molecule is actually very different in terms of how they're loading the dose and how they're extending the dose over time, compared to either pegozafermin or efruxifermin. And it'll be interesting to see the data and how that strategy works in terms of overall safety, in terms of the Cmax exposures, and then the efficacy, which we really do believe is driven by those trough levels. Right. Interesting. That's the very important points, so now looking beyond the FGF21 agents, of course, there's a number of agents in NASH, as everyone knows, in various different drug classes. I wanted to get your view on how EFX fits in the treatment landscape, especially with regards to Rezdiffra, which is now approved, as well as the GLP-1s, including the dual agonists, you know, that there are now well-known with some recent data... yeah. I think in general, we see the NASH treatment landscape to be very similar to the diabetes market. You know, in terms of being really large enough to support multiple mechanisms. I do think that patients are going to be treated, you know, really depending on the stage of their disease. I do think, you know, whether a patient's an F1 versus an F4 will impact which treatment that patient's offered. I think they're going to look very closely at the patient's comorbidities. Some of the patients are diabetic, some of the patients are not. You know, I think if the patients are diabetic, you're going to look at agents that help improve their glycemic control, which is an aspect of the EFX mechanism, but not for, say, something like Rezdiffra that really doesn't have an impact on glycemic control. I think, you know, when we think about the field, I think there are going to be drugs that are given as monotherapy, and then I think there will be combination therapy. EFX really has a unique profile when it comes to its, you know, rapid antifibrotic activity in terms of, like, overall fibrosis improvement. But I think the other thing that's really important is the depth of response that we see, and we see patients reversing multiple fibrosis stages, and both the cirrhotic and the non-cirrhotic patient populations. In HARMONY, we saw roughly... I mean, it was 30% of patients achieving, you know, a two-stage improvement in fibrosis. So that was F patients going back to F... F3 patients going back to, say, for example, F1. Mm-hmm. And so I think that gives us a unique proposition to patients if they're really focused on needing rapid antifibrotic activity. I think, you know, efruxifermin is really differentiated in the field. We've also, you know, in terms of combination, generated some interesting combination data in a small extension to our phase II program, where we added efruxifermin to patients that were on stable GLP-1 therapy. And, you know, our primary endpoint there was really to look at tolerability, understanding that there is some overlap in the safety profiles. But what we saw in that small study, that there was really no impact to the overall safety profile of giving both together versus GLP alone. But what was interesting, when we gave the combination therapy, we did see multiple benefits over the GLP alone, in terms of helping reduce markers of liver steatosis, injury, fibrosis, and also we helped improve, you know, the glycemic control, the dyslipidemia, and maintain the weight loss in those patients. So I do think that that's an interesting, you know, combination in terms of the complementary mechanisms. You know, efruxifermin is an insulin sensitizer. The GLP-1s are insulin secretagogues. And then we are allowing, in our phase III program, patients to come in on stable GLP-1 use, and I think that is going to be an interesting aspect of our phase III readout, because we will be able to look at EFX alone, but EFX in combination with GLP-1. Mm-hmm. It's interesting. So, obviously, as you mentioned, the depth of response, as well as the rapidity of the response, lends itself well, I think, in a number of patient profiles for monotherapy, but then there's also the case for combination therapy with GLP-1s as well. Correct. Yeah. Great. All right. So, then, you know, just taking a step back and looking at the broader landscape, how do you view the overall market opportunity in NASH or MASH now? And as you mentioned, this is something that would be segmented across the different severity stages of patients. How would you think about that? Yeah. So I think we look at it really as a significant market. You know, we have one drug approved this year in the F2, F3 patient population, and this represents several million patients alone. I think the payer coverage is going to be critical, and so far, payers seem to be understanding that this disease is costly, and they're covering, you know, Rezdiffra as a newly approved agent, which I think is great for the field. For cirrhotic disease, there's nothing approved, and I think it's very clear that this is really going to have a significant cost to the healthcare system. We are segmenting by both the cirrhotic and non-cirrhotic disease. I do think when you think about, you know, the long-term outcomes for cirrhotic patients, you know, you're really seeing a 50% survival rate at five years, and so it really does represent a significant unmet need. Okay. Fantastic. Sorry, was there something else? I don't know. Do you want to talk about commercialization? Yes, actually, I was going to bring that up. I think, you know, in terms of how you just described the segmenting of the states, you know, I wanted to get a sense for how you're thinking for EFX whether it's second or third to market, and how the impacts of the payer coverage now could progress further once you come on the market? Yeah, so I think, you know, in terms of commercialization, you know, we're in phase III, so you can see that we're just starting to really think about this, and I think we're really cognizant of the risks in the market and also all of the opportunities. I think we know that the market is going to evolve over the next several years, and that's where I think it comes into how we've really designed our phase III studies, really in order to be able to characterize EFX alone, but also, you know, in combination with the other agents that are approved. But I think overall, we really just believe that, you know, an efficacious agent like EFX really has the potential to become, you know, a backbone of therapy for future regimens, and, you know, with the ultimate goal of driving down fibrosis in the largest amount of patients. And so I think it's gonna be something we're gonna see how the market evolves. But I think it's being adaptable and running the phase III program to generate the data that we need to support, you know, the, the broadest aspects of our commercialization. Okay. So with that, let's review your most recent phase II-B data. You have data- Yeah ... as you mentioned, both in fibrotic and cirrhotic patients now, including, some very recent data that was, presented at EASL. I just wondering if you could walk us through some of that data? Yeah, sure, so let me start with our HARMONY week 96 data, and so HARMONY was our phase II-B study in non-cirrhotic F2 and F3 patients, and like I mentioned, we really think that the 96-week data that we've shown really is the strongest reported efficacy data that's really been seen across the NASH field to date. I'm gonna talk through the data. I was gonna focus on our completer analysis and really on the 50 mg dose group, although we looked at both 20 and 50 in that study, so 75% of patients achieved a one-stage improvement in fibrosis with no worsening of NASH, versus 24% on placebo after 96 weeks of treatment, and this really, you know, I think equates to a 50% treatment effect, which just really hasn't been seen in the NASH field. And you know not you know like doing the comparison like if we look at the Rezdiffra phase III program, understanding it's an ITT analysis, but roughly they show a 10% treatment effect. And so you can see there, there's a large difference between these two agents in terms of overall response. I think that the important thing you know in the data was that we had a number of early responders at week 24. And it was very great to see that those responses were sustained. So it was 92% of patients who responded at week 24 sustained their response out to week 96. So we could see that the responses... Once a patient responded earlier, that was maintained. I mentioned earlier, again, focusing on the 50 mg dose, 36% of patients achieved a two-stage improvement in fibrosis after 96 weeks. I think, you know, that's a data point that you really don't hear other companies talking about, is how many of their patients achieved a two-stage. Again, that was a response that was sustained and deepened over the treatment period. At week 24, it was roughly 15% of patients had that two-stage response, and it went up to 36% after 96 weeks. Lastly, really, the thing that I think it's important to focus on is that our histopathology data was corroborated by our non-invasive test, that basically, in terms of markers of liver injury or markers of liver fibrosis. Mm-hmm. And then really the last thing I was gonna say was, like, what's also important to, to do is, like, if we look at our markers of liver fibrosis, and, you know, maybe in particular, looking at our liver stiffness data by FibroScan, that we see continuous responses over time. So it was a deepening response, you know, so what we saw at 24 week deepened out to week 48, and then from 48, deepened again out to week 96, so that you can see these patients are continuing to respond over the 96 weeks of treatment. Right. Right. And I think the point has been made before that you really haven't yet seen any sort of treatment plateauing. Yes. And so that's incredibly encouraging, given the already robust efficacy that you've seen. Yeah. Turning beyond sort of this really strong efficacy, are there other aspects of EFX's overall clinical profile that also stand out? Well, do you know, I think, you know, obviously, in terms of our dose administration, it is a once weekly SubQ injection, so similar to the GLP-1s. Obviously, Rezdiffra is an oral medication, so there are some differences there. And then in terms of safety, I think, you know, when you look at the safety profile of a number of these agents, you know, it's. They're relatively similar. I mean, and the most commonly reported adverse events are mild to moderate transient GI events. You know, with diarrhea being the most frequently reported, which is very similar to what you see with Rezdiffra and with the GLP-1s. Right. Okay. So, turning to your phase III program, as you mentioned, you now have three phase III trials ongoing, including the most recently started, the Outcomes study. And so wanted to get a description on the trial design and endpoints for those three trials, and also describe how they fit together in your overall clinical strategy? Yep. Maybe I'll talk about the overall strategy, first of all, and then I'll get into each of the three studies. I mean, I think the benefits of running them as a program is, as we really are focused on, you know, our partners, which are the clinical sites. And one of the challenges always in NASH clinical development is the screen failure rate. And so by running it as a program with all of our sites participating in all three studies, it really is a philosophy where there's really a home just about for every patient that they screen into the study, that they can go into, to one of the three studies. So it becomes a really efficient way of running a program. Whether a patient's F1 to actually F4, there's a place in our program for those patients to participate in. Maybe I'll talk to you about the three different studies, and then I'll see if you have any questions. We have two non-cirrhotic studies. The first study is the SYNCHRONY Histology study, and that's in the F2, F3 patient population, and it's a randomized placebo-controlled study. We're evaluating both doses of efruxifermin, both the 20 and 50 mg dose. The primary endpoint there is a week 52 liver biopsy, with the primary endpoint being a greater than one-stage improvement in fibrosis and NASH resolution. Those patients, after week 52, will continue on their randomized dose and will be followed out to long-term clinical outcomes. Uh- In terms of the s- Sorry, go ahead. I'll take a question, and then I'll do the next study. No, no, no. I think getting all three of them described helps for the follow-on questions. Okay, cool. So the next study is our SYNCHRONY Real-World Study. And then this study is where we're really using patients coming in, and they can either have a liver biopsy, or they can be non-invasively identified and followed out for long-term safety. So this is a short study. It's only a one-year duration, and the primary endpoint is actually safety and tolerability. And so this study allows us to capture patients that are F1, that were identified in screening for the histology study, but not eligible in that study to go into the real-world study. And it also allows us to really supplement our safety exposure database that we'll really need in terms of the filing. And those patients really are going to be followed in terms of non-invasive markers. So there's no histology at the end of that study, but we will be looking at all of the traditional non-invasive tests that we've looked at the program to date in terms of MRI- PDFF, in terms of liver fat, liver fibrosis, and liver injury markers. And then the third study is our SYNCHRONY Outcomes study, and that's in the compensated cirrhotic patient population. And here we're actually evaluating just the 50 mg dose group of efruxifermin. And there's two cohorts in this study. The first cohort of patients will be followed out to week 96, and then have a liver biopsy. And then those patients will continue on their assigned treatment out to long-term outcomes. And then the second group of patients in the second cohort are not going to receive a liver biopsy. Those patients will just be followed out to, to long-term outcomes. Right. Great. So across those three studies, you have then the histology, which obviously will set you up for accelerated approval in the F2, F3 patient population. The outcome study in the compensated cirrhotic patients, which would not only function to provide full approval in F2, F3, but also in those cirrhotic patients. Then the real world, which would provide not only a sufficient safety database, but also significant amount of non-invasive test data, not only for your drug, but also for the greater space. Yeah. Well, and really, you know, it's how we imagine the drug will be used in the real world. We see with the Rezdiffra approval that, you know, a biopsy is not needed for diagnosis, and then these patients are being followed non-invasively, and so you can see with this program, we basically have... You know, we obviously are very focused on the registrational needs of getting the drug approved, but also generating, you know, the appropriate data that we really think that would help with our commercial launch, and as well as, you know, the combination aspects to some of the studies in terms of what drugs were allowed in the background, but then also the data to understand how to follow patients in the real world, where we're really not expecting either biopsies for diagnosis or for understanding treatment benefit after initial treatment initiation. Right. Excellent. Okay, and then, I wanted to ask about the upcoming readout, in the first quarter. As you mentioned, that's in, cirrhotics, and it's a ninety-six-week, readout. Of course, in HARMONY, we recently had that, and the, responses really across the board broadened and deepened. So the question is: Would you expect to see similar further improvements in responses in the cirrhotic patients as well? Yeah. Based on, you know, the 96-week from HARMONY, you know, where we did see both the broadening and deepening, I do think that we are very hopeful to see the same in SYMMETRY. I do think, you know, we do understand that the F4 patient population is more difficult to treat, and I think if you look at, you know, the overall collagen burden in that patient population, you know, it's can be very significant, depending on the patient. It can range from really five to 30% of their liver. We do expect that, you know, to see that fibrosis improvement of one stage, it's going to take longer, hence the 96-week endpoint in that phase III study. But I think mechanistically, we don't think there's really a reason why we wouldn't see improved response with longer treatment. And so the data's gonna be... I mean, I know at Akero, we're all very excited about that data coming up in Q1. Sure. Okay, couple last quick questions. First, I wanted to ask about, you know, going back to commercialization. I recognize it's still a bit early yet, but in terms of ex-U.S. opportunities, what could you say there? And then finally, just on your cash runway, what does that look like? So maybe I'll. I mean, in terms of Europe, I do think it's complicated in terms of strategy, and we really are just starting to develop our strategy, Ed, and so I don't really have a lot to say about going into Europe at this point. You know, our commercial lead is delving into that, and I think, again, it will be an evolving sort of situation and watching the market. Our studies, we have a large component of our studies that are being run in Europe. It's also really interesting, you know, the differences in the guidances from the different regulators. And so what's really great about Europe is that the Europeans completely accept histology as an approval pathway for the F4 patients. And so, I think, you know, when you always think about Europe, what I'm always thinking about is they want to be really focused on the patients with the highest unmet medical need. And so I think, you know, we've also designed our program to really make sure that we're taking that into consideration, and I think that the Europeans are really gonna be focused on the F 4 patient population. In terms of cash balance, our most recently reported balance was $848 million on our public cash guidance. What we've basically said, that funds both of our non-cirrhotic phase III studies through their primary endpoint, and fully funds our operating plans into the second half of 2027. Fantastic. Kitty, thank you so much. We've run out of time, but got it all in just the nick of time. Thanks for your perspectives. I really appreciate it. Thanks, Ed.