Hello, and welcome to the eighth annual H.C. Wainwright MASH Investor Conference. My name is Ed Arce. I'm one of the senior biotech analysts here at HCW, and our next presenting company is 89bio. I'm very pleased to have with us the CEO, Rohan Palekar. Rohan, thank you so much for joining us. Hey, Ed. It's great to be on. I look forward to our discussion. Absolutely, as do I. So, let's start with a quick snapshot of 89bio and then perhaps what we can look forward to over the next 12-18 months. Sure. So, as you know, we are focused on liver and cardiometabolic diseases, and we think pegozafermin, our FGF21 analog, has the true potential to transform the lives of patients in these diseases. And, we're excited. We're currently in three phase III studies, two in MASH, which we initiated this year, and we have a phase III study ongoing in severe hypertriglyceridemia. And as we look forward to the next 12 to 18 months, the primary one from a data perspective is we expect to have data from our severe hypertriglyceridemia study in 2025, so that's gonna be the first phase III readout with pegozafermin. And then, as you think about the two studies ongoing in MASH, we would expect to present updates as we look forward to enrolling those studies over the next 12 to 18 months. Those studies started in the first and second quarter of this year. Now, at the same time, as we think about the next 12 to 18 months, we continue to ensure that we get ready for a BLA submission. We've had great success in scaling up our manufacturing process and getting that ready. And then we start thinking about how do we commercialize the asset, were we to do it on our own. So it's an exciting time period for the company at this point, and we're looking forward to getting everything ready for a BLA submission. Fantastic. All right, so, your lead asset, as you mentioned, is pegozafermin, or PGZ, as I'll call it, an FGF21 analog agonist. I wanted to give you a couple of minutes just to go over how that mechanism works, what are its advantages, and in particular, you know, how is it different from a couple of the other FGF21s in development? Sure. So, Ed, FGF21 is a endogenous metabolic hormone, which controls energy, carbohydrate, and lipid metabolism in the body. So it has direct effects on lipids, it has direct effects on insulin sensitivity, and really kind of addresses the metabolic milieu in the body. Now, importantly, it also has a direct effect on the liver. So there are multiple FGFR receptors on the liver, and so what it does on the liver is it results in fatty acid oxidation, so breakdown of fats there. It prevents de novo lipogenesis, or the generation of fat in the liver. But then importantly, it is believed to actually have a direct impact on fibrosis and inflammation in the liver, and it does this by upregulating adiponectin, which is another hormone, which has been shown in animal studies to downregulate stellate cell activity. So what is unique about FGF21, as distinct from some of the other mechanisms in development, is it has broad metabolic properties and works in the periphery, but also has direct effects on the liver. And why is this important? So when you think about MASH, MASH is a liver disease, but at its core, it's a metabolic dysregulation these patients have. So it's really important to address what's happening in the liver, but also address the broader metabolic issues, because otherwise you could be working on the liver, but if you continue to deposit additional fat into the liver, it's gonna get overwhelmed at one time, right? So that's a unique difference versus some of the other mechanisms. And you could contrast it with some... Let's take GLP-1, which the incretins work peripherally. They don't have a direct effect on the liver. In fact, there are no known GLP-1 receptors on the liver. So they're working purely indirectly, and this is where FGF21 is unique because it's not only working more broadly in the body, but it's also working directly on the liver, and I think this is an important distinction when you think about this mechanism relative to some of the other mechanisms in development for MASH. I think your last question was around how we differentiate versus some of the other FGF21s. Now, FGF21, in its native state, has an incredibly short half-life. So different companies have taken different technologies to extend the half-life. We use what's called glycoPEGylation, which is a unique way of PEGylating the hormone. What this allows us to do is the glycoPEGylation, which is distinct from classic pegylation, gives a very strong and flexible linker, and it allows us to extend the half-life, allowing for weekly or every two-week dosing without compromising the efficacy, and that's an important distinction. Other technologies use fusion protein technologies. Again, they extend the half-life, but in a different manner. As we all know, there's another leading drug in development in phase 3, efruxifermin, and I think we offer some unique differences versus efruxifermin. I think on an efficacy perspective, both the molecules have shown really nice efficacy, and not that differentiated on efficacy. I think there is four points of difference we see. One is, to date, we have shown a better tolerability profile, especially when it comes down to GI adverse events. We've consistently, across the studies over the many years, going back to phase 1, have shown a very nice tolerability profile. The second is, we are studying the molecule once a week and once every two weeks, versus efruxifermin is once a week. And so when you think about it from a patient perspective, it's 26 less injections a year, and in our research, two-thirds of patients would prefer that dosing regimen, assuming other things are equal. And these two points had become important, which is tolerability and convenience, because in a commercial setting, we all know that patient persistency and compliance is driven by convenience and safety tolerability. In a clinical trial setting, you can control that. You know, you get patients to come back to the study site, they get the injection, that's all good. But in the real world, these two become really, really important. Two other slight differences is our product is a liquid pre-filled syringe, and what this might allow, as you think about life cycle planning, a potential for creating a combination product with, say, an incretin therapy. The incretin therapies, as we know, are liquid products, and it's unclear whether a lyophilized product can be combined with a liquid product in a single injection. And so when you think about a life cycle perspective, this could be something unique. And then finally, we're studying our product as distinct from the other FGF21 agents in two distinct indications, and that's gonna give us a lot of leverage and synergies, especially when you think about it from a commercialization perspective. We've seen that in other classes of drugs, where you have multiple indications, it allows you to get to a new target audience also. So a couple of differences, but we think this class could become the winner in this space, and our belief is it's not one winner takes all. There'll be multiple agents which are successful, but we think pegozafermin offers some unique opportunities here. Excellent. Okay, so with all of that, wanted to get your take, or review on how pegozafermin would fit in the overall treatment landscape, especially now with regards to, of course, the first approved drug, Rezdiffra, on the market now, as well as, the GLP-1s, both the single and dual agonists. Yeah. So first, let me say, we are all, all the companies in this space developing. We're really thrilled that now there is a product available for patients. So it's, it's wonderful that Rezdiffra now is on the market. So here is how we think about pegozafermin's positioning. We see pegozafermin being positioned for patients with advanced fibrosis, and so this is predominantly patients who would be F3 fibrosis and then the compensated cirrhotic patients. Now, there will be some F2s who are high risk. Here is what our research is telling us in conversations with physicians. You know, in the real world, people are not gonna do biopsies to classify people as F1, F2, F3, F4. They'll use non-invasive markers to do that, but really, what they're looking at is, what is the risk for these patients? And the risk is predominantly, what's their risk of fibrosis progression? And you can broadly classify, people could be low risk, which are more like that F0, F1, some F2, going all the way to medium to high risk. And then clearly, once you're compensated cirrhotic, you're very high risk. Now, if you think about a risk paradigm, the way your treatment objectives would be is really driven by what's your risk. So if someone is a low-risk patient, your treatment objective is resolve the steatohepatitis. Someone could stay in that stage for multiple years. However, when you become high risk, which are more like the F3 patients, your primary treatment objective is prevent progression of fibrosis to cirrhosis, because physicians know once you become cirrhotic, that's problematic. And if you are compensated cirrhotic, the primary treatment objective is prevent a decompensation event. So if you think about that paradigm, if your goal is resolve steatohepatitis, a good metabolic drug is great, anti-obesity, diabetes drugs, because you could stay in that state, as I mentioned, for 10 or 15 years. And we think the incretin therapies will play a very, very important role there. But when you're in that advanced state, and your goal is to prevent progression to cirrhosis or to prevent a decompensation event, the paradigm changes a little, and you're looking for a potent antifibrotic. You want a metabolic benefit, but a potent antifibrotic, and that's where pegozafermin really fits in. Now, those patients could be on a metabolic drug, like a incretin, a Rezdiffra, potentially, if they have continued to progress. And we're fortunate in that we've shown really nice data on top of GLP-1s. You know, in our study, in the phase 2b study, we showed that, which makes sense, given the mechanisms is very different, so we don't see ourselves directly competing, but we are seeing ourselves as complementary to some of these other drugs, and we think we have a unique niche, and to date, albeit in phase 2b studies, FGF21 has shown the best potential in that advanced fibrosis, and then in the compensated cirrhotics, to date, FGF21 is really the class of drugs which has shown a best benefit, and that's a huge opportunity, and it's unlikely that incretins work there. In fact, semaglutide had done a study, and they didn't see any benefit in the compensated cirrhotics. All right. Before I jump into the phase 2b data from the ENLIVEN study, I just wanted to quickly ask you, you know, given what you've just said and sort of the evolving treatment landscape, what do you see is the overall market opportunity specifically for pegozafermin? Yeah. So we think there is a very significant patient population who are going to fit within that advanced cirrhotic patient population. So if you, you know, if you forecast out 10 years and you look at some of the epi studies, just in the F2, F3, the epi studies would say there's estimated to be about 13 million patients. Now, we do recognize that over time, if you treat patients earlier, what could happen is that pool of patients who progress could drop, but yet you're talking about somewhere close to about 10 million patients. But here is the important thing. The diagnosis rate today is very low. It's about 7%. So there's maybe about 550,000, plus or minus 50,000 patients, who are being diagnosed with MASH today. On a conservative estimate, over the next decade, we would expect that number to actually go all the way up to, let's say, 17%-18%. It could be up to 25%. And if you think about that, now all of a sudden, you have 1.8 million patients in this pool of diagnosed patients who would be eligible for a drug, and that could be a market for pegozafermin. And if you do the same math in F4, we think there could be about 800,000 to 1 million patients in a decade's time who would be in that compensated cirrhotic patient population, and that would be a clear TAM for FGF21 agents and potentially only FGF21 agents. Great. All right, so let's review the phase IIb data, both at the 24-week and 48-week time points. What, what have you reported there? Yeah. So in our phase IIb study, we looked at F2, F3 patients, and as you mentioned, we studied two different dosing regimens, weekly and every two weeks. And at week 24, which was the primary analysis, we did a repeat biopsy, and then we continued patients through week 48, where we looked at non-invasive markers. There were roughly 220 patients in this study. And what we saw at the primary histology endpoint at week 24, we saw very robust changes and statistically significant changes on both the endpoints, which are used for registration, which is a one-point change in fibrosis with no worsening of MASH or MASH resolution with no worsening of fibrosis. So specifically, on the more important endpoint, which is fibrosis reversal, we saw a placebo-adjusted delta of 20%. So placebo was 7%, and the active was between 26% to 28%. So a very robust one-point change on fibrosis. And when you compare this with the other datasets presented, it stacks up very, very favorably. So the only other drugs which have shown a 20% delta, which are in late-stage development, was the other FGF21 analog. And to put it in context, Rezdiffra was between a 10%-12% delta on fibrosis. So we feel very good about the opportunity, and importantly, ours was at 24 weeks, like a Rezdiffra was done at one year. The other thing I think, Ed, which is important to point out, is one way is to look at the fibrosis delta. But as we all know, each one of these studies were done slightly differently. The duration was different, but importantly, the biopsy reading methodology was very different. We used a consensus panel where we had three readers independently, with no communication between them, and then we took the consensus read or the mode as applicable. What this does is it tends to reduce the placebo response but also the active drug response, and so one way to compare when you think about cross-trial comparisons is to do what's called relative risk or odds ratio, and here we have an odds ratio of, like, 3.5, which is significantly higher than all the other studies to date. Most of the other studies are, like, in the two, two. You know, when you take a look at Rezdiffra, or even if you take a look at some of the GLP-1 data, which was recently presented, you know, when you look at the T2 agents, the tirzepatide or the sotagliflozin, while their placebo-adjusted delta was comparable or lower than what we've seen, on a relative risk ratio, they were significantly lower, suggesting that pegozafermin potentially has a best-in-class fibrosis effect similar to other FGF21 agent. Right. All right, so in ENLIVEN, I wanted to also ask you about two subset of patients, those that were on a stable dose of GLP-1 and what you saw there, as well as a smaller subset of patients that were actually compensated cirrhotics and what you saw in those patients. Sure, and I should mention one point you had asked also on the 48-week data, as I mentioned, we continued all the patients to 48 weeks in a placebo-adjusted, blinded fashion, and we did see maintenance of response across all these non-invasive markers at week 48, and what we would expect is, as you continue to treat these patients for a longer duration, were we to biopsy them, we would expect, as seen with the other FGF21 agent, a better histology response, you know? Answering your specific question, you're right, we did have 20% of our patients on stable dose of a GLP-1. Predominantly, it was semaglutide. Very limited, actually. I think only one patient in tirzepatide, because when the study was done. And what we saw at the end of 24 weeks, very consistent response on histology, and then across all the NITs, an improvement versus patients who were just on incretin. So whether you looked at it on things like liver transaminases, liver fat reduction, you looked at it at markers of fibrosis, like PRO-C3 or ELF, we saw a benefit on top of it. And importantly, we also saw benefit on metabolics. Like, even on hemoglobin A1C, we saw additional benefit on top of patients who were just on a GLP-1 and got placebo. And this goes back to my earlier comment, we expect there would be polypharmacy use in this category, and we feel these patients on GLP-1 who progress could really benefit from pegozafermin. As regards your second part on compensated cirrhotics, we did have 14 patients who, on re-read of their biopsy samples, were seen to be compensated cirrhotics. So it's a small data set, but it was very encouraging to see that 45% of those who had a repeat biopsy saw a reversal of fibrosis. Now, that's a small data set on biopsy read, but what we looked at is how did the non-invasives do on those small sample, both at week 24 and week 48. And that's what gives us a lot of confidence that we could see something positive in a large study, because all the non-invasive markers at both week 24 and week 48 were concordant and all moved in the right direction. So it's very encouraging to see that even in compensated cirrhotics, pegozafermin could have a nice therapeutic role. Great. All right, so turning to the phase III program, you're now recruiting two phase III trials, ENLIGHTEN- Fibrosis, and ENLIGHTEN Cirrhosis. Both of them feature both a histology portion for accelerated approval and a long-term outcomes portion for full approval. So I wanted to get you to walk us through the trial design, and also the endpoints, and also how they sort of fit together, to combine for your overall clinical strategy. The ENLIGHTEN-Fibrosis study is a study focused on F2, F3 patients. We are studying two different dosing regimens, 30mg given once a week and 44mg given once every two weeks. We're gonna enroll approximately 1,000 patients, and at the end of 52 weeks, we'll do a repeat biopsy in a subsample of that, not the entire 1,000 patients, and look for a co-primary endpoint of reversal of fibrosis and MASH resolution with no worsening of fibrosis. Were we to have positive data on that, we could file for accelerated approval in the U.S. and conditional approval in Europe, and we've got regulatory buy-in to that. Now, we continue all those patients, and at the end of three years, we do another biopsy, and assuming that we show a benefit on outcomes, with the primary outcome being progression to cirrhosis, we could file for full approval, so to convert that accelerated approval into full approval. So that's the design of the fibrosis study, and we think that would be our first indication, which would be looking at 24-week data, 12-month data for reversal of fibrosis at week 52. The second study is ENLIGHTEN-Cirrhosis, which is enrolling compensated cirrhotic patients. Here we are only studying a single dose, which is the 30mg given once a week. A very similar design, where after 24 months, as distinct from in the fibrosis study, it's after 12 months, we will do a repeat biopsy, and if we show a reversal of fibrosis, which is the primary endpoint, we could file for accelerated approval in the U.S., conditional approval in Europe. And this was a big win, Ed, because to the best of our knowledge, we were the first company to get approval from the regulatory bodies that we could file for accelerated approval were we to show a reversal of fibrosis. We will continue all those patients for outcomes, the primary outcome event here being decompensation events. And here again, we had a success with the regulatory bodies to kind of how we define decompensation events to make it a more tractable and attractive study, where within a reasonable time period, we would expect decompensation events. It's about 750 patients. Not all the patients would be required for the histology component, but for the outcome component, it would be in that range of patients we would enroll. All right, one final question I did want to ask about your upcoming readout next year, switching gears to hypertriglyceridemia or severe hypertriglyceridemia. The ENTRUST study is reading out next year, and in the phase 2 INTRIGUE study, we've had an unusually high proportion of patients that actually achieved normalization of TG. Yeah. And so clearly, strong results there. And you've, you've described the phase 3 as de-risk. Given what you've already seen, what would be your expectations for the results of phase 3? Yeah. We are very bullish on that study because, as you mentioned, we saw very strong results, not just a normalization of TGs, but also TG reduction, right? Between 57%-63% reduction in triglycerides, and we showed this on top of existing standard of care, whether they were on fibrates, fish oils, and more, mostly patients who on high-intensity statins. Sorry, on statins, but a large number on high-intensity statins. We have very similar inclusion criteria. We have a very similar endpoint. The big difference is it's a 26-week endpoint, and actually, we think with longer duration, we should see really nice reductions. Having said all of that, you know, as you think about larger studies, you do see in larger studies, greater variability. So it's difficult to put an exact number on what we would expect, but we would expect very similar results to what we could have seen in an INTRIGUE with a high level of confidence. And I say the high level of confidence is because we're seeing reduction in triglyceride across a multitude of studies. It was not just that study. You know, FGF21 has consistently seen that. So we're thinking, you know, we should see something very similar and with a very similar patient population that we are enrolling in the study. Excellent. Well, Rohan, I think we've reached the limit of our time here, but I wanted to thank you again for your time, and perspectives, and insights on your lead drug and on your programs, and certainly wish you luck next year for that readout. Thanks a lot. Thank you. We appreciate it.