I keep eating my lunch there, so I forget what. Great. Thanks everyone for being here. I think we can get started. My name is Yanan Zhu, and I'm a biotech analyst here at Wells Fargo. It is our great pleasure to have the management team of 89bio with us today for this fireside chat. On stage with me is Rohan Palekar, CEO of the company. Hi, Rohan. Hi. Thank you for having me here. Thanks for having us at this meeting. Great. Great. So I think, if you don't mind, could you start us off by providing a brief overview of the company's platform and programs? Sure. So we are a late-stage clinical company based in liver and cardiometabolic diseases. And our lead program, called pegozafermin, is a FGF21 analog, which we believe can be transformational in these disease states. I say that based on the mechanism of how FGF21 works, but also the really strong clinical data we've shown in both MASH, which is fatty liver disease, the steatohepatitis, as well as severe hypertriglyceridemia. And Yanan, where we are just now with the company is, we've just initiated two Phase 3 studies in the MASH program, one in the pre-cirrhotic population, one in the cirrhosis population, and both these studies have started enrolling globally. And the second one is we have a program in severe hypertriglyceridemia, where we are in Phase 3, and we expect to report results from the Phase 3 next year. To close out, the company is well capitalized. We ended Q2 with approximately $530 million, and shortly after the end of the quarter, we had warrants which were exercised. We brought another $25 million, so approximately. So we're in a pretty strong cash position just now. Wonderful. Maybe a couple of questions on a broader landscape. With the advent of GLP-1 drugs and their use in diabetes, obesity, and potentially also in MASH, based on ongoing Phase 3 studies, how do you see the NASH or MASH market evolve, and what might it look like when pegozafermin reaches the market? Sure. So we think the GLP-1 from the incretin class has a role to play in diabetes. Clearly, they have great data as well as in obesity. However, when you think about the MASH landscape, there's a spectrum of diseases in MASH, right? You start off with early fibrosis, you then progress to late fibrosis, which is like F3, and then these patients, some patients unfortunately become cirrhotic, which is their fourth stage. In the earlier stages of MASH, the primary treatment objective is resolve the steatohepatitis, because people can stay in that stage for a long time. As you progress into further stages of MASH and advanced fibrosis, the primary treatment objective is you want a highly potent antifibrotic agent, because you want to prevent progression of cirrhosis. And then clearly, once you are in cirrhosis, you want to prevent a decompensation event. Based on the data presented with some of the GLP-1s, it appears that they have a very strong role as it comes to resolving steatohepatitis. So it's in that earlier treatment population, you're gonna see a lot of utilization. We would expect you want to address the diabetes as well as the, you know, the obesity. Where we see the role for molecules like pegozafermin and FGF21 classes in that advanced fibrosis stage, where you're really looking for a potent antifibrotic, and clearly in the cirrhosis stage, where the two FGF21 seem to have shown the most promising data. The last comment I'd make is we recognize that by the time we come to market, a number of these patients are going to be on GLP-1 or incretin therapies, and we have seen really nice data on top of GLP-1s. So in our Phase 2b study, we had roughly 40 patients, 37 patients, who were on background, stable doses of background GLP, and we added pegozafermin on top of that, and we see really nice benefits when we are added on top of GLP-1. So we think they're, in some ways, complementary because they work mechanistically very differently in the body, but there's a unique positioning for pegozafermin in the market. Got it. Thank you. Maybe to follow up on the GLP-1 catalyst upcoming. Novo is reporting data for Semaglutide from their Phase 3 MASH study in Q4 2024. What might be the read-through to 89 Bio? This is a large study they're doing in Phase 3 on the backs of their Phase 2 data. To remind the listeners, so in the Phase 2 data, they did see a benefit on MASH resolution, but they missed a statistical significance on a fibrosis benefit, right? As we think about this data, I would expect they're going to continue to see nice results on MASH resolution. All the GLP-1 therapies have seen it. I think the fibrosis data is a little bit... It's a fifty-fifty. Some people will say they're gonna see a benefit, some might say it's unlikely. I think the key one is, what is the magnitude of benefit they would observe? Even when you look at some of the more potent GLP-1-based therapies, which recently presented their data... While they see a benefit of fibrosis, when you look at the total impact or the benefit relative to placebo, and you compare that with pegozafermin, it tends to be lower. So I think this is going to be an important data readout, but we don't think it dramatically changes the positioning for where pegozafermin has a unique opportunity, which is that advanced fibrosis patient population and the cirrhosis population. I mean, it's interesting, like Sema is actually not studying a cirrhosis population. They did a Phase 2 study in cirrhosis, and that one, honestly, it missed on all endpoints. Placebo actually did better than Sema in that study. Interesting. How about thoughts on the recent approval of Rezdiffra and its potential market uptake? How do you think pegozafermin will position into the MASH market? Which patient segment you hope to serve too? So I'll first start by saying it's wonderful that Rezdiffra got approval. All of us are in this drug development business to help the patients, and there's a very significant number of patients, and there was no approved therapy. So it's, it's great to see a product get past the finish line from a patient perspective. From a company developing drugs, it's great to see a drug get across the finish line because it sets the tone for a regulatory pathway for approval. So all of those are really positives. I can only comment on what we see in the public data, what Madrigal's put out. It looks like the launch is going reasonably well, right? They're getting great payer coverage. It looks like there's physician adoption. The Q2 was a very small quarter, but it looks like there's good momentum. In our discussions with physicians, KOLs, we hear very high awareness of the drug, but also importantly, a lot of intent to treat with Rezdiffra. Now, as I think about it in the context of pegozafermin, when you look at Rezdiffra's data relative to ours, so they had a fibrosis benefit between 10% and 12% in a year study. We showed a benefit on fibrosis relative to placebo at 20%. You also look at some of the other markers, and while Rezdiffra had benefit, that numerically seems to be lower than what we are seeing with pegozafermin. So I think what would more likely happen is this would be a very good agent in that earlier to mid stages of MASH, where it's more a metabolic disease. But going back to our positioning, which is the more advanced stage, which is F3s and F4s, we think that's the sweet spot relative to, you know, Rezdiffra. Got it. That's very clear. How, you know, moving closer to the FGF21 space, how is pegozafermin differentiated from Akero's drug candidate? Sure. To remind the listeners, the Akero candidate called efruxifermin, it is a different molecule targeting FGF21. And the reason I bring this out is, the two companies have taken different approaches to engineer the FGF21 to extend the half-life. Ours is a glycopegylated version, so it's a different, more improved way of pegylating the molecule to extend the half-life, whereas efruxifermin is a fusion protein. It's a technology used very often, you know, you have IgG backbone to extend the half-life. When you look at the data presented on the two molecules, and you look at the phase 2b results from both the drugs, and you also look at some of the preclinical work and binding results, you see an efficacy profile which is very similar. Both the drugs had about a 20% placebo-adjusted delta on fibrosis, okay? And it's always difficult to make cross-trial comparisons, but that's just kind of, and you'll see some metabolic markers, we do better, some metabolic markers, they might do better. But the most important endpoint in this disease state is fibrosis benefit, right? So what is the points of difference? So we see there are four points of difference. The first one is, to date, in the clinical studies, we have seen a drug which has shown a better tolerability profile relative to efruxifermin, especially when it comes to the context of GI adverse events. And this is important when you think about the commercialization of the product, because it's an asymptomatic condition. People are gonna be on this drug chronically. You would know from other disease states, a well-tolerated drug makes a big difference in that, right? That's one part where we have seen a very different profile to date in all our trials. The second is dosing convenience. We are developing our drug to be delivered subcutaneously once a week or once every two weeks. Efruxifermin is being developed as a drug given only once a week. The every two-week dosing, again, from a patient compliance, persistency, and convenience perspective, adds a lot of value. It's 26 less injections, right? And then all our researchers, when we talk to patients, they go, "Wow, that's a big benefit!" As long as the other markers are the same, right? We think that could be a significant differentiator in a commercial setting. The third I would mention is, we are a liquid formulation, so our commercial presentation is a liquid in a prefilled syringe. The efruxifermin program, as we know, as we've seen in the public domain, what they've said is, it's a lyophilized product, which needs to be reconstituted. Per se, that's not a big issue. However, having a liquid formulation may allow us to co-formulate with a GLP-1. So all the GLP-1 drugs currently are liquids. There are orals being developed, but because we had a liquid product, we might have the potential as part of life cycle management, to create a single co-formulation injection. Right? So that could be very interesting, something we would think about, which could be a very different approach. And then the last thing I would say is, we are developing pegozafermin in two indications, in both MASH as well as severe hypertriglyceridemia. And again, when you think about it, when you come to the market, it allows us to target additional physicians. There's an overlap, and it creates a different opportunity to build pegozafermin relative to efruxifermin. Got it. Thank you for elaborating on those points. Perhaps, if you don't mind, could you review the data from pegozafermin's phase 2b study in the F2, F3 population? And also, you know, please compare the fibrosis improvement with the competitors, Akero's compound and Lilly's GLP-1. And also, please compare NASH resolution with those compounds and help us understand how where do all those data points fall. Okay. Let me try and do this in as efficient manner. The phase 2b study was a study in F2, F3 patients. I'll come back to a small subsample of F4 patients in the study, in approximately 220 patients, where we studied different doses of pegozafermin given once a week or once every two weeks versus placebo. It was a 52-week study with a primary endpoint at six months, where we did histology, and the primary endpoints were the two standard FDA-approved endpoints, which were fibrosis improvement in one stage or MASH resolution with no worsening of fibrosis. Okay? We biopsy patients at the start. At the end of six months, we re-biopsy them, and we look at the difference versus baseline. But we continue all these patients in a blinded fashion to week 48. If I were to highlight the key results on the fibrosis improvement, we saw a highly statistical significance and a 20% delta, 19% and 20% delta, at the 44 milligrams given once every two weeks and the 30 milligrams given once a week. Those are the doses we are moving forward into phase 3. We also saw very nice impact on MASH resolution, again, in the mid-20% delta versus placebo. Importantly, we saw really good benefits on all the other secondary markers, so liver fat reduction in the mid-50s%, nice change in liver transaminases, all the non-invasive markers of liver stiffness, as well as very nice changes on metabolic markers like lipids, LDL, and glycemic control. The drug was well tolerated, very few discontinuations in the study. The only AEs of significance were mild, grade one GI events, which were early. So well-tolerated drug. We did not see any statistical or clinically meaningful changes on bone markers, which has always been coming up, or BMD, or on key vital signs. Okay? Two other comments on the data. We had a small group of patients, 14 patients, who had F4 disease at baseline, and in those patients, we re-biopsied, 11 of them were on drug, and we saw a very dramatic change on fibrosis, despite it only being a 24-week study. So very encouraging on that. We also had patients on background GLP-1, where we saw very nice data. The last thing on efficacy, as I mentioned, we continued these patients onto week 48. Now, at week 48, we did not re-biopsy them, but we looked at a lot of non-invasive markers, and all of the non-invasive markers continued to sustain between week 24 and week 48. Okay. To answer your question on comparing us versus efruxifermin and, say, tirzepatide, right? So when you look at the fibrosis benefit, you see a very comparable benefit between the studies. At week 24, we saw a 20% delta, efruxifermin saw a 20% relative additional benefit versus placebo, so not that different. Tirzepatide also saw a very similar 20%. Okay? However, all these trials were done with a very different construct. We used a very rigorous methodology on reading the biopsies, so we used a three-panel, where three independent readers read each slide separately without communicating with one another, and then we took the score across all three. If all three agreed, otherwise, we took the mode. The other programs have typically done two readers, and if they disagree, they have a consensus call to decide what's the number. When you take this very stringent methodology we did, you have a much lower placebo response. So for example, our placebo response was 7%. In tirzepatide's case, the placebo response was 30%. So one way to do cross-trial comparisons, Yanan, is you do what's a relative risk or how does the drug affect relative to placebo. And when you look at that, our drug effect relative to placebo is about three point five x what placebo saw. Efruxifermin was in the twos, and tirzepatide was below, like one point seven, right? So it's important to look at what was the delta, which looks similar, but what was also the relative risk or the odds ratio. And so we think we have a molecule which potentially has among the best fibrosis data, either when you take it numerically, but clearly when you look at the relative risk. On NASH resolution, a very similar story. Now, there you do see our numbers. Absolute numbers are lower. We had a 2% placebo response on NASH resolution in our study. Others have seen a response in the teens, mid-teens, up to 20% placebo response. So they see a higher placebo response as well as a higher drug response. But when you look at the odds ratio of relative risk, we actually have amongst the best datasets. Got it. How do we think about to read the data with the delta versus a ratio? Like you said, risk reduction. Like the two, what's the pros and cons of using either method to, you know, evaluate efficacy? Yes. I mean, the reason in MASH you want to look at both is because, as I mentioned, each one of these studies, the way biopsies were read was very different. The methodologies were different. But the second one is the readers were different in different studies. And there is inherent biases some pathologists might have on how they read a study. So it's important to think about each study is its kind of self-contained construct, right? And so if you want to compare one study versus the other, the only way to equalize it is to look at, within that study, how did the drug do relative to placebo? Because it's that same reader using the same methodology, who read both the placebo slide and the active drug slide, right? So if they were... I'm just going to generalize: If someone is very strict in reading fibrosis, they will be strict in reading the placebo slide as well as the active drug slide, right? Right. So if they have low scores on drug, they'll have low scores on placebo. Conversely, if someone is more liberal and sees any change they view as a change in fibrosis, you're going to have a higher placebo rate, and you're going to have a higher drug rate. So the numerical numbers look much bigger, but that doesn't mean that the drug effect was any more. So we think it's important to consider both of them, and so it's not one versus the other. It's both are important. Got it. Thank you for explaining that. What is the relative importance of fibrosis endpoint versus the NASH resolution endpoint in the eyes of treating physicians? So in the eyes of the physicians, it's all about fibrosis benefit. I mean, it's important that you are impacting the underlying disease, but really what their focus is, is I want to prevent the progression of fibrosis, because it's the progression of fibrosis which results in bad liver events, and in due course, results in, you know, advanced fibrosis and unfortunately, for some patients, cirrhosis, and it's very similar with payers also. They are really focused on, because that's where health outcome costs are generated, you know? That's the issue, so. Got it. Thank you. The company is running a Phase 3 study, as you mentioned at, in the beginning. The histology endpoints are measured at one year. Can you talk about your expectation for the histology prime, primary endpoints? What is the bar for success? I think we feel a high level of confidence that we should see positive data, right? At 24 weeks, we saw highly statistically significant benefit on both fibrosis as well as NASH resolution, right? And amongst the best in the category. We've then shown at week 48, we have seen a maintenance of all the underlying, you know, disease parameters being down, whether it's transaminases, liver fat, et cetera. So we expect at week 48, when we rebiopsy at year one, we should see very nice histology benefits. You know, so. But that's why we do clinical studies, right? To see. What is the bar? I think there is. It comes back to a little bit. I think if you talk to some of the KOLs, they will say anything in the F2, F3 population, a placebo delta of 15% is clinically meaningful. At 10% is where I would start using the drug, but a really clinically meaningful benefit would be in the 15% range, right?... in an F4 population, that's lower. They would say even a 10% is clinically meaningful. If I can show a 10% delta versus placebo, they feel that drug really could bring value to their patients. Great. Thanks for the insights there. How is the pace of enrollment? When could we expect data? So it's, it's early in the studies. We initiated the F2, F3 study in pre-cirrhotics in March of this year. And the cirrhosis study started in May of this year, so it's early on enrollment. Here's what I can say. In the US, the sites are coming up really rapidly. There's a lot of sites, so would suggest that the PIs are very interested in the trial and getting engaged. The screening is going really well. We're screening a lot of patients, which would support the hypothesis that there's a lot of these patients out there in the marketplace, right? So that's going well. It's a long screening period, so it's a little early just now to say how enrollment specifically is. As regards to your other question on data, what we haven't given a firm guidance because we wanna see how enrollment takes place over the next six, twelve months. What we can say is that for the histology portion of the F2, F3, what we've said on clinicaltrials.gov in our posting is that we would expect top line results from the histology portion, but at the end of twenty twenty-six. Got it. Is that from all the patients or from part of the patients? Great question. So it is from a part of the patient. So that study is enrolling approximately a thousand patients, the F2, F3 study. We do not need all the thousand patients from a statistical powering perspective for the histology endpoint, so it's a subsegment of that. We haven't disclosed the exact number. It's a smaller number of that, but it would be the histology readout from that smaller number of patients. Got it. Could patients in the phase III study take GLP-1 and/or Rezdiffra? If so, what proportion of patients do you think will go that route? So they are allowed to be on GLP-1s, as long as they have been on a stable dose of GLP-1s, okay? And they got to be a stable dose coming into the study, because you don't want someone starting it in the study, and you don't want someone going, because GLP-1s have a long titration period, right? It's tough to predict exactly what that number would be, but I wouldn't be surprised if it's a third, if not slightly more, of the patients could be on GLP-1. We think that number will be higher in the U.S. It's probably gonna be well higher than a third of the patients in the U.S. However, OUS, which is where a significant part of the study would enroll, GLP-1 utilization is not that prevalent. In fact, for obesity, GLP-1s are not being used outside the U.S. as of now, when we are enrolling. And then as it relates to Rezdiffra, at this point in time, patients are not allowed to be on Rezdiffra. Now, Rezdiffra has just got approved. By the time someone were to come in and be on a stable dose of Rezdiffra, we probably have enrolled all our patients, right? And again, going back to the comment about an international study, by the time Rezdiffra gets approved in the international markets, we would be well down our path of, you know, getting to potentially hopefully finishing enrollment. Got it. Got it. So the trial is powered with the assumption of there could be a third of patients on GLP-1. Can I assume that? Yeah. Yeah, we do that, and what we would do is this is a priority. It's stratified on GLP-1 use, because you just wanna make sure you don't end up with an imbalance across the arms, so it is stratified for GLP-1 use. Great. For the outcomes endpoint, can you talk about what the endpoint is and what the bar for success is, and what kind of effect size do you-- did you use in your powering assumption? Sure. So it's a little different for the two studies. So the outcome event in the F2, F3 study is predominantly progression to cirrhosis. Okay? So these are F2, F3 patients who become cirrhotic. We expect roughly 90% of these patients are gonna be progression to cirrhosis. Now, the other events could be decompensation, MACE event, MELD score going really high, but that's kind of rare for F2, F3 patients. Based on the data we've seen to date, we have a high level of confidence we should see that. So recently, Intercept put out their data. Even though they closed down the Ocaliva study, they had. At four years they stopped the study, but they looked at, and each arm, they had over 700 patients, and they saw about a 25% reduction in progression to cirrhosis. This is despite the fact that their fibrosis benefit was only about 10% delta. So we think with a 20% delta, we have a very good chance of seeing a benefit. And in fact, in our phase IIB study in the F3 patients who were on placebo, approximately 19% had progressed to cirrhosis versus less than 9% on our drug, okay? So that's where we think that event is gonna be the primary driver of an outcome, and we see pretty good data. Now, in the cirrhosis study, the outcome events are slightly different. The outcome events in the cirrhosis study are primarily decompensation events. Now, you can also have that MACE event, MELD score going really high, liver transplant, but that'll be few. When you think about decompensation events, and this was a very significant win we got with the regulators, we have defined the decompensation event. The FDA has certain definitions of decompensation events in their guidelines, but those are really at the endpoint of decompensation. We've got them to agree to talk about a decompensation event earlier than that. We haven't disclosed them, but these are predominantly SAEs having hepatic encephalopathy, where you get confused because... Or you could have varices. Those are the key events. The way we powered the study, like any event study, we've taken a very conservative approach, looking at historical data, how people progress in placebo, and then a hazard ratio, which is a reasonable hazard ratio. So not being overly conservative, in which case then you'd be doing 3,000 and 5,000 patient studies, or not overly aggressive that, you know, your drug has to show a phenomenal benefit. Got it. Got it. Very helpful. One catalyst coming up in the space is Akero's readout for their twenty-four month F4, phase 2b study. Yep. 1Q25. What will you focus on, and what might be the read-through to your compound? So I think what we're going to be looking at is clearly, what's the benefit they see on fibrosis? But beyond that, we want to look at what the total dataset looks like, right? Are they actually having an impact on the disease course here? Because it's a small study, so you don't want to always rely on one number, but I do think that's an important to see. Look, at—in their nine-month data, they saw a 10% fibrosis benefit. They missed that stat sig, but we think that's because they went too short, and it's a couple of patients might have made them a stat sig, right? We do think there's a read-through to our drug, because, as I mentioned, the drugs are very similar in many ways as it ties to efficacy. So if they see good data on that, I think it translates. We feel much more bullish and positive on our F4 study. Got it. Very helpful. I think in the remainder of the time, perhaps let's touch on SHTG. Sure. Indication. You have ongoing phase 3 study, reading out in 2025. Yep. A couple of RNA therapeutics programs are also in Phase 3 development. Any thoughts on the differentiation of your compound and how competitive it is against the RNA therapeutic drugs? Sure. So I think the ones you're referencing to are targeting APOC3, and we think we have a differentiated molecule really based on our mechanism. So when you think about these SHTG patients, a lot of them also have metabolic dysregulation. So many of them, in fact, close to 100%, have liver fat or liver abnormalities, and about two-thirds of them have pre-diabetes or diabetic. And so when we talk to physicians, what our research has shown is, they want to drop triglycerides, but they also want to address the other metabolic dysregulation. And we not only reduce triglycerides, so when you compare our data versus plozasiran, our triglyceride reduction on placebo-adjusted basis is very similar. But we see a benefit on liver fat reduction, which to date, none of them have published. We see better benefit on ALT. We see better benefits on hemoglobin A1c, and in fact, they actually saw a worsening of hemoglobin A1c, and that's in their AE tables, actually. And then the last thing I would say is, we are neutral on LDL, versus in that study, the APOC3 saw a 60% increase in LDL. And in a patient who is at a risk of cardiovascular disease, that's less than ideal. So we think we have a very differentiated molecule because of our mechanism and the value we bring to these patients. That's super helpful. Thank you for all of the insight. I think with that, we're out of time. Thank you, Rohan- Sure. - for a very helpful and informative session. Appreciate it. Thank you very much. Thanks, everyone. Appreciate it.