All right, good morning everyone. Thanks so much for joining us. I'm really pleased to be joined by Rohan Palekar, CEO of 89bio. Thank you so much. Andrea, great to be here. Thanks for having us. Yeah, maybe to start, let's just talk about the NASH space, the evolution. There have been so many developments, both on the clinical side as well as the first approved drug last year. How do you see the NASH space evolving from here? I think it's been a really exciting time to be in NASH, right? For many years, there was a lot of, like, let's say, skepticism, like, where's the space going? I think I would characterize it by people are now recognizing the importance and how big this category is because it's a really large category. I would say there's three things which have been really important in the last 12 months to 18 months. The first was, as you pointed out, Rezdiffra getting approved, because there was always this question about, can you actually get something past the finish line? We've always believed in it. I think this showed that if you have a drug with good efficacy, you can get across the finish line, and that's huge. The second one has been is, I think there's going to be even more excitement and energy with the new mechanisms coming into play, right? Some of the GLP-based ones have shown what I'd like to say, good data, not wow data. I think when those come to the market, the market's actually going to expand pretty significantly because there's going to be a lot more education, a lot more awareness, a lot more screening for NASH. I think that bodes well for a company like 89bio, because by the time pegozafermin comes to market, we expect this category to grow significantly. I think the third, which is more recent this year, which is incredibly exciting for the FGF21 field and pegozafermin, is the data from the competing FGF21, which really showed the power of what a good, potent molecule targeting FGF21 can do for the cirrhotic space. There was always this belief, like, once you're cirrhotic, you can't reverse it. We have always believed that you can make a difference with a good molecule. I think in some ways, some of the prior therapies tested might not have been that effective. And we've shown it in a small sample set. Efruxifermin had shown it in a small data set. Now I think it's pretty clear that with our drugs, we can impact cirrhosis. This is the market with the highest unmet need. Patients need a better drug. Physicians are looking for a better drug. It's also one where your pricing potential is significantly higher. Especially when you think about it in the global context, in other markets where pricing pressures might be different, I think the pricing dynamics in the cirrhosis market is very different than NASH. Look, that's why we are incredibly excited being in both the pre-cirrhotic and cirrhotic patient population and moving forward with our studies. You referenced the FGF21 class here. Obviously, a lot of updates across the class here. Maybe just to level set, how does pegozafermin differentiate, or how do you see the differentiation versus others within the class? I think I would say there's three points of difference. When you think about differentiation against molecules, right, you can put it across efficacy, safety, tolerability, and then what I'm going to say is the dosing and convenience regimens, right? When you look at the three drugs in development with FGF21 and efficacy, there's a lot of similarities. You see pretty similar data sets on non-invasive markers and on key histology measures. Having said that, when you look at it on a relative risk, when you look at the construct of a trial, how did the drug do versus placebo, pegozafermin really stands out. There was a recent paper in Hepatology, which came out in March, independent meta-analysis. They looked at 29 different studies, 9,300 patients, and they actually put pegozafermin as the top from a histology perspective on its ability to impact both NASH resolution and fibrosis. We think that could, if that plays out in phase III, that's going to be important. Let's talk about the safety and tolerability. I think here there is a very clear difference between pegozafermin and the others in the class. In tolerability, we have consistently shown much lower rates of GI effects, and especially the more problematic ones like nausea and vomiting. Like take vomiting, we're below 5%. Others are showing rates between 15%. That's a pretty high number. This becomes important because these are chronic asymptomatic conditions. People need to stay on the drug for a long time period. We do know from other therapeutic classes, take GLP-1s, that the number one reason for discontinuation is these tolerability aids. We think that is a key point of difference. On the safety front, a key point of difference is bone mineral density. We have not seen any clinically meaningful or statistically significant changes on either BMD or bone biomarkers. Other FGF21s have seen those, whether it is on bone biomarkers or most recently on BMD changes in the F4 population where the competing drug showed over two years a 7% change. That is a clinically meaningful change. Can it be managed? Yes. If it is competitive and there are two options, physicians are going to lean towards the one with a better safety profile. I think that is a key point of difference, safety tolerability. The last one I'm going to bring up is the dosing and the product formulation. Our drug is being developed once a week and once every two weeks. Efruxifermin is once a week. From a patient perspective, that's a meaningful difference. To have 26 less injections if the every two weeks works would be very meaningful. Interestingly, from a physician perspective, with physicians actually like they go, we are really glad that you have multiple dosing regimens because they can decide based on the profile of their patients which regimen to use. Tied to the formulation, an important point to note is, which could be a very significant differentiator, we are a liquid product in a prefilled syringe. Essentially, it'll be shipped that way. The patient just injects. Efruxifermin is a lyophilized product, so it's got to be reconstituted before you inject. Now, per se, you can do that. It's typically less convenient. The important thing is, because we are a liquid product, we have a potential to co-formulate it with a GLP-1. We think this could be a very interesting lifecycle management because a lot of these patients, we believe, could be on GLP-1s. We have shown added benefits on top of GLP-1s, and mechanistically, Andrea, they work way differently. There could be a lot of synergies. We think if we were able to develop, and we are already thinking through this, working on a co-formulated product, it could be a very interesting differentiation. I think that's kind of the puts and takes on what's different. I will close by saying, if FGF21 delivers on the promise, which we do believe it will, I think this market's going to be so big for FGF21. It's in the billions of dollars. There can be more than one successful product. You've seen that in GLP-1s. Look at immunology space, you know there's a lot of spaces where there's multiple successful products. We think pegozafermin has the best in class potential here. These differences that you've spoken about, what do you attribute that to? We think a lot of the ones on safety tolerability is probably driven based on the structure of our molecule, so relative to the others. We are a glycopegylated version of FGF21. That is how we have extended the half-life. Others have used different technologies, and others have used—in the two who are in development—are fusion proteins. One speculation is, because the structure is different, it results in a different tissue distribution, and that could be activating different receptors, resulting in a slightly different safety and tolerability profile. GI events have been observed with all the FGF21. I think there have been six or seven in development over the last decade. It is not that you would not expect them, but the rates the pegylated molecules see are in the teens versus the fusion proteins see them in the 30% range for nausea, for example. We think it's more based on the different structures of the molecule. And then on the formulation, the difference is, I think we were able to work with a really good company who does formulation development and develop a liquid formulation. It's pretty rare today where you see people launching with a lyophilized product. You know, I think that's more, and it just might have been the chemical properties of our molecule. It's a stable pH. It's a neutral pH, which allowed us to do it. Got it. You know, maybe just one more point here on the bone mineral density loss that has been observed. What gives you the confidence that with additional dosing, with additional time on treatment, that you won't see that signal emerge? Here's why we feel confident. I'll caveat by saying we don't know what happens two and five years out. That's why we're going to study it in longer term. Here's why we feel we have a level of confidence based on the data we have today. Just to remind our listeners is we have data through week 48. The important thing is we looked at DEXA, but we also looked at multiple bone biomarkers, the P1NP, which is formation, CTX, which is resorption, and osteocalcin. We didn't see on any of these four, so the three bone biomarkers or DEXA, and we did DEXA at hip, femoral neck, which is the most important, and then spine, which is the most sensitive. Now you're looking across six different measures, and we are not seeing anything which is jumping out either clinically meaningful or statistically. When we talk to some of the bone experts, because we take this very seriously, right? We want to understand our drug. They go, look, 48 weeks might not be long enough. You might want to go longer. If you were to see a trend, you would have started seeing it by week 48. We did all these six at week 24. We did all these six at week 48. That is kind of why we feel confident that we are not seeing something which is going to end up being clinically meaningful. Maybe to that point, what is considered clinically meaningful? On DEXA, they would say like a 2%, higher than 2% annually on femoral neck. Femoral neck is the most important one because that's kind of at the end of the day what results most likely in fragile fractures. DEXA, as we all know, like it's BMD is a biomarker for suggesting what's your risk of fractures because that's what really matters, right? That they would say, you know, 2%, 2.5%. It's not that it cannot be treated because you can manage it. On bone biomarkers, the variability is much higher. They would say 25%-50% change is meaningful, right? And like we've published our data at week 24. It's in the New England Supplement, but that's what they would say is clinically meaningful. For the first time when they saw the 7% change on efruxifermin in the F4, I think some of the experts started saying, okay, I need to pay attention to that. Previously, when it was 1% and 2%, they were like, you know. Talk to us about the risk that this population has to being osteopenic. Interestingly, when we looked at our baseline, they're actually at a lower risk. Most of these patients, when you look at their T-scores, they're not even close to being osteopenic. It's typically -1 and then osteoporotic. We do exclude osteoporotics, which is - 2.5. Their risk is pretty low. Most of these obese patients, they actually, from a bone perspective, they're structurally pretty strong. The risk per se is not as great. I'll go back to even in a situation where it was to be observed, the benefit risk, I would argue, works in favor of the drug, right? Let's take cirrhotic patient population. We also did what's called the FRAX score, where you look at the 10-year fracture risk. It's a very standard scale used across multiple therapeutic areas, multiple drug classes. The threshold there, for femoral neck, is a 3% threshold. We were 0.3%-0.7%. Placebo was 0.3%, right? You contrast that with if I can reverse someone's cirrhosis, the benefit risk is clearly in favor of the drug. Got it. Of course. Maybe talk to us about your phase III program here in ENLIGHTEN-Fibrosis and ENLIGHTEN-Cirrhosis. Where do those trials stand right now? Sure. ENLIGHTEN- Fibrosis is the F2-F3 study. It's a study in approximately a little over 1,000 patients where we are looking at a histology endpoint at the end of week 52, one year, and then we continue patients for outcomes. It's a subsample of the 1,000 patients where we are looking at histology. Started the study in first quarter of 2024. It's a global study. We estimate somewhere between 250-300 sites will be at the end of the day. Most of the sites are activated. A lot of enthusiasm. Screening has gone outstanding. The PIs are really excited about our protocol, the construct of the protocol, the burden on patients. Enrollment is going where we think it should be tracking towards. Based on that, we still feel pretty comfortable with our guidance that we will have the histology data in the first half of 2027. Okay. The cirrhosis study, which we're incredibly excited about. This is a study where we are studying the high dose, 30 mg once a week in compensated cirrhotics, roughly 750 patients. In a subsample of that patient population, we will do histology at the end of two years. If we have positive data there, we have in writing approval from the regulatory agencies, both FDA and EMA. We can file for accelerated approval. That study is in approximately 250 sites. Most of the sites have got activated. Here, the PIs are really, really excited. It is kind of sad in one way. There are a lot of these patients. Like we did not know how enrollment is going to go. Enrollment is going very, it is pretty much on track where we were hoping to see. Why they like our protocol is the burden of the protocol is very manageable. That's a big deal relative to some of our competing trials, protocols in F4. In what way? A lot of, you know, when patients, when the PI has an option, it's like, what's your site visits? What are you asking to take? Are patients getting the drug at home? How are you handling that? Because they know patients need to be in these studies for four and five years. If I have an option as a PI between study A, B, and C, as long as there's not that much difference in the efficacy, what I believe in, they tend to gravitate towards the one which is the best for them and their patients, importantly, to ensure the patients stay compliant. Andrea, this ties to the other one. The reason they like our study is they feel our drug is the best tolerated drug. They know that these patients have to stay in the study for four and five years. If it's not a well-tolerated drug, they actually have very limited incentive to put a patient on the drug because they know patients are going to drop out. They do not like it. The sponsor gets upset. Like, that is going really well. Enrollment there is, again, as I said, on track, and we feel very confident we will have the two-year histology data, excuse me, in 2028. How has enrollment been impacted by the availability of Rezdiffra? And how are you controlling or maybe managing or stratifying for patients who might be Rezdiffra experienced? To date, we've not had any impact with Rezdiffra approval. Some sites have said, look, we do inform the patients that there is an approved drug, or you can be in this clinical study. Interestingly, they say a lot of patients are very happy to be in the clinical study. I think part is probably a function of the benefit which Rezdiffra offers. Part sometimes says they can't get Rezdiffra, might not be covered by their plan or something. Again, this is a U.S. phenomenon. The rest of the world, Rezdiffra is approved, so it really does not impact it. Over time, could that change as Rezdiffra gets more extensively used? It potentially could. We will allow patients who are on stable dose of Rezdiffra to enter the study. Okay, so we will allow that, just like we're allowing patients who are on stable dose of GLP-1s to come into the study. At this point, we're not planning to stratify for Rezdiffra. We don't expect that many patients will be in. For GLP-1s, we are stratifying to make sure there's no imbalance. Again, because Rezdiffra, by the time we expect to finish enrollment, maybe Rezdiffra gets approved in Europe by then, but we don't think it's going to be that big a deal and rest of the world not so. Over half our study is going to be enrolled in rest of the world. Maybe as you think about where Rezdiffra will be at the time that pegozafermin could be on the market, how important is it then to look at that cohort of patients who are experienced or are on that stable background of Rezdiffra so that physicians know how to utilize both drugs together? We do think that is important from a commercial perspective. Educate physicians. I think that between now and when we get approved, as Rezdiffra's utilization gets more extensive, it might behoove to do some kind of small studies to understand that. Now, we do believe because mechanistically, the way thyroid hormone beta works and FGF21 works is very distinctive. And just like we've shown benefit on top of GLP-1s, we expect we should see benefit on top of Rezdiffra. It could be a very interesting, you know, study to do so that you've generated data at the time of approval and launch purely from a commercial perspective as distinct from a regulatory perspective. Got it. As you think about these two trials that you have ongoing, anything you can share here in terms of the powering assumptions, the effect size, how are you thinking about really structuring the study so that you can pull out the signal that you're looking for? Sure. Just on the fibrosis study, maybe we can start there. The histology portion, the way we've powered it is there is extensive data on what a placebo response can be. We know what our drug response was. We showed a placebo-adjusted delta of 20%. Look, experts will say anything above 15% is great, meaning Rezdiffra was 10%-12%, sema is 14%. Anything above 15% is good. We've taken what we think is the placebo response, a lot of history. In phase III, you ideally power at 90%, right? Minimum you'll go is 85%. There are companies who do 80%. To To me, that's taking too much risk in a phase III. That's how we've powered that. Now, the outcomes portion of the F2-F3, it's event-based. We have a pretty good, and most of the events in that study will be progression to cirrhosis. Again, there is, I would not say great, but there is enough data from other studies on rates of progression to cirrhosis to give you a sense of what your placebo response will be. We know in our study in six months in the F3 population, we had 19% of placebo patients progressed versus 9% of ours. You pick a hazard ratio. What we have done is what we publicly said is we have gone middle of the road on hazard ratios. We have not given an exact number, but we have not gone incredibly aggressive like a 0.5 or very conservative like a 0.8. It is more in that 0.6-0.7, but in that range, right? You back into how many events you need. That is how we have powered that study. Again, very similar powering assumptions, the 85%-90%. The F4 study, the methodology is roughly the same. Histology, we've looked at placebo responses. There are studies with placebo responses, symmetry data from Akero. That was on the higher end. The placebo was 15%. If you look at some of the Gilead studies, slightly shorter duration, they would tend to be in the lower teens. There, the clinically meaningful benefit physicians would expect is slightly lower. They would say clinically meaningful is 10%, 15% is great. Anything about 20% is exceptional. We use that to power how big the cohort needs to be for histology. The outcomes, as you might collect, we have worked with the FDA and EMA on how outcomes will be defined. The primary outcomes in F4 is decompensation events. If you look at the guidance document from FDA, the placebo rate is pretty low. It's about 3% for those outcome events. If you look at the NASH CRN database, that would make the study either you've got to do thousands of patients or it would be really long to get to your events. We worked with the FDA to redefine how those decompensation events are evaluated and to bring them a little bit forward in the progress. Based on that, we expect the events to come in more sooner. We think we should see those events, but we'll be the first ones to see it. There is published literature on how those events come in. We used what the placebo response would be, hazard ratio, as I said, between 0.6 and 7. That's how we've powered the study. What are these events? Have you shared specifically? Yeah. So what we've, so there's three, primarily there's three decompensation events. It's ascites, it's varices, and it's hepatic encephalopathy. The classic definition of them, I'll just pick one, varices for example. If you look at the guidance document, it says it's got to be a bleeding varice. For a cirrhotic patient to get there, it typically could be 8 years-10 years. And honestly, once you have a bleeding varice, it's about a 6 months-12 months to liver transplant or mortality kind of. But no one goes from, so if you, that's when I quoted the 3% rate, that's if you use that definition. But no one goes from no varices to a bleeding varice, right? You start with whale signs, small varices, large varices. So it's a progression. What we worked with the FDA to say, look, bleeding varices, that is so far down, that does not make sense. People are decompensated before they are, you know, they have a vein which has exploded and they are throwing up blood, right? The FDA agreed with us. We are bringing that forward. It is in the progression of varices. For comparative reasons, we have not disclosed exactly it, but that will give you a construct. Similarly, like it is ascites, you know, ascites can be all the way from I have got 10 ml of fluid to I have got 500 ml and I need paracentesis or I have bacterial infection. Again, it is a spectrum. We have kind of brought it forward. That is all. Got it. When you think about the 2018 guideline for NASH, cirrhotic NASH, and the path to being able to secure approval, there's been very much a focus on clinical hard outcomes here. Yet the FDA has, you've aligned with the FDA on the use of a biopsy endpoint. What do you attribute that, that shift in thinking from the agency? I think three things I would say. One is more general to the guidance document and then more specific to our drug. I think when those guidelines were put out, they were relying on data, which was probably from 2015, 2016. There was not a lot of data. I can see them saying, I have no idea how to evaluate this. Okay. Since then, there have been some F4 studies. Now what did, why did, why do we think we got the approval? We built a strong scientific argument based on data that if you reverse someone from F4 to F3, and you look at the Kaplan-Meier curves, there is a benefit on outcomes. Our whole basis was scientifically that would make sense. Now, why do we think, I'm going back to our end of phase two meeting, why do we think they gave us that leeway? From their perspective, the FDA's perspective is, I want to approve someone on accelerated approval if I have a high level of confidence that it's going to work on outcomes. If you put yourself in their shoes, the last thing they want to do is approve something on accelerated approval and then outcomes is not going to work and they have to pull the product off the market. They looked at our data and their medical reviewers were caught, they had a high level of confidence that if we show benefit on histology and accelerated approval, we will show a benefit on outcome. That might not apply for every other drug. As we understand, other mechanisms have gone there and the FDA has not agreed. I don't know which ones, but so that's, I think, one big one, Andrea. They felt very confident that if with pegozafermin, based on the data we've generated, that if we were to reverse the cirrhosis, it will translate to outcomes. I think the second thing which they were very interested in our conversation was benefit risk. And this was both in F2, F3, but also in F4. They felt the benefit risk with our molecules supports bringing this product to market, were we to show a histology benefit. I think that's the conversation. I think part was scientific grounded in new data. You know, there's a publication in 2021, which we leveraged. This after the guidance came out, which shows that there is a difference in outcome survival, mortality between F3 and F4, right? And it's pretty clear. It's pretty broad when you look at the curves. You referenced the commercial opportunity here. How do you think pegozafermin fits into the treatment landscape in NASH? Yeah. We think the sweet spot for pegozafermin is the advanced fibrosis patient. We think, let's start with the extreme end. We think in compensated cirrhotics, we think pegozafermin could have a very dominant position. In our market research, FGF21 is expected to dominate that space. Again, this is all pending positive data. We would get within the FGF21 space more than 50% of the market based on a better safety and tolerability profile. There are two other mechanisms that are studying F4, but based on the data generated to date, it looks like FGF21 will get a disproportionate share of that market. We do think there is a large market opportunity for pegozafermin in that advanced fibrosis patient. This is bridging fibrosis F3. Many of those patients probably would have already gone through a metabolic drug, but they yet have advanced fibrosis. The objective in that patient population, the treatment objective is prevent progression to cirrhosis. As distinct from someone who's early in NASH, the treatment objective might be just resolved steatohepatitis. If your goal is prevent progression to fibrosis, they're going to look for the most potent antifibrotic. As a class, FGF21 sees the best data and we've shown really good data. We think that's the sweet spot. This is millions of patients in that advanced fibrosis and cirrhotic population who would be the target. In real world, we all know no one's doing a biopsy to beautifully say this is F3 versus F4 or this is F2. There will be spillover effect. People will use it across the spectrum of F2, F3. Again, we think our positioning is going to be more advanced fibrosis patients. We think that allows us to get a higher pricing relative to, we think the GLP-1s are going to play a very dominant position in that earlier treatment paradigm. We think, I should also mention in our research, we expect about in the F3 patients, about half our utilization would be monotherapy, half on top of GLP-1s. In the cirrhosis market, where GLP-1s are not used extensively, we think over two thirds will be monotherapy. Maybe to that point in terms of the combination with GLP-1, and you referenced earlier, your formulation does enable you to do a co-formulation essentially. Where do you stand with that work? We are currently doing all, we've got, we feel comfortable we've developed formulations which look sufficiently stable. The next stage would be to finish all that work and then actually test it probably in clinic to make sure that, you know, look, we're also looking forward to seeing what the Novo data looks like with zalfermin. Albeit, zalfermin's not as potent. We don't think it's as potent or well tolerated FGF21 like ours, but I think that would be informative because it would be another data set to suggest, you know. Again, in the Novo study, they're yet being given a separate injection. We would have to study the co-formulation in a clinical setting just to make sure that there's nothing else which gets funky. Because when you're developing it, what you're trying to do is when you generate the co-formulation, you want to see there is no hindrance against key receptors. Most importantly, that the two moieties are stable in themselves. Rohan, thank you so much. Thank you everyone for joining us. Awesome. Thanks for the time. Thanks. Appreciate it.