Brian Abrams, Senior Biotech Analyst at RBC Capital Markets. Our next featured company is 89bio, represented by their CEO, Rohan. Thanks so much for joining us. Nice to be here, Brian. Thanks for having us. Thank you. Kicking Kicking things off to set the stage, there's obviously been a lot of developments in the FGF21 space. You guys have always been one of the leaders. What's the latest on some of the overall mechanistic rationale for FGF21 in MASH? Maybe remind us some of the data for early drug dosing that's validated its potential to be a player in the MASH space. Yeah. I think it's important when you think about MASH and the mechanism FGF21 plays is, what is MASH, right? While it is a liver disorder, at its core, it's a metabolic dysregulation. When you think about any mechanism which is going to be highly effective in MASH, you want something that is addressing what's happening in the liver, which is the liver fat, which gets inflamed, becomes fibrotic, and worst case, cirrhosis, but also the underlying metabolic dysregulation. This is where FGF21 is unique relative to the other mechanisms being developed. FGF21 is an endogenous metabolic hormone that controls energy, lipid, carbohydrate metabolism, but then importantly, also has direct effects on the liver, where it has an independent pathway to address fibrosis in the liver. Think about it, we're addressing the metabolic pathway, but we are also hitting the liver directly based on receptors which are on the liver. If I contrast this with, say, GLP-1s, where there are no GLP-1 receptors in the liver, and so everything works through the periphery, FGF21 is unique in that way. We see that in our study results. With pegozafermin, which is an FGF21 analog, which we engineered to extend the half-life while retaining the potency of the molecule, we conducted a pretty large phase IIB study, 220 patients, and we saw really robust changes on key liver histology markers, so reduction in fibrosis stage, as well as MASH resolution. When you look at the competitive data set, recently there was a paper in histology which came out, which compared 29 different trials, and it looked at fibrosis changes as well as MASH resolution. Pegozafermin really stood out. That is kind of one of the reasons we have a high level of confidence in our studies that we should see good data in our phase III studies. In addition to what we saw in the liver, we saw really good changes across various metabolic markers, so whether it is liver fat, whether it is ALT, as well as lipid changes. Got it. There have been developments as well of late for some of your peers in the space. Now that you've had time to digest some of the recent data from AASLD, from one of the other FGF21s, efruxifermin, in both F4 patients over 96 weeks, and then I think some of their longer-term data in the non-cirrhotic patients as well. What's your latest thinking about the role of pegozafermin and of FGF21s overall in this F4, this really severe population? Is there anything that you're, any learnings from the data as it continues to roll out that's influencing how you're thinking about the future strategy for your drug? Sure. I think the data presented at AASLD with efruxifermin in F4 is another validation of the potential which FGF21 has in this patient population, who's a patient population with the highest unmet need, and arguably once upon a time was thought the most difficult population to treat. We all know once you're cirrhotic, currently there's no approved drugs. In some ways for the patient, it's kind of a downhill journey. There was always a belief that once you become cirrhotic, you cannot reverse cirrhosis. With FGF21 analogs, we've always believed you could do it. We had shown it in a small data set that over 45% of our patients saw a reversal of cirrhosis with no worsening of MASH. If you look at the absolute numbers of who improved their fibrosis stage from F4 to F3, we had literally over three quarters of those patients. We had always believed it in the small data set. I think the efruxifermin data set, which is a much larger data set, really showed the power of FGF21 over a long treatment period on reversal of fibrosis. We think this is incredibly encouraging for the field because it is going to be transformational for patients if this bears out in a phase III study. I think the data which was presented also showed that it applies and it worked across the broad spectrum of cirrhotic patients, right? When you think about cirrhosis, it is not one exact patient, right? It is a broad spectrum of patients who have cirrhosis. I think the other thing which is important to note, which we had already factored into our study, is when you're treating F4 patients, you got to have the study run long enough to allow the drug enough time to make a difference. You saw this in the study that over 24 months of treatment, you saw the benefit. In the short term, when they had looked at the data at nine months, the benefit was not that as profound. We've always believed that. The way we've set up our phase III study, which is an ongoing study, is we're going to do a repeat biopsy at the end of 24 months, which gives you enough time for the liver to reheal. You're trying to reduce the injury and insult to the liver brand, and then you're giving the liver enough time to heal. This is important in F4 because the fibrotic matrix these patients have is really dense. They did not get there overnight. It took them like 15-20 years to get there. You have to give the drug enough time to work. That is why we have set up our study in such a manner that we treat these patients for two years, then do a repeat biopsy, and hopefully we will show a reversal of fibrosis. What is really important is we were able to work with the regulatory agencies. To the best of our knowledge, we are the only company today who has publicly disclosed that if you show a reversal of fibrosis in this F4 patient population, we could file for accelerated approval in the U.S. and conditional approval in Europe. This is important because it reduces the time to bring this important therapy to market for these patients. What's your level of confidence that the regulatory path will be the same versus maybe even more accelerated versus maybe any changes, given some of the changes at the FDA? Yeah, it's tough to speculate where the agency might go. I think here's what we can say is we have in writing from the FDA that if we were to show a reversal of fibrosis, we could file for accelerated approval, similarly in the EU, right? We do know that. Subsequently, we've had multiple conversations with the agency. They've obviously signed off on the protocol, including under the new administration. We've had discussions with the agency on our protocol. They've sent us requests for information. We feel at this point in time, we feel pretty confident that things don't change. This is a study which is going to read out in 2028. That's a long horizon, right? Three years, things could change. My belief is the agency recognizes that the F4 patient population is in dire need for new therapies, right? These patients have really bad outcomes. When you're cirrhotic, it's not a good place to be in. I think our relationship with them has been, because we have breakthrough designation in Europe, we have PRIME designation, is let's work with the sponsor to actually bring effective therapies to market. Can you talk a little bit about the, I guess, how that study enrollment is going right now from the ENLIGHTENED Cirrhosis F4 study and just anything you could say on the powering for the, I guess, for both the histology and the outcomes endpoints? Sure. Just to remind the listeners, the F4 study is a study in approximately 750 patients where we are bringing in compensated cirrhotics, and it has two stages to the study. There is one stage, which is the histology portion of it, where we will enroll these patients, and after two years, we will do a repeat biopsy, and that would support an approval for accelerated approval if we see a reversal of fibrosis. We will continue those patients onto outcomes, but we will also add additional patients for outcomes because at the end of the day, to get full approval for the drug, you have to show outcomes. The outcomes are predominantly decompensation events. There are other things like mortality, liver transplant, but it is predominantly decompensation events. It is important to note that we worked with the regulators in how we define the decompensation events, right? The way the current guidance document is written, Brian, it's really late in the decompensation paradigm, and it would take a really long time to get to those events. What we worked with the agency is to accelerate that earlier in the progression to decompensation to count as an event. For example, when you think one of the decompensation events is varices, and the way it's defined is variceal bleeds. No one goes from no varices to variceal bleeds. That takes multiple years. Honestly, if you have a bleeding varix, you've got 6 to 12 months, right? The agency recognizes that. You go from no varices to small varices to large varices before it gets so engorged that it's bleeding, right? That's how we have kind of designed the study in a manner which makes it tractable and to get to events in a reasonable time period. That's important to note. To answer your question, on the enrollment, the study is being done globally. It's approximately 225-250 sites. Pretty much all the sites have come up, have been initiated, and the enthusiasm for the study has exceeded our expectations, which kind of is tragic from a patient perspective, suggesting there's a lot of these patients. The PIs are really excited about the opportunity that there is something for the F4 patients. The data which FGF21s have shown is the most promising. Two weeks ago, I was at ESAL, had a chance to meet a lot of our investigators at a reception we did. This study is something they were looking forward to. Any views on how long it may take some of these outcomes measures, even with some of the modifications you're making to accelerate or to improve the sensitivity there, just based on, I guess, the long-term data we saw from your peer recently, where I guess we didn't quite at two years start to see some of those potential signals, but maybe with some of the measures you're looking at, maybe you would have seen them. I don't know. What's your view on that? It's a great question. I think the challenge here is no one's really done an outcome study, right? We are relying a little bit on the historical databases. There's a database called the NASH CRN, which looked at longitudinally how events have occurred in the F4 patient population. If you look at that database, the event rate for decompensation events as defined by the guidance document is maybe 3% or 4%, 3%. This is in a placebo patient, right? Because a bulk of the agents were being placebos. We anticipate the way we've defined it, it could be in the double digits, okay? If you look at a publication or presentation from AASLD three years ago where they've looked at the events earlier in the time horizon, they actually have the rate closer to the high teens. We've obviously not gone that aggressive in the powering of our study. So we've had to make some assumptions on it. I think there's one important point to note in the competitive data set where, as you mentioned, there are very few events in two years. One of the things in F4 studies is the decompensation events is not linear. It tends to start slowly and then becomes parabolic, right? Because when you're well compensated, in the first couple of years of being well compensated, you're not expecting a lot of decompensation events. After three or four years, it accelerates. The way we are structuring our study is it's two cohorts. One cohort is the more well compensated patients who will be part of the histology database, sorry, histology outcome, histology endpoint. We are kind of supplementing it with patients who are further along in clinically significant portal hypertension to drive more events. That makes a lot of sense. Maybe you can kind of remind us how the or talk about how the F2, F3 study is going. I know that's another important pivotal initiative. How's the conduct been for F2, F3s? What are you seeing there on the ground in terms of are you seeing a comparable level of enthusiasm? What's kind of your latest view on how the results from that study coupled with the histology two-year data from the F4s, how does that all play together for what you might expect as an initial kind of approval indication and label? Sure. A bunch of questions in that. Just to remind our listeners, the F2, F3 study is a study in a little over 1,000 patients, which are classic F2, F3. That study has two components. There is one cohort where we will do a repeat biopsy after one year, which will look at histology. That would look at the classic endpoints of fibrosis improvement and MASH resolution and if that will. [audio distortion] We are a glycoPEGylated version. The efruxifermin is a fusion protein. The Boston molecule is a fusion protein. Whether the structure results in a different tissue distribution. PEGylated molecules do tend to get directed more towards the liver, which might not be impacting some of the bone stuff. That is, but it is speculative, right? You do see the PEGylated molecules are not seeing something, but some of the others aren't seeing something. I know we only have a minute and a half left. Just maybe quickly, can you, I guess, where do you guys stand with regards to manufacturing now? I know you have some manufacturing capacity in China. How are you guys potentially impacted by the tariffs? What's your flexibility on manufacturing for Rohan? Sure. It's a little bit of a moving target, right? You're right. Currently, we manufacture all our product in Europe for our clinical studies. We have, for commercial reasons, scaled up manufacturing in China with a CDMO who has a large scale reactor, which is the volumes we need for commercial. We're continuing to do that. Currently now, the tariffs have dropped pretty significantly. We also have the opportunity to go back to our European vendor to scale up manufacturing there. Another option to address the tariffs is we could do our, what I'm going to call, API. Think about it. FGF21, which is the API in China, but then actually do the substantial transformation of glycopegylation in Europe at multiple different vendors. That's a path we're doing. That might address some of the tariff issues because the actual transformation in creating pegozafermin will take place in Europe. An important point to note, which our drug product has always been made in the US. And we will continue making that in the US. You create pegozafermin, but then you actually create the drug product, which is putting it in the vial in a formulation. That is all being done in the US. We think we are, I will never say we are 100% insulated from how policy changes take place, but we feel pretty good. Yeah. Good. With that, we've got to wrap up. Rohan, thanks so much. Great to see you. Thank you very much.