All right, let's go ahead and get started. Good afternoon, everyone. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name is Tom Smith. I'm one of the senior biotech analysts here at Leerink. It's my pleasure to welcome our next company to the stage, 89bio. Happy to be joined up here by CEO Rohan Palekar. Rohan, thanks for joining us. Thanks for having us, Tom. An extremely exciting time in the space for MASH therapeutics. We have an ongoing launch, first approved, commercialized therapeutic. In particular, exciting time, I think, for the FGF21 class, where we've recently seen some really exciting, validating data in a very difficult-to-treat patient subset. Rohan, maybe you could just kind of kick us off here for those in the audience who may be a little less familiar with the 89bio story, and then we can hop into Q&A. Sure. 89bio is a late-stage clinical development company focused on MASH and liver and cardiometabolic diseases. Our lead program is pegozafermin, which is an FGF21 analog, which we are developing in two distinct indications, both which we believe have multibillion-dollar potential. We are in MASH with two significant global phase 3 studies, which are currently enrolling. In severe hypertriglyceridemia, we have a phase 3 study, which has completed enrollment. We expect results from that in the first quarter of next year. As a mechanism, we think FGF21 has the potential to be transformational in these indications. Based on the phase 2 data, we are really optimistic about the potential for pegozafermin here. It's a biologic agent. We give it every week or every two weeks. In the case of the MASH program, we are also studying an every two-week dosing interval, which we think offers something unique. I will hit on, because I'm sure you're going to have the question where we are on from a cash perspective. We ended December with $440 million. In January, we raised another $287 million in gross proceeds. This gives us a really good runway through our next two key catalyst events, which is the readout in the phase 3 program in SHTG and the readout in our F2-F3 MASH study, the histology readout. Great. Helpful overview. I want to start with the recent positive data we saw for the FGF21 class in compensated cirrhotic MASH, 96 weeks of treatment with efruxifermin, statistically significant, clinically meaningful delta. Up to 39% of patients experienced a one-stage improvement in fibrosis, essentially a reversal of cirrhosis. Rohan, maybe you could just talk through how meaningful and how validating is this for the FGF21 class? How do you think this positions the class and pegozafermin within the broader landscape of MASH treatments? Yes. Tom, we think it was a great data set from efruxifermin, right? As we all know, F4 is the toughest to treat population. It has been a graveyard for drug development. Many drugs have failed. We always believed that FGF21 could really be transformational for these patients. I think this data really bears out that FGF21 is going to be able to reverse fibrosis or reverse cirrhosis in this patient population, something even the experts thought was a high bar. I say that because the data was pretty unequivocal that FGF21 can work. It was not just like on one endpoint you hit. It was across the entire magnitude of different endpoints. You saw really good data. We think there is a very clear read-through from this to our phase 3 study in F4. I say this for a couple of reasons. The mechanism of FGF21 looks incredibly promising. Second is the dose we are studying is equivalent to the dose which was studied in this study. We are studying a 30 milligram given once a week. Efruxifermin studied 50 milligram given once a week. We believe these doses are very, very comparable based on a lot of other data we have. We think we have picked the right duration for our phase 3 study. We have a study which is a 2 year study. This data set showed that at two years, you can reverse fibrosis in the cirrhotic population. We think it is incredibly exciting to see this data. Obviously, we are looking for more additional data, right, as they tease it out. On first glance, based on the top-line results, it actually bodes well, not just for pegozafermin, but for the field in general and for these patients who have F4 disease. Yeah, agreed. We expect they have not committed to this, but we expect this will probably be a late-breaker at EASL. In terms of those additional data points that you're hoping to see, I guess, what are you most interested in from the 96-week SYMMETRY study? Yeah, so I think there's a couple of things which would be helpful to provide greater color to the trial they did, right? I think if there was data providing a little bit more clarity on whether there were particular patients who responded better versus other patients, I think that could be incredibly helpful. Like how progressed were they towards decompensation? I think another one which would be interesting is they did not see many decompensation events, which I think we were a little surprised with that. We would have thought in two years. I think understanding that would be helpful because we've kind of got a target patient we are enrolling. We've made certain assumptions on decompensation rates. As we've powered our study, it would be great to validate those assumptions. Like on the histology component, we're feeling really good with the assumptions we made, right? Based on the 24% delta, even if I don't go that high, we are well-powered on the histology component. I think some of these would be helpful. I think the other one which would be really important to learn is a little bit more clarity on their bone marker findings. We think this is an important distinguishing factor, right? They've talked about they saw a 5% change in bone mineral density. In our studies to date, we have not seen anything statistically meaningful or clinically meaningful changes on bone biomarkers. In an F4 population, this becomes important because a lot of these patients are sarcopenic. I think just understanding that a little bit more can help us tweak our study if we need to. Maybe we don't need to, but I think this would be important. Yeah, that makes sense to me. You have alluded to historically the ability to tweak enlightened cirrhosis, I think largely probably based on the findings from symmetry. Are there any changes planned at the moment or you feel confident in the way that you have kind of designed and the early execution on that? Sure. Just to remind the audience, our F4 study, which we call ENLIGHTEN- Cirrhosis, is a study which has two components. It has a histology cohort, which are well-compensated cirrhotics. We have a group which we will continue to enroll, which is the outcomes cohort. The histology cohort will be studied at the end of two years. We will look at the histology response, which is a 1 stage improvement in fibrosis. We continue all those patients for outcomes. Upon the histology readout, we hope if we have positive data, we plan to file for accelerated approval in the U.S. and conditional approval in Europe. We have got a lot of questions. Has the FDA and EMA bought into this? Yes, the answer is we've got confirmation from both the regulatory bodies that if we were to show a 1 point change in fibrosis or greater, we can file for accelerated approval or conditional approval. We have to continue all those patients for outcomes, right? I think, Tom, what we are looking at is obviously we wanted a validation that the histology cohort is well-powered. We feel very good about the powering assumptions we made. We were very conservative in our powering assumptions. Based on what SYMMETRY showed, we feel pretty confident there. The question comes is the outcomes component, right? One of the things, and this goes back to my point, is looking at what were their decompensation events, how did they do it? We have done something unique in our trial design where we got alignment with the regulators on how outcomes are defined. In the classic definition of decompensation events, which the FDA has, it's a pretty high bar. They are extreme events. We worked with the agency to redefine those events to bring them earlier in the progression. Because otherwise, these studies are not tractable. To get the number of events you need in the outcome study, you would have to enroll tens of thousands of patients, right? We have always said we a priori in the protocol, we have said we can do a sample size re-estimation based on how the events accrue. To answer your question, based on what we've seen to date, there's no reason to change something. I think as we get more data from SYMMETRY, if they present it or there's a publication, we have that flexibility to tweak it. Yeah, that makes sense. OK. And just on enlightened cirrhosis, what can you tell us about enrollment into the study in the early days? And have you seen any inflection kind of post-SYMMETRY? I know we're still very much in the wake of SYMMETRY, but have you seen any notable uptick? Answer is yes and yes. The first part is we've been pleasantly surprised with the excitement the PIs have had and in the screening in the study. This was even before SYMMETRY read out. The reason we were a little cautious is we didn't know how many of these F4 patients are being seen in these offices. Clearly, there was incredible enthusiasm, and we saw incredible screening. After the data has come out, that has actually accelerated the people coming into the funnel. Now, it's early to tell that, in fact, all of those patients have F4, and do they go through their biopsies and go through all the screening procedures? Clearly, a lot of the PIs, at least in the US, were aware of the data or have been made aware of the data. My sense is Akero is also probably seeing a lift in the screening. OUS is still early. Our OUS sites are just coming up. Again, based on what we are hearing from the investigators, and we have some additional investigator meetings, a lot of enthusiasm for this study. That's great. That's why we felt pretty good when we put out our guidance that we'll expect the 2 year histology results in 2028. Got it. OK. One of the questions we get, I think, most often from investors is in comparing the potency between efruxifermin and pegozafermin. You alluded to this, having a number of data sets where you feel comfortable that 30 mg weekly pegozafermin is equivalent to 50 mg efruxifermin weekly. Maybe just highlight, I guess, what is the most compelling data set you think you have that proves that out and gives you confidence that your potency is roughly equivalent when we think about reversing fibrosis? I think the most compelling is honestly clinical data. To me, clinical data trumps a lot of what you can do in vitro, right? Sorry, in vivo. When you look at the clinical data, and the only true comparable is the F2-F3 studies, which were very similar, similar patient population. We saw very similar changes in the fibrosis delta, right, on an absolute basis. On a relative risk basis, we actually see much stronger numbers than efruxifermin saw at 50 mg versus our 30. In fact, there is a recent hepatology paper which just came out. It is a meta-analysis. I think it looks at 29 NASH studies in phase 2 and phase 3. The authors say pegozafermin has shown the most potent fibrosis benefit. That is on the clinical, I would argue. On the preclinical, I will highlight two things. One is both companies have done potency against the key FGFR receptors. That's 1C, 2C, and 3C. You look at our EC50s, they look very comparable. When you compare the EC50s on binding to these relative to native FGF21, we look very similar. The last one, which is I think a little bit, Tom, where the confusion comes is we are 30 mg, they are 50 mg. Are we just giving less of a drug? I think you have to look at what is the size of the molecule, the molecular weight, the PK properties. What is the moles delivered? Their molecular weight is nearly two and a half times ours. We are 40 kilodalton. They are a 92 kilodalton molecule. Our PKs are somewhat similar. When you put that and you look at the number of FGF21 moles delivered, which is the active protein, it's very comparable. Arguably, we might even be higher. I can go on. I would say these are the top three I would direct, you know, clinical data, potency, and moles of FGF21 delivered. Got it. Great. Looking ahead, I think the next kind of novel FGF21 readout that we're looking for comes from Novo. They have a combination study with their FGF21's alfermin, looking plus or minus with SEMA. I guess, what are your expectations? We could see those data imminently, potentially. It's an F2-F4 study. A lot of arms in that study, rather complicated design. What are your expectations for that readout? What kind of read-through do you see to pegozafermin from that study? Tom, there's not a lot we know about the alfermin, right? What we've seen is a phase I poster from about two years ago. It looks like it has activity like FGF21, but it had a lot of issues on tolerability in that study. In fact, it hit multiple MTDs and the dose being studied, right? I think, look, there's a very good chance that it should show a benefit on top of, sorry, on top of semaglutide. We've seen it with pegozafermin. Efruxifermin has seen it. I'd like to believe they should see it. Actually, look, that works well for us. It bodes well for us if they show a benefit on top of semaglutide. We've shown it, but this will be a bigger data set validating that FGF21 adds value on top of sema, right, on top of a GLP-1 for that matter. Given their tolerability profile, we think we'll still have a differentiated profile, OK? If you now fast forward, they are way behind in development. If they had to take and develop Zalfermin to bring it to market, it would be many years behind us. If I fast forward to a commercial state, now you're a physician, you've got this data showing SEMA plus FGF21 is better than SEMA by itself, you're probably going to want to combine semaglutide with the best FGF21 molecule. We like to believe that based on the profile we've seen today, pegozafermin might be the best one. I think the last thing I'm going to say is, pegozafermin is a liquid formulation in a prefilled syringe, unlike our competitor, which has a lyophilized product. Based on our formulation, we believe we have the potential to combine it with a GLP-1 in a single injection. Our PK and our pH values would suggest that is a high potential. If I think we see something good here, maybe there is some really interesting lifecycle programs we are already considering with pegozafermin. Interesting. OK. When do you think we might get some visibility on some of those lifecycle management strategies? I think we continue to do the experiments because while we think pegozafermin by itself as a monotherapy is going to be incredibly powerful, we do think there will be patients who could benefit from something like that. So stay tuned. Yeah. Yep. Makes sense. Yeah, we've always thought that this was a polypharmacy combination therapy market longer term. That makes a lot of sense to me. We want to offer physicians the option, right? You can think about other cases. Vytorin is a classic case, right? It is not like the existing drugs were not there. You offer, for some patients, I might want to use a combo product. Yep. Makes sense. OK. We've talked a lot about potency as it relates to fibrosis improvement. I guess with respect to safety tolerability, we've always felt like pegozafermin has had an edge compared to most of the rest of the FGF21 class. I guess after seeing the 96-week SYMMETRY data, maybe you could just remind us how you kind of stack up to efruxifermin on things like on-target GI adverse events, but also some you alluded to the BMD signal that they've seen. We've also historically seen some CNS effects with their compound in some of the earlier studies that maybe are dose-dependent. How do you think about we just made the argument around kind of equivalent potency, but why are they seeing some of these things? Yeah. It has been interesting. There have been seven FGF21s which have gone into the clinic, either six or seven. This goes back to the days when Lilly and Pfizer were the first two companies doing it. What's been interesting is while everyone is seeing metabolic changes, some higher, some lower, they've been somewhat consistent. However, the side effect profiles of the different molecules have been different. I think this goes back to the way different companies have re-engineered their molecules to change the half-life. Every company has tried to re-engineer a molecule because the half-life of FGF21 is less than two hours. We've done a glycopegylation. Efruxifermin did a fusion protein. Others have done a fusion protein. Some have done monoclonal antibodies. Some have done alkalizing agents, right? The reason I bring this up is we think this is part of the reason you might see slightly different AE profiles. To your point, we have consistently seen a lower GI AE profile than what efruxifermin, or for that matter, the other fusion protein has seen. For the more problematic ones, like say nausea, where they have consistently seen like in the 30% response rate, we see it in the teens. Pegozafermin, which was the other pegylated FGF21, also saw it in the teens. It is not in one study, right? When Amgen had the drug, they started with a 210 dose, dropped to 140, 70, now 50, but they continue to see that. The bone mineral density and bone biomarker findings is more recent, and it is very interesting, right? They saw about a 5% change versus placebo based on bone mineral density on DEXA scans at week 96. We've got it through week 48. Through week 48, we've seen no clinically meaningful or statistically significant changes versus placebo on either bone markers. We looked at all the three key bone markers as well as bone mineral density. We took it a step further. We did what's called the FRAX scoring, which looks at the risk of fractures over a 10-year risk. The changes, what's called a threshold, is there's a 3% threshold where you want to treat someone, typically, say, with bisphosphonates. In ours, when we project out, placebo was 0.3%, so well below. Pegozafermin was between 0.3 to 0.7%. Remember, threshold 3%, right? There is something fundamentally different. To your point, efruxifermin has seen tremors in multiple studies. We think part of this is probably due to the tissue distribution, which results in activation of different receptors. A little speculative, but clearly an Fc backbone results in certain different types of tissue distribution. Biologics, we have not done tissue distribution studies. When we have talked to many of the experts, they think that is probably the reason you are seeing a slightly different AE profile across the different molecules. Got it. That makes sense. I want to ask about the ongoing ENLIGHTEN-Fibrosis study in F2-F3 NASH. If you could just provide an update, how is enrollment in that study going to date? Have you seen any impact now that we have Rezdiffra that is commercially available? Maybe any impact from the SYMMETRY results, even though in a different setting? We are feeling good about how that study has been progressing. It started in the first half of last year. Based on that, Tom, that's why eight days ago we said we feel very good about having top-line results in the first half of 2027, OK? We've got a way to go. There is enthusiasm to do that study. I think we are in this little bit of a sweet spot just now where there's not a lot of competing. In fact, there's only one competing phase 3 study. There's not a lot of studies. In NASH studies, there is a huge funnel. It all comes down to finding the right patients who do not have screen failures, right? A lot of our international sites are just coming up. International sites historically have always done better in identifying the right patients and managing screen failures. We are feeling pretty good about how that study is progressing. It is a key focus area for us because that would be our lead study to get accelerated approval. I'm sorry, I missed the second part of your question. No, that was, if you've seen any changes post-Rezdiffra or post-SYMMETRY? OK. Rezdiffra has not, honestly, it's not coming up that much. We will be allowing patients as long as they're on stable dose of Rezdiffra. We don't hear from a lot of sites that because of Rezdiffra's approval, they are directing everyone there. There are sites who are absolutely, I think most sites are offering patients that option. We're not hearing feedback as that's a big one. As I said, over half the patients, half the subjects in our study will come in international markets where really Rezdiffra is not going to be approved. Yep. That makes sense. Yeah, I was just curious if you saw any change maybe towards the top of the funnel in terms of patients coming in. No. There's a lot of patients. Rezdiffra has got to, I think, what, 11,000 or 12,000 patients. We're talking in the U.S., there's millions of these patients. We're not hearing it to date. I'm not saying it's something we keep an eye on. Understood. With respect to dosing frequency, you alluded to the Q2 week dosing. You've got the 44 milligram arm in ENLIGHTEN- Fibrosis versus Akero and Novo, who are both weekly. There is a competitor out there that's looking at monthly dosing. How do you guys think about the importance of dosing frequency? What is a meaningful difference between weekly, Q2 week, monthly? Is the monthly differentiating? How do you think about that? Yeah. I think longer frequency is better, right? We think the delta between every two and every four weeks is not as significant, but there will be some benefit with going at the longer therapy. I think the question is, as long as it is a convenient injection and a single injection. What we've heard is the competitor in their phase 2 trial had multiple injections in their phase with the monthly dosing. If it is a painful or a large injection, which is multiple injections, that is going to turn off patients, right? We were very focused on making sure ours is a single injection, not a significant volume. Think about it, because that is a 300 milligram injection. Patients will trade off taking a more convenient, easier injection than a high-volume, painful injection. I think that is an important consideration to take. Clearly, in our research, where we really focused on weekly versus every two weeks, two-thirds of patients would prefer an every 2 week versus a weekly injection, as long as other things are equal. OK? That's an important criteria. Yep. That makes sense. OK. I want to shift gears and talk about SHTG. You have the ongoing phase 3 study on the basis of the phase 2 ENTRIGUE data. Maybe you could just remind us a little bit on the design. You recently provided an update. You're going to keep that study blinded through the full 52-week treatment period. The primary endpoint is still 26 weeks. It sounds like no material changes to study design. It's more about a length of period of time where we're keeping the study blinded. Just talk about, I guess, the regulatory feedback that went into that decision. To remind the audience, we had a phase 2 study where we studied four different doses of pegozafermin for eight weeks in patients with severe hypertriglyceridemia. This is trigs of about 500. We saw really nice data. We saw really nice data on top of existing standard of care: fish oils, fibrates, statins, everything. Based on that, we've designed the phase 3 study, a randomized double-blind control study, where we are studying two different dosing regimens of pegozafermin: 20 milligrams once a week, 30 milligrams once a week versus placebo. It is a 52-week study with a primary endpoint at week 26. The primary endpoint is the same as in the phase 2 study, which is change in triglycerides from baseline. That is an approvable endpoint for full approval. We've got that alignment with the agency. We'd always wanted to do a longer study because the agency's point has always been, we're fine with the 26-week endpoint for primary endpoint, but we want to see persistency of benefit for over a year, pretty typical for the lipid division, because they know this is a chronic state. You're going to treat for a long time period. In our recent discussions with the agency, they said, look, you can unblind at week 26, but you take the risk of introducing a bias in a study, which is a pivotal study. For one example, a bias could be as you unblind it, we unblind it, the physicians and patients remain blinded. They are now seeing what is the AE profile. I'm just using one example of why bias comes in. They see, oh, they had these kind of AEs. The next time a patient walks into the office, the physician says, oh, that's drug-related or that's treatment-related, right? You've introduced a bias. You've introduced a bias when they see the data, and now they are making an assessment of someone on placebo and encouraging them to come off the drug. We are looking at this indication as a follow-on to NASH. Strategically, we've talked about this is an SBLA. We'll file after we get NASH. We know we need a second study, which needs to be done. As long as we get the second study completed by the time we get NASH approval, which is a couple of years away, it doesn't matter whether we unblind this year or in the first quarter of next year, because we can yet get the second study completed in a timing. If NASH was not there, and this was our only indication, I think we would have, maybe we would have taken a risk of unblinding with 26 weeks. Given that we have to do a second study, we just felt, why take the risk of having a review matter come up with the FDA? We can still get the second study done in time. Honestly, why upset the FDA, right? That is the reason we did it, which was very different when we started this study. When we started this study, we did not have the NASH program. We did not have alignment on when NASH could get approved, all that stuff. Right. This actually, keeping it blinded through 52 weeks matches, I think, what other competitor phase 3 studies are doing. That's exactly. The APOC3, like for Ionis, they're doing the same thing. Their primary endpoint is week 26, but they're waiting till 52 to unblind the study. Yep. That makes sense. Just strategically, yeah, you alluded to the need for one additional study. I guess, what is the decision point for starting that study? What's the latest timing in terms of SHTG relative to NASH? Yeah. So we want to look at what the ENTRUST data is. And then maybe we want to just take one dose into the next phase 3. We think the next phase 3 would be a very similarly structured phase 3. It might be a smaller study because we might take a single dose. And the timing, the way you should think about it is we'd like to, if we see positive data from ENTRUST, rapidly start the second study and ensure that we can read out the second study by the time NASH could get approved. Got it. That sounds great. A lot of optionality, I think, around that program. Yeah, unfortunately, we're up against time. We'll have to leave it there. Rohan, thanks for joining us. Thank you. you for the insights. We'll stay tuned to the 89bio story. Thanks. Thanks a lot, Tom.