Hello everyone, and welcome to Oppenheimer's 34th Annual Healthcare Conference. I'm Jay Olson, one of the biotech analysts here at Oppenheimer. Thank you for joining us today. It's my pleasure to welcome 89bio to our conference, and it's an honor to introduce Rohan Palekar, Chief Executive Officer. If you have any questions during our discussion, please feel free to submit them using the Q&A function. With that, we'll get started. Thank you so much for joining us here today, Rohan. Thanks for having us, Jay. Looking forward to the discussion. We appreciate it. Yeah, likewise. It's our pleasure. So maybe could you start off by giving us an overview of 89bio's innovative approach to addressing NASH and SHTG? Sure. So as many of your audience probably know, we are a late-stage clinical development company focused on liver and cardiometabolic diseases. Our lead program, pegozafermin, is an FGF21 analog, which we believe can be transformational in the treatment of these disorders. There's a couple of reasons why I say that. One is the FGF21 as a target is truly unique, and it's a very promising therapeutic target because it addresses not only what is happening in the manifestations of these diseases, but it addresses the core underlying metabolic dysregulation these patients have. When you think about it, these patients have a metabolic dysregulation. NASH is the liver manifestation of it. Severe hypertriglyceridemia is a cardiac manifestation. And this endogenous metabolic hormone has very broad effects, right? It regulates lipid, carbohydrate, energy metabolism. It acts as an insulin sensitizer. So the way we are developing this drug is we're thinking about it as a pipeline and a product, right? It's two indications which have synergies both from a development perspective and then long-term, Jay, from a commercialization perspective, right? Now, in addition to that, I'd say we've taken some really innovative approaches to the way we're developing it. So let's take NASH, for example, right? We came up with an innovative approach to doing a cirrhotic study, and we were the first company to get the agency to agree to an Accelerated Approval in cirrhotic diseases. We got them to align on revising the way outcomes are defined. So we've taken pretty innovative approaches to the way we are thinking about our development plan, all with the interest of rapidly progressing the molecule through the clinic to get it to patients. On the regulatory front, we've taken a pretty innovative approach, and it goes back to the pipeline and the product where we got the agency to agree that we can leverage safety databases across these indications. So if I take NASH, for example, in addition to the two phase III studies we're doing, we're going to leverage the database from the severe hypertriglyceridemia study for the safety database. So we did not have to do a standalone real-world safety study. So there's a bunch of kind of creative and innovative approaches the company has taken, which allows us to be incredibly capital-intensive, but at the same time move the program forward and increase the probability of success. Great. Thank you so much for that. That's super helpful. And I'm glad you mentioned the cirrhotic patient population. Definitely want to come back to that. But first, can you just talk about what you learned in the phase II study in NASH and how that compares to other NASH drug candidates? And also, can you highlight the 48-week study that read out in November and anything from Rohit Loomba's presentation at AASLD? Sure. So the Phase II-B study was a very robust study. This was a study which read out in March of last year and then published in the New England Journal in June of last year, 220 patients, F2, F3 predominantly. So a couple of key things we learned. One is we have very strong histology results, arguably on fibrosis benefit, the best in category data comparable to the only other drug, another FGF21, which has shown a 20% delta versus placebo. Very nice benefits across all metabolic markers, okay, which is important, suggesting that the product really has broad effects. The third thing I would say is we were very pleased to see that both the doses we tested worked. So we saw really nice results with the once-a-week injection, but also we were pleasantly surprised, encouraged, actually, I would say, that the once-every-two-week dose worked really well. This is important because from a patient perspective, we know nearly two-thirds of them would prefer a less frequent dosing. Two other points, I think, on the efficacy side. We had a small subsample of patients who, upon reading the biopsies with three panels, were identified as cirrhotic patients, F4 patients, okay? And in 12 of those patients, 11 on drug, one on placebo, we had repeat biopsies. And we saw very encouraging data, small sample set, that we actually can reverse fibrosis in a cirrhotic population. So that was another efficacy point, which was an important learning as we think about our development plan moving forward. And the last thing I would say from an efficacy perspective what we learned is we work very well on top of incretin therapies. Incretins is currently the hot topic in the marketplace. So we had about 20% of our patients were on GLP-1s. They were on stable dose on GLP-1s. And then we put them on pegozafermin, or they continued on placebo. And we saw really nice incremental benefits on top of GLP-1s. So that's from the efficacy what we learned. On the safety and tolerability, it showed that the drug continues to be very well tolerated. It's an area of key differentiation from the other FGF21 candidates where we are seeing the classic FGF21 side effects like GI events, but at a much lower rate than, say, what efruxifermin has shown or the Boston Pharma product has shown to date. And this, again, is very critical in a chronic condition because that drives persistency and compliance. The last comment I would make on the study, which is very important, what we're taking into the phase III is we used a unique methodology to read the biopsy slides. So we used a three-panel reading as distinct from using a single reader or two readers and then a consensus. So here we had three independent pathologists, all experts, read the slide. And then there was an a priori algorithm which determined what was the ordinal score to include. And so this removes a lot of the biases and the social dynamic. And I think now people are saying this is probably the best way to actually make biopsy reading less subjective or make it as there is a subjectivity. It's humans who are reading it, right? And so we're going to move forward using that same data sorry, same methodology in the phase III. So those were the key highlights, I would say. The 48-week data, which was presented late November, early December, was an important dataset. So we had continued these patients for 48 weeks in a blinded fashion. It was placebo control. 24 weeks was the histology data I was talking about. And what we were looking for is whether there was maintenance of benefit across all these markers. We did not rebiopsy the patients. And we were very happy to see that there continued to be nice maintenance of benefit across all the non-invasive markers. So whether it was liver fat reduction, ALT transaminases, non-invasive markers of fibrosis. And in some ways, it put to bed or put to rest a question whether there's tachyphylaxis with FGF21. We were really happy to see that data because there was a previous molecule, previous FGF21 molecule, where they showed okay data, not great data, 2024, but at week 48, there was no response. There were concerns raised. Just on the AASLD, you asked what Dr. Loomba presented. He presented at a plenary session the F4 data, which I was referencing. What was really encouraging, not just the histology benefit, but those patients saw benefits on NITs across liver inflammation, fibrosis, liver fat, which were all consistent with the fibrosis benefit seen. This gives us a greater level of confidence as we move into our phase III in the cirrhotic population. Great. Thank you so much. Super, super summary. And really appreciate your highlighting all those key points. And I'm glad you mentioned GLP-1. And yes, everyone's asking about it now. So maybe just to follow up on that. Since Lilly had their tirzepatide data, phase II data in NASH last week, and they had robust NASH resolution, but they only showed clinically meaningful fibrosis improvement. So we suspect, as do others, that that did not reach statistical significance. I guess, what are your thoughts on that tirzepatide NASH data? And how do you think GLP-1s will impact the NASH landscape longer term? Sure. So, Jay, our perspective was we kind of expected this data, right? We expected that they were going to see a benefit on NASH resolution. We expected they were going to see results slightly better than what SEMA showed, just because the molecule is probably more potent as a diabetic and an anti-obesity drug. So if you recollect, SEMA, at its high dose, was like 59%. We thought it could be in the 60s. It was 70%. But based on what we had seen with SEMA and the mechanism on how GLP-1s work, we were not expecting to see a benefit on fibrosis, right? They might have hit it. But clearly, they did not, as you mentioned, or we don't believe they did. Otherwise, they would have mentioned it. And we think it really goes to the point that now this is the second study with GLP-1s, which are long and robust studies. SEMA was 320 patients. This was 190. SEMA was a year and a half. It really goes to the core. Can incretins in this short time period really make a difference on fibrosis, which arguably is the most important factor, especially in advanced fibrosis or advanced NASH patients and cirrhotic patients, right? And so our gut is clinically meaningful. Let's assume it's a 10% cutoff. They probably saw something in that level. We actually did some reverse math. If they had hit the treatment effects we observed, they should have hit stat sig with the size of the study, right? Now, I recognize that NASH patients, a lot of them have obesity and diabetes. So incretins will be used. But here's, I think, how we see this market evolve, Jay. Look, NASH is a long, progressive disease. In the earliest stages of the disease, the treatment objective is really about addressing steatohepatitis because those patients are not at high risk. They're at low risk. And so there, you're trying to treat the underlying metabolic issues, primarily diabetes, obesity. We think Incretins are going to use extensively there. But as patients progress, and patients will progress, even though if they're on GLP-1s, they will progress, what happens is the treatment objective changes slightly. It's not about resolving steatohepatitis. It's preventing progression of fibrosis. And then if you're cirrhotic, preventing progression to decompensation. And so there, you need an effective antifibrotic. Recollect, we are showing in 24 weeks impact on fibrosis. These are drugs in 48 and 72 weeks not showing a benefit. What we see is Incretins will get used extensively. They will get used in that earlier population. But as people progress, they're probably going to either need something more or something different. So we think like the sweet spot for pegozafermin and FGF21 is that advanced fibrosis patient. Then clearly, in the cirrhotic patient population where metabolic issue is not the big driver and fibrosis is the driver, we think we could have a very dominant play. Look, the prevalence of NASH is a pretty big market because I think you're asking is, how does this affect NASH landscape more broadly, right? It's a large market. While in the earliest stages of NASH, people treated might decrease if people stay on their therapy for a long time period with the Incretin. But at the same time, we expect the market to be growing. Diagnosis rates are going to grow. People are going to get more effective therapies for it. So in some ways, we actually think it's good that there are different drugs which could work. And we think, given the fact that we've shown really nice data on top of GLP-1s, we think we're in a pretty sweet spot that even if someone's on an incretin, there's going to be this need. And we've shown a benefit on top of it. Thank you. That's super, super helpful perspective there. I appreciate the additional color on that. And then I guess, congrats on your progress with the FDA reaching alignment on your Phase III program for pegozafermin. Can you just talk about your Phase III studies, both the F2, F3, and the F4 NASH patients? And I guess, in your discussions with the FDA, you had modified definitions of certain events. I guess, what events are you considering for this trial? And what would you believe would be a clinically meaningful dataset? Sure. So we were very pleased with the outcomes of our discussion, both with FDA and EMA. I think it's important because this is a global study as well as this opportunity in Europe, right? So where we got alignment is on two studies for NASH, two phase III studies. So let's just break them down. So the first study, the first phase III study, is in the F2, F3 patient population, where we got alignment with them that we would do 52 weeks. And we would do a repeat biopsy, a histology study. And if that were positive, we could file for accelerated approval, okay? And we're going to use a coprimary endpoint of fibrosis improvement at one stage with no worsening of NASH and NASH resolution with no worsening of fibrosis. In some ways, Jay, this is more standard. Others have done this. We'll continue those patients for outcomes. The predominant outcome in an F2, F3 patient population is going to be progression to cirrhosis. We think we are a good chance of showing a nice benefit there because in the ENLIVEN study, in our Phase IIb study, when we looked at those F3 patients, in 24 weeks, we had 19% of patients in the placebo on progressed to cirrhosis versus less than 9% on our active drug. So we feel pretty good about our ability to show a benefit and outcomes in that F2, F3 population, okay? The huge win we got with the agencies was in the cirrhotic F4, compensated cirrhotic population. So the current guidance document requires you to do an outcome study. And there was no path for a Subpart H accelerated approval based on histology. We got alignment that we can pursue a study with a histology endpoint and, if positive, seek accelerated approval or conditional approval in Europe. So we'll enroll these patients. 24 months later, we will rebiopsy them and look whether we've changed their fibrosis status by at least 1 point. If that is positive, we could actually file and get approval for the F4 population. That was one big success. The second one is we will continue those patients for outcomes. The predominant outcome event in an F4 population is decompensation. That's 90% of the events. Here, what has happened is the way the FDA had defined decompensation events, they were pretty much on the end, really close to a decompensation effort. But remember, it is a long journey to get there. People don't wake up one day from compensated and next morning are decompensated, right? And if you go that far, it takes a long time to get there, which makes it a very difficult study to execute. And arguably, can you actually reverse those patients? So, for example, one of the decompensation events is variceal bleeds, okay? But by the time someone has a bleeding varices, it typically could be 12 months to transplant or some bad event. But no one goes from no varices to a bleeding varices. And so what we got to talk with them is, can we assess something in this progression and use that as the definition of someone has a decompensation outcome event? And they agreed with that. So what this allows us to do is it makes it a more tractable study, a study which can be done with a reasonable end and in a reasonable time period. I should mention, so the first study, the F2, F3 study is projected to start this quarter. So there's like six weeks left. The F4 study is projected to start in the second quarter. Okay, excellent. Thank you so much. It's really, really good insights there. Appreciate you describing that. And then I guess since Akero missed statistical significance on fibrosis improvement in their phase II-B SYMMETRY study in F4 patients at 36 weeks, what would you say to investors who try to read across from that to the entire FGF21 class and pegozafermin in particular? And what are some of the key points of differentiation between pegozafermin and efruxifermin? Yeah. So none of us ever want to miss a study on our primary endpoint, right? Now, but having said that, actually, that dataset in totality, SYMMETRY was a strong dataset. And in our conversations with KOLs, they were actually very encouraged by that data because it's arguably the best data to date in an F4 population. Before the study came out, we had asked KOLs, "What's your bar from an efficacy perspective? And what's your concern on this study?" And the bar was a 10% delta would be clinically meaningful. The biggest concern they had on the study was, is nine months long enough? So interestingly, they did hit a 10% delta. But it was not adequately powered at 10% to show a statistical benefit. But when you look at, Jay, the totality of all the other benefits observed across the metabolic markers, one would argue that actually, the drug did have good effects in F4. And this actually encourages us that in a longer study with a longer end, you should see a benefit. So fundamentally, we think mechanistically, FGF, it validated FGF21 could have a benefit on cirrhotic patients. But the key one is do a larger study, run it longer. And so we are doing a 24-week endpoint in our phase III study. I think from a differentiator perspective, I'll go back to where I started. I think the key differentiators between the molecules' efficacy, we look more similar than different. I think the key differentiators is our tolerability profile continues to be slightly better, especially with the every-two-week dosing. The convenience of a once-every-two-week dosing is a very meaningful differentiator in the eyes of both clinicians as well as patients. Okay, that's helpful. Yeah, definitely appreciate you leveraging those lessons learned. Yeah. I guess I think you touched upon this briefly. But assuming that you start your phase III study in F4 patients in the second quarter, when do you expect to see data from that study? We haven't guided at this point. I think we'll provide updates at a later time once we start enrolling patients. I mean, we're making great progress in both the studies. The sites have been identified. There's a lot of enthusiasm from the sites to engage in these studies. I always like to wait till actually the study has started and we get real-world, you know, a sense of how the enrollment's going. At that point, we would be in a better position to provide guidance. Okay, makes perfect sense. Then going back to your F2, F3 study, which you mentioned that you'll be starting relatively soon, will you stratify patients in those studies according to background GLP-1s? I guess when are you going to disclose the detailed study design? To answer to your first question, yes, we will stratify for GLP-1 use across the arms because we expect a fair number of patients who will be on GLP-1s. We want to make sure there's good balance. In the past, Jay, we have provided an update when we initiate the studies. That's when we've historically given more details. Okay, all right. We'll look forward to that. Then, just looking ahead to the resmetirom PDUFA, do you, I guess, if you were to look into your crystal ball, do you expect it to get approved? And if so, what impact do you think it will have on the NASH landscape? I think we're pretty excited about where the NASH landscape's heading. Everything I've looked at would suggest they should get approval. They clearly are seeing a benefit. We got the New England paper last week. No kind of surprises there per se, some additional nuances. But clearly, the drug has a benefit. The benefit-risk looks pretty good. I mean, that was, if you recollect last year, the biggest issue with the Intercept filing, the benefit-risk. So look, there's a lot of eyes on the resmetirom approval. And we're wishing for Madrigal success, right? Because patients will have a benefit, sorry, a drug and a therapeutic option. And we're looking for kind of what the commercial uptake is going to be. We hear from the clinicians we talk to and the experts. There is a bolus of patients who are looking for a good drug, you know, for any drug for that matter at this point, so. Okay, great. Yeah, we totally agree with you on all that. Anything in particular you'll be looking for either in the resmetirom label or pricing? So I think from a label perspective, look, I know there's a big question, are they going to require biopsies? We don't think they're going to require biopsies. It's going to be in the label, in the clinical trial section, we assume. But I think just understanding that, I think it'll be also when you see a label, you also get an insight into how the FDA is thinking about where the drug is. And then I think the pricing is going to be important. We've heard that Madrigal is talking about a more premium price than what was previously expected. I think that will be important to inform how this category might get priced and how we should be thinking about it. Okay, got it. I do want to make sure we have a few minutes to talk about SHTG. But one last, maybe one last NASH question. So looking ahead into the future one day when hopefully resmetirom and pegozafermin are both available to patients with NASH, how do you picture them complementing each other in the treatment landscape? So we believe resmetirom is a very strong agent for NASH resolution. But the fibrotic benefit is not as strong, right? And we think that's the big differentiator where pegozafermin has a fibrotic benefit, right, where a strong fibrotic agent is FGF. And we think that's incredibly important and relevant in the advanced NASH, the F3, F4, where there's an urgent need to stop progression of fibrosis, right? So we think there will be overlap in how these play. But one is more a metabolic versus we are a strong metabolic, but also a very strong antifibrotic agent, you know? Okay, got it. Makes perfect sense. Thank you for that. All right, so shifting over to SHTG, can you just remind us what you found in the phase II ENTRIGUE study? And then how are you leveraging those learnings for pegozafermin in your phase III INTRuST trial? Sure. So in the ENTRIGUE study, we were very pleased to see very strong reductions in triglycerides, right, at the high dose, 63% from baseline, albeit in a very short, in 8 weeks. And then importantly, Jay, we saw the benefit on top of existing therapies, whether they were on fish oils, fibrates, or even high-intensity statins. And that's very important because that's where we think we'll get used in patients who are already on these therapies and not seeing a response, right? So very nice triglyceride reduction. The second thing which was important is we saw very nice changes on lipids, things like non-HDL cholesterol, ApoB. These are really predictors of cardiovascular benefit, very, very strong numbers. Third is we saw very nice changes on MRI-PDFF liver fat and other metabolic changes like glycemic control. What we are hearing from physicians is they want to treat this entire patient, not just reduce their triglycerides, but address things like their liver issues, right? In our study, 100% of them had liver fat. Average was 20%. It was like a NASH patient. And then the last is we had good tolerability. So what this did is it informed our INTRuST study. We're using the same primary endpoint. The FDA has agreed that primary endpoint reduction in triglycerides from baseline is supportive of a full approval, right? So in some ways, INTRuST is just a larger, it's a 360-patient study for a 26-week primary endpoint of the INTRIGUE trial, right? Because we know it works. And so kind of like, don't mess it up. So in some ways, it's a pretty de-risked program going into phase III. Okay, got it. We're almost out of time. But maybe just one more question on SHTG. So you did add a slide to your competitive landscape for SHTG where you compared pegozafermin to plozasiran. And I was just wondering if you could highlight some of the most important differentiating features between those two. So we think pegozafermin stacks up really well relative to the agent. So when you look at the triglyceride reduction on a placebo-adjusted basis, we're about the same, right? However, we offer benefits which the ApoC-III don't. That is benefits on liver fat, ALT changes, and glycemic control. These are all important from a physician perspective. The other thing which was interesting is they saw a 60% increase in LDL. We did not see a change in LDL, right? And I think that could be problematic in a patient population who has already got cardiovascular risk. And second is in the AE table, they talk about 19% having changes on glycemic control. We see a benefit of glycemic control. Recollect, I said, two-thirds of these patients have prediabetes or diabetes. That's a concern, right? So we think we have a very differentiated profile from these drugs. They could be very successful in the FCS population. But in the broader SHTG population, the 500-1,000, we think we have a very favorable and differentiated profile. Excellent. Thank you so much, Rohan. We'll wrap things up there. I really appreciate your making time to bring us up to speed on all the impressive work you're doing at 89bio. So thank you so much for your time today. Thanks, everyone, for joining us. Thanks, Jay. Thanks. All right, pleasure.