89bio, Inc. (ETNB) Earnings Call Transcript & Summary

Good morning, everyone. I'm Ellie Merle, one of the biotech analysts here at UBS. Very happy to have 89bio here with us for a fireside chat. And joining us from 89 is Rohan Palekar, Chief Executive Officer. Rohan, thank you so much for joining us today. Before we dive into specifics, can you start off giving us a brief high-level overview of 89 and summarize some of the highlights of your recent progress and upcoming milestones?

Sure. Ellie, first of all, thanks for inviting us, and it's great to be here. So as some of you might know, 89bio is a late-stage clinical development company focused on cardiometabolic and liver disease. And our lead program is an FGF21 analog called pegozafermin, which is in Phase III development in MASH, which was previously called NASH, as well as severe hypertriglyceridemia. And we think pegozafermin has the potential to really transform these disease states. And I say that based on the mechanism of action, FGF21. And then importantly, the data we've shown in our Phase II studies in both these indications, in MASH as well as SHTG. We've made very significant progress in the last 18 months, where we are now in three Phase III studies. So this year -- earlier this year, we initiated 2 Phase III studies in MASH, one in the pre-cirrhotic population, which is F2 and F3, and a second study in the F4 cirrhotic population. And we also have a Phase III study in severe hypertriglyceridemia. So this is patients with trigs above 500 mg per deciliter. That study started in 2023, and we expect results in 2025. So it's exciting. We're going to have our first Phase III readout next year. It's a biologic agent given as an injectable. And we dose patients once a week or once every 2 weeks. We have scaled up our commercial manufacturing, and that's been a big accomplishment this year, where we are making production at commercial scale. And that's what's going to be used in the trials. And then just to close out, from a capital position, we ended third quarter, which we put out our results last week with $424 million. So we're in a good solid position from a cash perspective.

Great. And in the MASH space, which I guess, I will call it MASH now, there's a lot of different mechanisms in development. Can you frame for us sort of where FGF21s fit in your view across the landscape? And in particular, how maybe FGF21s work directly on fibrosis, whereas some of the other mechanisms might not act directly on fibrosis?

Sure. So FGF21 is an endogenous metabolic hormone, predominantly produced in the liver, acts on the liver as well as in the periphery. And it controls energy metabolism, carbohydrate lipid metabolism in the body. And it is an insulin-sensitizing agent. So what's unique about FGF21 relative to other classes of drugs being developed, it works in multiple different ways to address the pathophysiology of MASH. So if you think about MASH, it's a liver disease, but at its core, it's a metabolic dysregulation, right, which results in surplus fats being generated in the liver and over time, that gets inflamed and becomes fibrotic, which is the highly problematic part of MASH. What FGF21 does is, and pegozafermin, in the liver, it has very direct effects on the liver. There are receptors in the liver. And here, it results in fatty acid oxidation, burning of the fat. It prevents de novo lipogenesis or the generation of new fat, but it also has a perpetuated direct effect on the fibrotic pathway. And it does this by upregulating another hormone called adiponectin in the liver, which is known to downregulate the hepatic stellate cell, and those are the ones which lay down the collagen matrix. So it has direct metabolic and fibrotic effects in the liver. But then importantly, it also works in the periphery. So in the broader ways, and this it works by activating receptors on your white adipose tissue or your fatty tissue. And that's what manages lipid levels. That's how we drop trigs pretty dramatically. So we also reduce the fat, which is being deposit into the liver. So it's got multiple different modalities. And so it's like if I contrast it with, say, something like an incretin therapy, which don't work directly on the liver. They work through the periphery, addressing insulin sensitivity, addressing obesity, all important underlying factors of MASH, but it's working indirectly. And then downstream, you will have a benefit in the liver. FGF21 in that respect is something unique.

Absolutely. And any thoughts on the recent ESSENCE data, and maybe what you're focused on at AASLD for the full data?

Yes. So Ellie, it's a no. I mean we've seen a snippet of the data, right? I think the ESSENCE data was, in some ways, what we expected, that they would show a benefit on fibrosis and MASH resolution. As you remember, previously, in their Phase II study, they didn't show a benefit on fibrosis versus placebo, they showed in MASH. But the numbers are what I'm going to call more moderate relative to see what pegozafermin showed, right? So after 18 months of therapy, they saw a placebo-adjusted delta of 14.5%. With pegozafermin, after 24 weeks of therapy, we're showing a 20% delta versus placebo. And we would expect over time that delta should widen. So we see there is a role for semaglutide based on this data, but we see it being factored more in the earlier stages of MASH is distinct from advanced fibrosis. So if you think about it, MASH is a progression, where we are positioning pegozafermin is for patients with advanced fibrosis and cirrhotics. And those patients, which are predominantly F3 patients, they need something which acts rapidly and prevents the progression of fibrosis. So when you think about, from a clinician's perspective, someone is at an early NASH -- sorry, I won't go back to NASH, early MASH. There, the treatment objective is resolve the steatohepatitis. As you progress further, the treatment objective changes slightly. It's about preventing progression of fibrosis, preventing a progression to cirrhosis. So if your goal is resolve steatohepatitis, because someone can be F1, F2 for like 20 years, 15 years, you can address that with a metabolic drug, which is highly effective on diabetes and obesity, like a GLP-1. But if your goal is to prevent someone from progressing to cirrhosis, you want a highly potent anti-fibrotic. So the way we see the market early evolving is people will be in GLP-1s. We recognize and acknowledge that. We show nice data on GLP-1. But in that advanced population, they're probably going to need something more than just a GLP-1 or an incretin-based therapy. And we see that's where a role pegozafermin plays. To answer your last question, so what are we hoping to see more? I think there's a couple of things, I think, on this data set, right? They had a very high placebo response, 20% to 23%. Contrast that with our placebo response was 7%. And so you've got to ask yourself, tirzepatide saw a 30% placebo response. Why is that happening? And so when you do cross-trial comparisons, one way to look at it is you do what's called relative risk or odds ratio, right? How did your drug do relative to placebo? And kind of their relative risk is 1.6. That's even lower like, Madrigal was 1.9. Our relative risk is about 3.5 odds ratio. So I think it will be important to understand that and how they did the stats plan. And then the last one, I think, which would be very interesting if they present the data, is what was the discontinuation rate? And how were those treated? We do know at this dose of 2.4 mgs in the real-world setting, which is the Wegovy dose, at the end of 1 year, a lot of people are off therapy. And that becomes important because for a condition like MASH, you need people to be on long-term therapy. So I think there's a bunch of stuff. Hopefully, next week, we'll see that data. But we think there is going to be a role for the incretins. We think for pegozafermin and the FGF21 class, this was a great clearing event because there was a lot of questions like is there need for another therapeutic modality. And I think this was pretty conclusive for the advanced patients, you're needing something more which is going to really hit on fibrosis.

Absolutely. That's helpful color. And especially, as we talk about the advanced patients, even going to the F4s or cirrhotics, you've included F4s in your Phase III study. Maybe historically there's been sort of thinking that F4s are too far gone. They're hard to treat. What gives you the confidence that FGF21s can be active there?

So I think -- so just contrast it a little bit with the prior drugs. You're right, F4 has been kind of a little bit of a tricky start for drug development. But I would argue that the drugs which were tried in F4, they went into those studies with very limited data on F4, and database on F2, F3, which arguably also was not as efficacious or as strong as what we are seeing even in that F2, F3 population. So there were drugs which had benefit, but they probably were not as potent as pegozafermin or FGF21, right? And that's really important when you think about treating these late-stage patients who have really a very dense fibrotic matrix. So what gives us a level of confidence, right? So we had a small group of patients with F4 disease in our Phase IIb study. And we saw very nice results in that small patient population at week 24 and week 48, both on histology. But then importantly, in all the other noninvasive markers, which looked at inflammation, transaminases, liver stiffness. The other competing FGF21 had a much larger study, and they've seen encouraging data in an F4 patient population, which leads us to believe that FGF21 could have good activity in this patient population. And the last comment I'd make is, from a scientific perspective, so just to say that, so we are looking at compensated cirrhotics, which is very different than a decompensated patient, right? The pathophysiology in early compensated cirrhosis is fundamentally not that different than, say, an advanced F3 patient. Both the FGF21 agents, including pegozafermin, has shown very dramatic benefits in that advanced population. So we think we should see a very nice benefit in these compensated cirrhotics, and that's kind of what's giving us the level of confidence and why we embarked on this Phase III study.

And I would be remiss if I didn't ask. Heading into early next year, we're going to be getting the 96-week data for Akero's F4 study. What are you looking to see? And how does this lead to your program? Like say, we don't see an increase in benefit from 36 weeks to 96 weeks? Like what does that mean in terms of how you think about the likelihood of success in Phase III versus if we do see an increase?

Sure. So we do think that they will see improvement in benefit between week 36 and week 96. We have confidence that you should see that. Because mechanistically, we think the drug should work. It's a good drug. Like our drug, it's a good drug, it should work. If you go back to the F2, F3 study, they did see a widening of the delta between week 24 and week 96, right? And this goes back to my comment, if you suppress the injury and insult to the liver, you give the liver time to heal. So I think what we would like to see, look, all of us want to see stat sig on the endpoint, right? But to me, I think that our -- as we look at it from a development perspective, I think what's going to be important to see is, did we see a widening of the gap? They had a 10% placebo-adjusted delta, which is clinically meaningful, interesting, right? Had they powered the study for that, everyone would have said this is the greatest thing, right? Because all the experts will tell you a 10% delta is clinically meaningful. 12% to 15% is great, right? So if you see a widening of the gap, that would be great. I think the second one is, is placebo going to be still as high? They had a placebo of 14%. Over 2 years, what the experts will say is it's unlikely that a cirrhotic placebo would be that high, right? But from our perspective, we want to see the totality of the data set because I think that's going to be important. So all these Phase III studies, we're going to look at histology at 2 years, but you need to run them for outcomes to get full approval. In some ways, it's unclear yet in cirrhotics that fibrosis reversal is all that matters for outcomes. But if we see really nice over 96 weeks that FGF21 dampens inflammation in the liver, transaminases are down, there's no liver fat, liver stiffness is down, that actually would suggest that you will see a benefit on the outcome irrespective of what happens in fibrosis, right? So I think there's a multitude of things we will be looking for. But at the end of the day, we remain bullish on the data set. Not surprisingly, we would expect there's a read-through to how we are seeing our data, and it's important. But again, we would look at the data set as in its totality versus one endpoint. The last thing I would say is we've initiated our study in second quarter of this year. It's early. I think we could also learn from this data set. This is going to be the first 2-year data if we need to make any changes to our protocol, right? So we made certain assumptions on what the placebo rate would be. That's how we powered the study, and we learn something very different. It gives us that flexibility. So yes. It's exciting. And it's great for patients, meaning, at the end of the day, from a patient perspective, there is nothing for these patients, right? And so I root for anyone who is successful in our space.

Absolutely. And certainly, the unmet need is the highest in the F4 population. So as it relates to the other FGF21s in this space, I mean, it seems like, look, we've probably seen the best fibrosis data from this class, but maybe how you see your program is differentiated and how it fits in the landscape with some of the other FGF21s?

Sure. So meaning the lead one is the efruxifermin, and we are kind of lockstep with them. Both of us are doing Phase III studies in F2, F3 and F4 population. So when we contrast these, there are some similarities and there are some differences. And it really starts with the way the 2 companies -- the structure of the molecules, the way the 2 companies have taken different technologies to extend the half-life of FGF21. So FGF21 has a very short half-life. So we used what's called glycoPEGylation, which is a unique type, a proprietary type of PEGylation to extend the half-life, and efruxifermin is a fusion protein. And the half-life of the two molecules are very similar, okay? The preclinical data looks pretty similar, albeit it came from 2 different companies. We think the efficacy of the 2 molecules is pretty similar, okay? You look at the histology data at week 24, both of us showed about a 20% response in the F2, F3. Some metabolic markers, they see a little better. Some metabolic markets, we see us slightly better. However, we think there are a couple of key differences. I'll highlight 4 differences. So one is, to date, we have seen a better tolerability profile relative to efruxifermin when it comes to GI events, okay? And this has been all the way back to the Phase I studies. GI events are observed with all FGF21s, but we see it at much lower rates. And especially with our every 2-week dosing, we see a significantly lower [ rate ]. Also we have not observed any statistically significant or clinically meaningful changes on bone markers or BMD using DEXA scans through 48 weeks. I think efruxifermin has presented some data, they're seeing some changes. It's unclear what's the clinical significance, but we do think there's a difference in the tolerability profile of these 2 drugs. The second difference is we are studying our molecule once a week and once every 2 weeks. Efruxifermin is only studying once a week. And I think this is an important distinction because, from a patient perspective, it's 26 less injections. And what all the patients tell us is, other things being equal, I'd rather take 26 less shots. And so these two -- first two factors, tolerability and convenience, we know in a real-world setting as distinct from clinical trials are the biggest drivers of patient persistency and compliance in a chronic disease. So when you think about a chronic disease like MASH, patient compliance is critical. And so we think that's two. The third, which is important, is we are a liquid formulation in a prefilled syringe. They are a lyophilized product. So it's got to be reconstituted before it gets injected. Again, it's not a very commonly used one. But as we think about life cycle management of our drug, we have a long patent runway. As a liquid formulation, we could potentially, if it's stable, combine it with a GLP-1 to create a single injection, right? We talked a lot about how people are going to be on GLP-1. It's unclear whether a lyophilized product can do that. I'm not saying it can or cannot, but we would think about -- because that would be a logical life cycle management plan for us. And then the last difference is we are pursuing a second indication in severe hypertriglyceridemia. And that has given us a lot of benefits from a development perspective because we can leverage the safety database. So a lot of synergies. And then when you think about the commercial setting, having a second indication gives you incredible synergies. It also allows you to tap into a different target physician audience who sees MASH patients. So SHTG is predominantly either in endocrinology, cardiology or primary care, MASH, GI, hep. However, a lot of these patients in endocrinology offices, if they were screened, they probably have MASH. So having the second indication will allow us to go into different physician offices and maybe tap into an audience we might not have got to, right? So this was one of the strategic reasons we pursued SHTG, that there is synergies both on the development side, the sharing of the safety database but also on the commercial footprint.

And we're getting this Phase III data next year in SHTG?

Yes.

Maybe just any more color on when next year we can expect it?

So we haven't provided guidance. Here is what I can say. So it's a 52-week study with a 26-week primary endpoint. We typically do disclose when enrollment is completed. We haven't disclosed that. So you can do the math. It's not happening in the first half, right? But it's not happening in December of next year either. But we are feeling very good based on where enrollment is, we will have data soon. But once we close enrollment, we will let people know.

Great. And maybe just as it relates to SHTG, there's a lot of different drugs in development here, and I think from the investor side there's not as much clarity on how to think about it as a commercial opportunity. How do you think about the landscape in SHTG?

Sure. So let me talk first kind of what's the opportunity and the patient size, and then let's talk about the drugs in development, right? So there are roughly approximately 4 million patients in the U.S. with severe hypertriglyceridemia, i.e. trigs above 500. About 1.8 million of those are diagnosed and being treated, okay? And there are drugs approved for it, fish oils, fibrates. But then the one which is used most extensively, even though it doesn't have a label, is statins, okay? The challenge is about half the patients, so a little less than 1 million patients, despite being on drugs, are unable to bring their triglycerides below 500. So they are being diagnosed. So it's a market you can tap into. They are in the health care system, they are taking drugs, but they're enable to bring the trigs below it. The second thing which is interesting is these patients with high trigs also have multiple comorbidities. So the published literature would say about 75% have liver fat. In our study, 100% of them had liver fat. They had like 20% liver fat, like a MASH patient. The other thing is about 2/3 of these patients have diabetes or pre-diabetes. The existing drugs, the fibrates, the fish oils or the statins, do nothing to address these other comorbidities. So what clinicians are telling us in all our research is, I want something for these patients who are what I'm going to call refractory to the existing drug, but then I also want something which addresses their broader metabolic issues. And that's where pegozafermin is unique. So in our Phase II study, we dropped triglycerides between 57% and 63% just in 8 weeks. The triglyceride baseline was like 730 at baseline. Importantly, we dropped liver fat by 45%. We dropped all the other lipids also. And we saw benefit in hemoglobin A1c, right? So we saw this broad metabolic profile in addition to trigs. We also saw this reduction in trigs on top of the patients who were on fibrates, fish oils or statins. And many of them were on high-intensity statins, so we had allowed patients to come in as long as they were on a stable dose. That's the same way we're doing the Phase III study. So we think we have a unique opportunity. Now the other major class of drugs -- to the best of our knowledge, there's only 1 class in late-stage development, that's the APoC3s, which have a unique and different way of acting on reducing triglycerides. And we'll see the first data set from Ionis in Phase III back half of next year. Now APoC3 mechanistically does drop trigs very well, but they don't offer some of the other metabolic benefits we are seeing, right? So they don't have impact on glycemic control. They -- it's unclear whether they see a reduction in liver fat. One company says they're seeing some, but not to the extent we're seeing. And in fact, in a recent Phase II study with one of the APoC3s from Arrowhead Pharmaceuticals, they actually saw worsening of glycemic control, 19% had worsening of glycemic control. And we actually had an LDL elevation of 60% at the high dose. And with similar placebo-adjusted reduction in trigs as we are seeing. So we think we have a unique position. And now I think this market is big enough. There's going to be multiple mechanisms used. The APoC3s are initially going after FCS, which is much higher trigs, like 2,000, and we think they're going to dominate that space. But in that sweet spot of what I'm going to call between 600 and 900, where patients have that level of trigs but also have comorbidities, our research is telling us it could be a unique positioning for pegozafermin.

Interesting. And what are you looking to see in the data? Are you measuring pancreatitis events? And what should we think about as good data from this Phase III?

Yes. So I think what would be good data is clearly, the primary endpoint is reduction in triglycerides from baseline. What I think we would be looking at very closely is we align patients on baseline existing standard of care. How do we do well on top of that? Because we see in the real-world marketplace, we're going to be used second line, payers are going to look for that data to reimburse us, right? To your question on acute pancreatitis, we will obviously look at it, but the study is not powered for that. So we were not powering the study because those -- the incidence of acute pancreatitis is -- it's not that high. It's in single digits. So otherwise, you'd have to power it very high. But then the other thing we'd be looking at is, are we going to see the benefits. So we are doing in a subsample MRI-PDFF to look at liver fat, because we want to see how we do on that. And then how do we do on these other lipids and metabolic markers like hemoglobin A1c, because to us, that's going to be the key differentiating factor. And then needless to say, we want to make sure it's a well-tolerated drug because these patients would be on chronic therapy.

Absolutely. And taking a step back in terms of thinking about the time lines to market, so if I'm understanding correctly, you need to run another Phase III in SHTG in order to file on that, sort of, maybe?

Maybe. So here's the thing, so if SHTG, Ellie, was our lead indication, and that was the first filing with pegozafermin, you're correct, the agency would require 2 well-controlled studies. However, given the fact that we have this large NASH program, which has 2 large studies with a very significant safety database, we are planning to reengage with the agency that if we already have an indication for NASH in the market, then for a supplemental BLA, is one study going to be enough, right? So very often, you see -- because one of the reasons the agency was asking for 2 studies, we had the discussion with the agency on the SHTG program before we had our NASH data, before we had a NASH program. So we couldn't talk to them that we're going to have thousands of patients being treated. So in that construct, they were like, both from a safety perspective and from an efficacy perspective, we are looking for 2 studies. Subsequently, we got our NASH data. We had our NASH regulatory interactions. We've launched these 2 studies. And we've said -- we've publicly said from 89bio's strategic perspective, MASH is the lead indication. And given that the delta between the time lines is not that significant, we want to lead with MASH, and then rapidly follow it up with SHTG. And we are optimistic. Let's see what the agency says, that maybe this one study is enough, or maybe they'll say this one study but you need some additional data, but you don't need another large 400-patient study. That's why I said maybe. Let's see how it goes.

Interesting. And I know you just kicked off the Phase III in MASH, but maybe how is enrollment going so far, and your latest on time lines for when we could see the data?

Sure. So just for the listeners, we launched our F2, F3 study in March of this year, we initiated that study. The site initiations in the U.S. has gone really, really well. So there is energy and enthusiasm and excitement for it. The international sites are just starting because it takes 6 months to get all the regulatory stuff aligned, but a lot of enthusiasm from the PIs to participate in the study. It is early to comment on enrollment just because it's an 8- to 12-week screening period. So it's a little early to comment on that. However, what we have said when we launched the study from a posting on clintrials.gov (sic) [ clinicaltrials.gov ], you have to put a date, we said the primary endpoint of histology, which is at 1 year, is expected end of '26. But typically, I would say could be plus 1 or 2 quarters, right, in that time zone. The outcomes portion of that study, it's a repeat biopsy at 3 years, so you can literally add 2 years post that, right? Now it's an event-based study. So if we have more events come in, it could come in earlier. But we're excited about what we're hearing from both the CRO as well as sites. There are patients out there who would like to be in the study. The cirrhosis study -- and I should mention that's approximately 1,000 patients. The cirrhosis study is a study in about 750 patients where we're studying a single dose. That started in second quarter of this year. We are very happy and encouraged that a lot of the sites are going to be common. So these studies are about 250 global sites. We get asked this question like, "Oh, but we thought you've only 80 sites." That's 80 sites which are currently on clintrials because they're all coming up. So there's a lot of synergies across these studies. That study, the screening is going incredibly well, which is suggesting that there is a lot of patients with compensated cirrhotics there. Again, really early to comment on enrollment. The histology portion there, unlike the pre-cirrhotic, is a 2-year endpoint. So it's not a 1-year endpoint. Based on the 2-year endpoint, what we have said in clintrials is that the histology component will read out sometime in 2028. And then outcomes is purely based on when events happen, right? It's a progression to decompensation events. So it's a little bit speculative to comment on that, right? But it's probably sometimes slightly beyond 2028. Yes.

Great. And last question, just from a cash runway perspective, sort of these are very large studies, significant undertakings, sort of what's your current cash runway?

Sure. So we ended the third quarter with $424 million. That gets us into 2026. It gets us past our severe hypertriglyceridemia Phase III readout but does not get us to the readout from the NASH study, which I talked about the time lines, right? So there is a gap there. We do have a line of credit which we recently renegotiated. It's up to $150 million, where next year we have the potential to draw down $65 million, $35 million is time-based, and then $30 million is on a milestone. So we have access to that capital if we elect to draw it down. So that's kind of where we sit today from a cash perspective.

And from a business development perspective, how are you thinking about maybe just your hopes to commercialize in the U.S., ex U.S., and any potential strategies that you're exploring?

Yes. So our goal at 89bio is to maximize the value of pegozafermin in the interest of patients. So our goal is -- we have confidence that this drug will work, and we'd like to get it to the maximum number of patients. So if you use that as your lens, we think having a potential partner to assist in development and commercialization, especially OUS, would makes sense in the interest of the patients, but then arguably in the interest of our shareholders, right? And there is a lot of interest in MASH, which is kind of coming back with Madrigal's approval and a lot of interest in FGF21. Now in the U.S., where you're targeting advanced fibrosis, which is more a GI and hep, you could as a company do it. But a strategic partner who is very experienced in the field might give you a bigger footprint to hit on it. So we continue to remain in conversations. But at the same time, we have a drug, which we think is great, and we want to make sure were we to do a partnership, in the interest of our shareholders, we do it on the right terms, right?

Absolutely. Well, it looks like we're at time. But Rohan, thank you so much for having us.

Thanks, Ellie. It's great having you here.