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

Well, welcome, everyone, and it's really a privilege for me to introduce our next participating company at the Cantor Global Healthcare Conference. First time Steve Seedhouse from the biotech team. And pleasure to welcome 89bio. I'm joined on stage by CEO, Rohan Palekar, and looking forward to the conversation.

Rohan, maybe to start, I would love to just pass the mic to you ask for an update on progress. You have several ongoing studies, all Phase III at the company in MASH and in SHTG. And then we'll dive into Q&A across the board on all of them.

Sure. So Steve, first of all, thanks for having us here. As you mentioned, we're incredibly excited about the progress we're making with pegozafermin, our FGF21 analog. And we have 3 ongoing studies. So we have our SHTG program, which will be the first study, which has completed enrollment. And we expect to read out results from that first pivotal study early next year. And then we have our 2 MASH programs, which are incredibly promising, one which is in the pre-cirrhotic MASH, which is enrolling patients, and then one in MASH cirrhosis, compensated cirrhosis, which is also enrolling patients. And we think the promise of FGF21 in MASH is tremendous. And specifically in the cirrhosis population, which is the population with the highest unmet need, we think FGF21s in pegozafermin could be transformational for those patients.

Let's start with SHTG and drill down on that. Just this data is upcoming. I feel like this hasn't really gotten a ton of focus, although there's a lot of developments in this field now, which is drawing attention to SHTG, drawing attention to at least vis-a-vis acute pancreatitis, the real outcomes benefits that could be manifesting here from reduction in triglycerides. You've been running this program. You have data coming up and the Phase II data are strong here. And so I would love to hear you sort of frame just what you're looking to see in the Phase III and what the possible next steps are as I understand that you can't file off of this, but would love to hear where you would take that indication after this Phase III.

Sure. So we agree with you. I think SHTG is a very significant unmet need, which is underappreciated, and there's really not a lot of focus on it. And I think part of it has to do with the existing drugs kind of the fibrates, fish oils, not great drugs. So I think physician just say, continue on your statin. Many of these people are on statins. However, these patients have a lot of issues and challenges. And most importantly, they have very significant comorbidities. So about 3/4 of them have fatty liver disease, which actually compounds the SHTG. 2/3 are prediabetic or diabetes, right? None of the existing drugs do that. So earlier this week, we saw the data from the APoC3s, which was a good data set, albeit very limited amount of data put out. But I think getting new drugs to the market, you're going to start seeing a greater raising of awareness, people diagnosing this and looking to treat this. The sweet spot for pegozafermin is our ability to drop triglycerides while addressing these other very important comorbidities, things like liver fat, where we see dramatic changes, improvement in glycemic control, improvement in lipids. And this is where we see a very clear differentiation versus the APoC3s who, in fact, are actually showing worsening of glycemic control. So even with olezarsen last week, they put out data at the Cardiology Meeting and The New England publication in HTG, not SHTG, where they saw a worsening of glycemic control. And so what are we looking for in our data set? We're hoping to see what we replicated in the Phase II, which was very nice triglyceride reduction. We saw absolute changes between 57% and 63%, improvement in liver fat and liver transaminases and then improvement in lipids and other metabolic markers. And if we see that, we think we would then consider how do we structure the next Phase III. As you pointed out, we do need to have a second study to file. We see this as an sBLA after MASH. And the beauty is that we can really design that second Phase III does not need to be a very large Phase III to really address some of the unique properties of pegozafermin, which will make it commercially an incredibly promising proposition.

Would that potentially entail just given what you mentioned about glycemic control, potential area of differentiation versus the APoC3s. Could you enroll a particular demographic of patient? Or does that manifest in certain key secondary endpoints that would be potentially in label?

So one way to think about it, we do think the way you structure the design of the study could really enhance for certain patient populations, which could actually impact the label. So for argument's sake, you can think about, so we show nice reductions in liver fat. You could actually end up with an indication, I'm just speculating, for the reduction of triglycerides in patients with fatty liver disease. Commercially, it sets you up very differently than the APoC3s. You could do the same in -- for the treatment of patients with severe hypertriglyceridemia with diabetes or with prediabetes, right? And then you position that in the commercial setting as a different start, right? The APoC3s have FCS. So they are like playing a little bit more in that space, high, high, high [ trigs ]. But the bulk of the patients are in that 500 to 900 range, and they are the patients with these comorbidities.

In your studies, do you think -- I mean, one of the points of conversation that looks like it manifested constructively so far for the APoC3s is just the ability to actually demonstrate a bona fide outcomes benefit. I think they showed an 85% reduction in acute pancreatitis. Is that something that in your trial design, you'd be able to look at? Are you expecting that type of magnitude of effect?

So we do look for it. It's a relatively small study, meaning it's 360 patients. I don't -- we haven't powered it to look for changes in acute pancreatitis. That was not the intention of the study. The incidence of acute pancreatitis cases in patients in this range of trigs, which I was talking about, it's pretty low actually.

500 to 900.

Yes, below 1,000. I mean, it's going to be interesting. I know they showed -- because days with the meta-analysis combining multiple studies. It will be interesting to see what the absolute number of cases was.

Yes, it will. There's been some chatter, frankly, at our conference, I think, just on this emerging landscape and pricing these medicines in this market. And maybe it's actually expectations are increasing for what the price point would be something similar to MASH in the $50,000 range. I think that's higher than maybe people have been thinking about because it's sort of dyslipidemia type bucket and people were thinking much less than that. I mean what's your perspective on pricing in this market?

Yes. So the way we've -- we've done some initial work. As you know, pricing, Steve, at the end of the day, the data drives, right? You have good data, you can command a better price. I think if you are all about just drug reduction, you are more towards cardiovascular pricing. Where you're offering other benefits, whether it's outcomes on AP, whether it is impacting your other metabolic profile, our research would suggest you have more pricing power. Question is, could you go all the way to MASH pricing? Is it somewhere in between? I think we will have the first set of information on that on how olezarsen looks at their pricing. But we don't hear from -- in our payer research, we didn't hear like -- you got to be like a [ second price ]. We did not hear that, if I can say that.

Okay. On cirrhosis, and let's move to cirrhotic MASH. And you have an interesting -- I think it's in your corporate presentation, certainly, you've said it publicly that something to the effect of you're the only company that's publicly stated that you have an agreement with the FDA on an accelerated approval pathway in cirrhotic MASH. So can you just characterize like what is the conversation that you've had with the FDA? And how broad spectrum was it? And like what's the nature of the agreement and their stance on accelerated approval in cirrhosis?

Sure. So let me start with the conclusion. So what we did get from the FDA, which was in writing that if we were to demonstrate improvement in fibrosis at the 2-year histology endpoint, it could be supportive of a filing for accelerated approval for that indication in compensated cirrhotic patients. It's a very similar one with EMA. Now interestingly, EMA actually in their equivalent of their guidance document, they've always had that door open for that conversation versus FDA guidance document did not. I think, Steve, the way I would characterize it is we built a scientific argument with the agency on why patients who reverse their fibrosis should see a benefit and outcome. So think about it this way. The agency approves a drug on accelerated approval if they believe that endpoint would be predictive of outcomes. But the last thing the agency wants to do is approve a drug and accelerated outcome, then they fail on outcomes and then they got to yank the drug of the market, right? So we built an argument based on the science, based on our data to make the case that if we show a benefit, there's a high likelihood that we will see the outcomes and the agency agreed. Now what I will contextualize it, the conversation was, I think they are making determinations based on the mechanism of the drug, the data and the science. They honestly believe that FGF21 has the power to do this and make a difference in outcomes. So I think that was one key consideration. So maybe that's why it's not a generalization that every drug this works for. The other thing which is very interesting in the course of the discussion at the end of Phase II meetings was their emphasis on benefit risk. And they did feel that pegozafermin has a very good benefit risk profile with the opportunity to actually impact outcomes. I would say they're very constructive and they want to help these patients with cirrhosis. And so that was kind of the construct of the conversation. And subsequent to the end of Phase II, as you know, we've got breakthrough designation. They've received our protocol. It's the primary endpoint in our protocol for interim analysis. They've commented on multiple things in the protocol. This has not come up. So it's not just they agreed to something at one meeting. They have -- if they had concerns with this, there were multiple opportunities to [ improve at ].

Was it part of those conversations on accelerated approval where you also made some refinements to the definitions of the hard clinical outcomes?

Yes...

And what changes would you highlight in cirrhosis and maybe talk about...

So it was in the same conversations. So the context there is for outcomes, there's a guidance document which talks about what are the outcomes. Now remember, the predominant outcomes here in this patient population is decompensation events. There are other kind of MALOs or major adverse liver outcomes like MELD score, liver transplant, HCC, all cause mortality. But those are not going to be the predominant outcome events you're going to see when you treat compensated cirrhosis. Now when you think about the decompensation events, there are primarily 3 decompensation events. It's [ variances ], ascites and hepatic encephalopathy. The way the guidance document is written today, those are defined in a manner which is the extreme end of decompensation, okay? If you use that definition, Steve, it would take a really long time to reach your events. And so the discussion we had with the agency is that's a really long time period. It really does not -- it's not a tractable clinical study. You would be running the study for 5, 10-plus years. So for example, I'll use one example because for confidential reasons, we haven't disclosed exactly what the outcome definitions we've revised them to, which the agency has agreed to. But for example, the guidance document defines varices, the decompensation event as varices bleeds. By the time someone gets to a bleeding varices, it can be 5, 10 years. And that's the end state. Once you have a bleeding varices where your vessel has got so endorsed that it bursts, you're within 6 months from a really bad outcome or transplant. But no one goes from cirrhosis well compensated to a bleeding varices overnight. You have red flag signs, you have small varices, you have large varices and over time it gets there. But along the way, you do have clinically significant portal hypertension and you are decompensating. And so the discussion we had and the agency again agreed with us. So what they said is we agree with you that this might be too late. So it's earlier in that treatment, we will consider that as a decompensation event. And you're scoping these patients anyway to get this. I can make the same case for ascites, right? It's one thing to have 10 ccs of fluid in your belly. It's very different when you have a liter and you have complications from it and you got to draw it out. So that -- hopefully, that explains kind of...

Yes. And that's obviously the outcomes data that would be coming subsequent to the interim histology analysis of 2 years. And on that histology analysis, I mean, what can you say just about the subset of patients that informs that analysis, the assumptions that you've made on histologic response, why you made those assumptions? What were the inputs?

Yes. So the trial is set for roughly 750 patients. There's a subset of those patients, which I'm going to just call for this conversation, the histology cohort, who would be analyzed at 2 years where we would do a repeat biopsy to look for reversal of fibrosis. Those patients are the patients who are -- I'm going to classify they are the more well compensated patients because we want them earlier in the compensation paradigm so that we can show a nice reversal of fibrosis. How did we identify those patients? You look at multiple noninvasive markers because they're all F4 patients. And you look at noninvasive markers to define whether they're well compensated. There are criteria like the Baveno criteria about whether they have CSPH already, okay? To answer your second part, Steve, on the powering. We look at some of the historical studies. So when we powered the study, for histology, we obviously did not have the efruxifermin data. So we looked at some of the other placebo responses from other studies. So there is the Gilead studies, there was the REVERSE study by Intercept. And they were all in the low teens of placebo response. They were shorter. Now interestingly, the efruxifermin study came in about the same 14%. So we took a placebo response. And then we looked at what would be a minimum threshold and a conservative threshold for placebo delta we would expect. And then you look at power in Phase III, you typically -- you want adequate power. People will define as adequate power 90% or 85%, but you can imagine that. And based on that, we decided what the end is. What I can say is the numbers we took, you always want to go more conservative. Efruxifermin showed that FGF21 has the potential to have a pretty big treatment delta. That would reduce the sample size significantly. But in Phase IIIs you want to go more conservative. Like a minimum threshold, if you talk to KOLs, they will say in F4, a minimum threshold is a 10% delta. They'll start using the drug, 12.5%, 15%. That's a really nice treatment delta where they will see really good adoption because F4 patients are pretty difficult to treat.

The histology reading in the F4 cirrhotic patients, is this the same sort of consensus read methodology that we're familiar with 89 doing in the non-cirrhotic Phase II? Is it any more challenging to adjudicate the histology in F4?

No, we are planning to use the same methodology. There is nothing which is unique about F4 versus F2, F3 and how the pathologists read biopsy slides.

Okay. And are you confident in the bone mineral density profile of pegozafermin in cirrhosis, because that's an area where you haven't seen any imbalances in bone mineral density. I think you've commented -- I don't know that you've published the data, you've commented on the biomarkers there as well, not being significant or clinically meaningfully different in non-cirrhotic. But in cirrhosis, how do you gain confidence that there isn't a subclinical effect that would emerge?

So I think it's more, Steve, grounded in the biology and how our molecule we think might not be having that effect. Our database, the sample is pretty small in F4 patients. We've looked at it. We don't see it. But that's why we're going to monitor it in Phase III. But there's nothing to suggest that a particular product or a particular drug should have based on the science that much of a difference in what they will see in F3 versus F4 on DMD, okay? So it's grounded in that, which is what gives us confidence. And we did not see anything which is clinically meaningful or statistically significant in the F3 patient population. That's more the basis of our confidence. But look, that's why we're doing the studies. We will monitor it, and we're going to track it.

In the non-cirrhotic setting, maybe I want to start. I mean, the news we got last week from the FDA was this acceptance of a letter of intent to begin exploring a potential new surrogate endpoint in MASH and FibroScan specifically was emphasized as that potential surrogate endpoint. And as we looked into the pathway, it looks like this could take several years to play out and everything needs to be validated. But it was a step, and I think the Director of the Division of Hepatology and Nutrition, who has previously on AdCom sort of said your NITs are not ready for prime time is now saying this is the first long-awaited step. What's your just initial reaction to that? And obviously, it doesn't affect your ongoing Phase III study, but it may affect the field. So I'm just curious your take on that. And is that surprising? Or is that sort of comment expected for you?

So I think it is a good step and very encouraging development for the field of MASH development. I think the MASH development field has got adversely impacted because of some of the challenges with clinical trial execution, right? So I think it's a good step for patients. At the end of the day, that's what we are all in this business for is bring drugs to help patients. So I think it's good. You're absolutely right. The FDA has been -- previously was a little bit more reticent, did not signal that. There was a lot -- we knew there was a lot of work being done around the space, right? And we had heard that they were looking to put out a publication sometime, right? So here's how we look at it. We think this is the first good step. Now just to remind us on the process. So the LOI is basically they're saying there's enough to suggest that it makes sense to evaluate this. The next stage is you put together what's called a qualification plan, which you aligned with the FDA that can take 6 to 8 months on how you are going to validate this endpoint. Then you generate the data, then you create a qualification package, which you submit. So it's like a submission to the FDA, the basis on which it gets approved. Now this could take multiple years. I think what was interesting is, in addition to the LOI, they put out a publication last week, which [indiscernible] as the lead author. In the publication, they talk about that to get approved for a reasonably likely surrogate endpoint, you want to show correlation with outcomes. They then go on to say, oh, but in MASH, there are no outcome studies. But they do open the door to say, if you can show that based on medicine and science and the biology that this NIT could be predictive of an outcome, they would be open to it. And that's what I think they're going to do with liver stiffness or VCTE, right, because there are no outcomes. Now as it comes to our specific program in pegozafermin, see, we don't think it impacts us any way today, right? Because by the time this happens, we would have fully enrolled and hopefully read out studies. Now if I'm surprised and, let's say, December 1, they say, oh, VCTE is approved. We can easily pivot. We are capturing VCTE anywhere in our studies. We do it at baseline. We could then say, okay, moving forward, that's the enrollment criteria. And it is an endpoint for us anyway.

I mean I think importantly, having that data in hand, given the profound fibrotic benefit that FGF21 including pegozafermin have demonstrated, right, you would expect that to manifest in FibroScan as well. And to the extent some drug developers 10 years from now are developing drugs for NASH and they only have FibroScan surrogate data, you would have that to hold up against.

I mean, in the commercial marketplace, so we've seen, to your point, at week 24, it's placebo-adjusted like literally 3.6 to 3.9 kilopascal change. No one else has shown that at week 24 on FibroScan in F2, F3, right? So we have that. If I fast forward in a commercial setting, having that, if we replicate the same thing in Phase III with histology, I think our package is much stronger than a company who walks in and just says, let me show you VCTE data, right? Because we are showing you both on histology and on this NIT.

Okay. And then this Phase III study, I mean, top line data is guided for first half '27, I believe, which implies enrollment completion basically, let's call it, first half '26 or maybe even first quarter of '26. I mean we're approaching that. So how confident are you just in how this enrollment in the study is tracking in that interim cohort? And just the availability of semaglutide now on label in MASH, is that baked into your projections? And...

So I think it's going to be interesting to see what is the adoption of Wegovy, right, once they actually launch. We do have -- in the U.S., so think about it, this is a U.S.-based phenomenon because ex U.S., which we expect is going to enroll more than 50% of our study, a, it's not approved. But b, the adoption of GLP-1s and incretins is not the same level as seen in the U.S. So in the U.S., we do see a fair number of patients already coming into the study who are on incretins. So we require 6 months of stable dose. Now they might have already been on Wegovy, whether for the obesity or whether they could have been on it for diabetes, right? So I think that's going to play in, but time will tell how it is. On the OUS sites, many of them in many countries have come on recently. And so I think we are looking forward to seeing how that -- what's the enrollment we see OUS, which is going to be a big driver. What I will say is as the studies are progressing, this applies to both studies. There's a lot of enthusiasm from the sites, the PIs and they're screening a lot of patients. Our site activation is very good. So both these studies are north of 250 sites who have already activated. The F2, F3 study is actually going to end up north of 300 sites. The F4 study essentially has enrolled -- sorry, activated all the sites. So I think the next few months is going to be very interesting to see how it all plays out.

I think -- I mean, one of the key features of your program in non-cirrhotic MASH, that's really been attractive is you implemented the consensus read methodology in Phase II in a way that I think is identical to what you're doing in Phase II.

That's correct.

Are the pathologists themselves the same? Or are there additional pathologists?

So there are some pathologists who are the same. For the Phase III, just because it's such a large global study, you need more than just 3, like you end up using 3, but you just have a bigger panel because when you have 1,000 patients, just think about the number of slides coming in, right? So you have a bigger. But there are some who are common.

Okay. And then just on the role or, I guess, the impact potentially of both semaglutide and Rezdiffra on the study. I mean, how is it handled particularly in the follow-up for outcomes, if a patient -- are they allowed to start either of those drugs while being enrolled in the study? And how is that treated in the analysis of the outcomes data?

Yes. So what we do is -- so to enroll you have to be on stable dose today, right? And then we are stratifying for GLP-1 use. At this point, we're not stratifying for Rezdiffra just because we don't know how many patients are going to end up being on Rezdiffra. Are they allowed to come in is they are -- we are allowing people to change medication like GLP-1s, they change, right? But at this point, we have not -- we're working through are we going to allow patients to come in, say, fresh on to Rezdiffra. And that's something we're going to have to work through. But again, I'll go back to -- it's more relevant to your point on outcomes. At the end of the day, these are long outcome studies and physicians are going to have and need that flexibility to allow it because otherwise, how do you retain patients.

Has there been any change or evolution in the last couple of months just in the strategic interest in the space and with all the developments in MASH, what are you sensing that?

So there is a group of strategics who remain interested in MASH clearly. And FGF21 specifically, you saw one of the transactions done earlier this year was with an FGF21, which was the first MASH deal in multiple years. I think strategics see the value that FGF21 could be really uniquely positioned in advanced fibrosis. And then in cirrhosis, they clearly see this might be the target to beat or might be the only target, which is going to work, right? And there's a recognition that this is a large market. And it's getting more derisked as we move forward. So there continues to be conversations. We continue to have those dialogues.

Terrific. Well, we're looking forward certainly to the upcoming SHTG data, and that's a quickly evolving field, and you're squarely entrenched in that landscape. And then obviously, the MASH data in the coming years will be super exciting as well. So I just want to thank Rohan and 89bio for attending the conference and everyone in the room and online for listening in.

Great. Thanks, Steve.