Akero Therapeutics, Inc. (AKRO) Earnings Call Transcript & Summary

Everyone, my name is Liisa Bayko. I'm one of the SMID-cap analysts here at Evercore, and welcome to Healthcare -- HealthCONx '24. We're very pleased to have Akero Therapeutics join us today. We're going to talk about FGF21 and NASH with Andrew Cheng, President and CEO. So just start us off with a brief company overview, so we can get everyone on the same page.

Sure. So we're a Phase III company. We're in 3 Phase III clinical trials for this study of NASH/MASH, both pre-cirrhotics and cirrhotics. And we're excited to be there. We've announced that we'll be having our Phase III readouts in -- for the first of them in '26 and then in the -- our histology study sometime in early '27. But importantly, we have a Phase IIb readout in our cirrhotic study in next February.

All eyes are focused on that. We're going to come to that in a second. But I just wanted to step back and sort of reflect on the evolution of thinking of the NASH or MASH field. And we now have the first product approved. What do you think the early trajectory suggests about the MASH market? There's always been some controversy, right?

Yes.

No drugs will get approved, then drugs got approved, then obesity drugs also got approved. So there's been kind of this constant sort of like bear thesis, but I think Rezdiffra seems to be off to a good start. What is that telling you about the market and...

Liisa, I would say that you're not giving enough credit. Rezdiffra is off to a fabulous start. Their -- Bill has really done really, really well. And it really shows that the market really is there. And yes, the bear thesis, we've talked about the GLP-1s and we've talked about -- but what we're seeing in the commercial space is that there's a lot of patient demand. And I think it's fantastic for the field. And I would also say that we saw data from AASLD where it looks like semaglutide hit their primary end point for Phase III. So more likely than not, that will be a drug that they're going to file and will be -- probably this time next year, the drug will be -- obviously, it's already available for diabetes and for obesity, but it will be indicated for NASH/MASH. So I think that will be a very important step in the marketplace to have. While Madrigal is doing extremely well, their -- to have someone like de novo come into the space and be talking about the disease and talking about NASH/MASH is very important.

What do you see as the role of FGF21s? We're coming -- you're kind of coming in and one -- there's a couple coming together. You're probably in the pack more or less of this sort of new wave of therapeutics, right? What are we -- the role there as opposed to kind of what we can do now with the Rezdiffra and semaglutide? What do you see as a role for Akero?

I think we've demonstrated very well that we're direct acting antifibrotic. I think that's the driving difference in that both -- our data has shown that an FGF21 can work well in reducing fibrosis more rapidly than has been previously seen. And our 96-week data have really seen numbers that we really haven't seen. Recall that in March of this year, we released the 2-year data from HARMONY and 3 out of 4 patients had a 1-stage improvement in fibrosis. And when you think about what the effect size was compared to placebo, it was roughly 50%, a little more than 50%. And for the drugs that are available, that's not what we're seeing. And so when you think about -- there's no question, Rezdiffra is doing well. The GLP-1 results that we saw last month at AASLD was good, but they're not in that same zone. So I would say that when you think about patients who need that antifibrotic benefit in a short period of time that can't -- FGFs will play -- EFX will play a very strong role.

Okay. Great. So there are several -- as we talked about this next wave of drugs coming, FGF21s are a big part of that. And there are actually several in development. We saw some recent data from Boston Pharma at the AASLD meeting. Can you sort of talk about the differences between the molecules and how you think efruxifermin is distinctively.

Yes. So let's start with Boston Pharma, Boston Pharma and their molecule and EFX are more similar than the others because they're Fc fusion proteins. The Boston Pharma study showed a roughly similar effect size, a little -- numerically, a little bit greater than what we saw, 1% or 2% at 24 weeks, but very much validates the mechanism. The other one is the company you had just before in this session, 89bio. They have an FGF21 that's PEGylated. They've shown about a similar effect size, about 20% in their ENLIVEN Phase IIb study, but I'm sure Rohan talked about that a little while ago when he was here. So overall, those -- the 2 of the agents are Fc fusion proteins. Boston Pharma is dosed once monthly. I believe, in their study, they had 300 milligrams once a month, which was 3 injections because the concentration is a 1 ml subcu like ours is. So we're 1 milligram -- 1 milliliter subcu once a week at 50 milligrams per week. And then I think -- but I understand that for the Boston Pharma compound, I think they're not sure if they're going to take that dose into Phase III. I think there was some of the -- AE profile may not have been what they'd hoped for and...

Yes. I talked to them, too. It seemed like they might be exploring some lower doses as well. Yes.

Yes. So I think that's something that is unclear at this moment. And I think -- I've also heard reports that they may be looking to try to give a single dose, a single injection may be 2 ml subcu, but that's a -- hopefully, that's better tolerated. But in general, that's a pretty large volume for subcu injection.

Okay. So what do you see as the distinguishing features of efruxifermin vis-à-vis that backdrop?

Yes. I would say that the distinguishing features are really the efficacy that we've demonstrated. I mean no company -- granted they haven't looked at 2 years, but 75% is a pretty high watermark in terms of antifibrotic activity. And although all 3 of the compounds are roughly the same at 24 weeks, we -- it remains to be seen whether it's true at 2 years. That's what I would say.

And what -- how -- what's the presentation of your product in Phase III? And what will it be for commercial?

Yes. So the presentation -- the Phase III presentation is the commercial formulation, which is a dual chamber injector. So it's a lyophilized compound. It's a 2-plunge injector. You push one chamber, which is the diluent into the lyophile. You invert that for a short period of time. And then you push the plunger a second time and you -- that's where the injection goes. It has a needle guard -- It's a 27-gauge needle, small volume, 1 ml, as I mentioned earlier. What's nice about that is that it's stable at room temperature. There's no cold chain storage needed for that. You take it home from the pharmacy, it can sit on the shelf in your kitchen or bathroom, wherever. And at the same time, once you push the first plunger, you don't need -- it's stable like that for 24 hours. So if you wanted to do that and do it the night before or the morning of and inject at night, that's your choice. So it's pretty flexible. It's a patient-friendly -- and it's not -- the technology is not unique to us. This is a previously patented formulation that's been approved for other drugs in the United States and in Europe.

Well, all eyes are focused on your upcoming data and we've been through this before, and we debriefed on that. And I actually was more optimistic than I think the stock would have shown. I thought there was a pretty decent signal there. Maybe it didn't -- wasn't a highly a [ stats ] thing and all that kind of stuff. But I guess, how are you thinking about the data now -- ahead of the data?

Sure.

Knowing kind of what...

What happened last October, yes.

What happened in the past and what kind of is...

What am I guiding?

I don't know, I mean, you've already started Phase III.

Correct.

So like, what is the purpose of the study? What do you get out of it? What are you looking for? Does it change your thinking about Phase III at all? All that...

All right. So there are a lot of questions there, Liisa. Let me see if I can dig through them.

You have 10 minutes.

Exactly, to dig. So what I'd say is that last fall, we looked at week 36, and it didn't hit the primary endpoint. It wasn't statistically significant. Yet at the same time, and the stock responded the way it did. Yet at the same time, these were the strongest results ever seen in NASH cirrhotics. Most of the other studies have been placebo-like. We had a roughly 10% effect size. What we're guiding towards and talking about is that with longer-term dosing, we believe that things should improve. And keep in mind, we're not powered for week 96. And as you mentioned, we've already started Phase III. We believe that this drug works. But what's helpful to us is that, let's say that things improve both on the EFX arm, it helps us guide our Phase III study. For instance, let's say we look at what are predictors of success, people with x kind of thing seem to have a response. We can amend the Phase III study to modify that. We just enrolled our first patient in September. We obviously -- it's more than 1,000 people. We have a long way to go to enroll that study. So there are ways that we can enhance the efficacy of the study. And recall that the primary end point for histology in that study is at 2 years. So this is very much an on-point endpoint. And we believe that even we'[re not guiding, we don't expect it to be statistically significant. We expect it to improve a trend towards improvement. And I think that would be very satisfactory to us. And numerically, some people have thrown out numbers. We had a 10% effect size. Let's just theoretically say, and this isn't -- I don't know the results. Let's say we had a 20% effect size, things improved, but it wasn't statistically significant. We only have 150 people in this study. As I mentioned earlier, our Phase III study is 1,000 people, the likelihood that with a 20% difference, you know what the probability of success would be. So I think we'd be encouraged by that. So it gives us a little bit of a preview of what could be. And it also tells us more about our compound. We just -- to have 2-year data in cirrhotics. It's not very common for studies in this field to: a, look at cirrhotics; and b, have sort of 2 biopsies. So I think it will be very helpful.

The thing I found encouraging is that it seems like your biomarkers seem to continue to improve. Can you maybe speak to that a little bit?

Yes. So I think in the -- we learned so much from the 96-week data in the pre-cirrhotic population. I think very much is on your point, is that what we saw is that things like FibroScan. They didn't plateau at week 24 or at week 48 or week 72. They continue to improve over time. And it makes sense. Same things with markers like Pro-C3, which is a marker of new collagen synthesis. It shows that we shut down new collagen synthesis, yet at the same time, we know that the degradative processes are ongoing. So if you're not making new collagen, but you're continuing to degrade it, it means that longer-term dosing would likely lead to the fibrotic changes and the benefits we saw at 2 years. I mentioned earlier the 75%, recognizing -- and the 50% effect size, whereas we saw roughly about a 20%, 21% at week 24. Now the difference in cirrhotics, of course, is the fibrotic burden is much greater. So will we have that magnitude of effect? Of course, not. But would -- should things improve, we very much expect them to improve. How much so? I think that's -- we'll wait and see.

What do you know about the sort of discontinuation rate in this study right now? Because that's one thing, I think, a lot about, right? This is a very long study. You're asking people to come in for yet another biopsy, albeit a third one, right? So, I mean, not a lot of people want to sign up for that. So I guess you maybe not have the full picture so far, but what do you understand about the discontinuation rates? And how will you interpret the data in that context?

Yes. I think it's very important to look at that. The discontinuation rate, I think, for these patients, there always -- there is some background, right, of discontinuation. I guarantee that we will not have the same number of patients we had at week 36, at week 96 because of the reason -- this, unlike the Phase III commercial formulation, this visit involves a weekly visit to the doctor's office to get the injection. It's a frozen solution, a Phase IIb solution. And for some patients, they just can't do that. That being said, unlike in phase -- the other Phase II study, HARMONY, which was for pre-cirrhotic patients for which there's an approved drug, there are other -- a lot of other trials ongoing, there really are very few options, unfortunately, for these patients. And they know, not on an individual basis, but they know how the study has read out, that 1/4 of patients after 36 weeks are no longer cirrhotic. Because these patients are sicker, they have a lot of incentive to stay in the study. So there is some, what we call administrative discontinuation. But I think we're pretty confident that we'll have a meaningful number of patients at week 96. It's not going to be -- we don't have 100% discontinuation.

You do have a sense? And can you share what the discontinuation rate is so far?

We haven't fully analyzed it yet, but I would say that we're -- I think when people think about it, people ask, well, is the discontinuation rate -- where would that be? I think for -- what we sort of give guidance that the discontinuation rate for adverse events is not linear when one thinks about 36 weeks, 9 months and you're going to dose another 12 months -- or excuse me, 60 weeks, a little more than 12 months, it's not 1.8x that. So the people who can tolerate the drug do tolerate it and have every incentive to stay in the study. But there are people who leave for administrative reasons. They -- the parent gets sick and they have to -- they go to Mexico or frankly, they have a new job and they can't continue to come in for weekly visits or the reason I mentioned earlier is just they -- when they -- they stay on the study as long as they can, but there's a point in which it just doesn't work for them.

And how will you express the data when it is reported? Will it -- are you focused on like per protocol? ITT? If you use some sort of imputation, can you...

Yes. So I think right now, we're thinking very much like we presented the data in the past for the 96-week data for HARMONY. So that is -- that will prevent -- what is the primary analysis, it's not the primary endpoint, but the primary analysis has been a completer analysis, but we'll also show an ITT analysis as well.

Okay. And for ITT, will there be any imputation for missing data? And how will you do that?

So we're still looking at that. I think we're looking at it multiple ways. And certainly, after we saw the Lilly data and how they've imputed for missing data, certainly something we're looking at.

Okay. And will you be also evaluating patients who did respond at 36 weeks and sort of the continued response there? Okay.

Very much so. So much as we did for the 96-week HARMONY data, we're looking at people who had a sustained response from week 36, and we saw it was roughly 90% of patients who were successful at week 24 and HARMONY maintained the results at week 96. At the same time, there were roughly -- the number of responders was almost equal in terms of people who, not only maintained, but new responders who weren't responders at week 24. So we're hopeful that we'll have additional responders at week 96 that weren't there at week 36.

Now if we kind of get confirmation through the study that this is, indeed, could be a drug for cirrhotic patients, does that change the way you think about pricing? Because that's maybe different from kind of...

Certainly.

It's different in a way, at least so far from what we know about. They have a Phase III ongoing as well and...

I mean, I think when one thinks about it, drugs that serve more advanced medical needs in general are priced differently than drugs that -- and smaller populations are priced differently than those that serve larger populations. In terms of the numbers, we're pretty early. We don't really have -- we're not as far along as that.

What's your thinking on kind of the bone effects you've seen? That's been a hot topic.

Yes. So I think we saw roughly about a 3% bone loss at the lumbar spine at 2 years in pre-cirrhotic patients, and that compares at 48 weeks when we looked at BMD and HARMONY, we saw no difference. It was placebo-like. So I think it's -- when we talked to our bone endocrinologists, for the majority of our patients are postmenopausal women in that study, and they expect to lose about 1.5% per annum, per year. So 3% is not that different. It's a pretty small amount. That being said, that the patients, a number of the patients had pretty poor bone health, and there were therapies that are already approved that weren't being followed. So when we look at that, they had, a, poor vitamin D levels; they weren't taking known anti-resorptive agents. So I think it's something that we're pushing harder in Phase III to say, "Hey, these patients do have advanced bone disease coming into the study. What can we do to get them on treatment?" So I think it's -- we'll be looking at the picture slightly differently in Phase III.

Do you see efruxifermin as a chronic therapy or maybe something you take for several years, kind of get your liver in better health and then sort of maybe take a holiday...

We don't really see that. I think the example would be what you see with the GLP-1s in diabetes, that when they get the target of 6.5, they don't discontinue them. Because the challenge for them is even if their fibrosis status improves, they still have the same underlying disease. Chances are that they're just going to get worse if they take them off the drug. So I think we see it as more of a chronic drug.

And what do you -- do you see opportunities beyond NASH -- sorry, MASH fibrosis?

We do. So we're beginning -- things that are direct-acting antifibrotics, that's something that the field of medicine needs very badly. And if -- drugs that work in this indication could also have other indications that we're considering.

Tell us briefly about your manufacturing and where...

It's being manufactured in Europe. It's -- we are not -- we have no exposure to China.

Okay. That was the...

That's what you want to know.

That subtle question there.

Yes. I understand. You're not the first person to ask me.

Okay. So give us a view, Andrew, on 2025. We know that the big data is coming early in the year. Anything else to look out for in 2025? And then just a comment on your cash position, how...

Sure. So the big data is in February. We have other analyses that we're presenting at EASL, taking at additional analyses that we have as we just did at AASLD. And lastly, since the light is red, I'll tell you that the -- our cash position is we have roughly $780 million in cash. And that takes us into the second half of 2027.

Okay. Wonderful. Thank you.

Thank you.