All right. Good morning, everyone. Thanks for joining us here on day three of the Leerink Partners Global Healthcare Conference. My name's Tom Smith, one of the senior biotech analysts here at Leerink, and it's my pleasure to welcome our next company to the stage, Altimmune. Very happy to be joined up here by CEO Jerry Durso, CMO Christophe Arbet-Engels.
Good job.
CFO Greg Weaver. Gentlemen, thanks for joining us.
Thanks for having us, Tom
... looking forward to the-
Good to see you again.
Looking forward to the discussion. Jerry, maybe you could just kick us off. 2025 a big year of clinical data for you guys. Also your regulatory feedback, and now we're moving into a phase 3 MASH program. I think there's quite a bit of an excitement around that. Maybe just kind of recap the 12-month highlights and then what we're looking forward to here in 2026.
Sure. It is gonna be an exciting year for Altimmune as we take all of the progress and now move the company forward towards execution of phase three. We had two readouts from our phase II MASH trial in 2025. You saw the 24-week data at midyear, and then we came with the 48-week data right at the end of the year in December there, again, which we think gives us a real good view of what pemvidutide can potentially deliver in the MASH patients population. Had an excellent discussion with the agency at our end-of-phase II meeting. Received breakthrough status, a breakthrough therapy designation, and got good clear alignment with the FDA on the main elements of the design for the phase III. A lot of progress.
At the same time, we have two phase II trials ongoing and other indications, MASH being the primary focus, but we'll deliver the phase II from our alcohol use disorder trial, AUD, that we're guiding towards top-line data in the third quarter of this year, as well as our alcohol-related liver disease trial, which is also in phase II, where we expect to complete enrollment. A lot happening. We've learned a lot about the opportunity to really differentiate pemvidutide. We believe very strongly it's a differentiated opportunity here in the MASH population, and so we can go into those elements, the phase III design, and I'm sure some other points on the finance side you wanna talk about.
Yeah. We're gonna hit on all of that. Let's bring us back high level and differentiation on Pemvi relative to the other incretins that are out there, and then specifically, I guess, probably the most question around survodutide.
Yeah
which is also a GLP-1 glucagon. Why do you think you have the right balance of receptor agonism?
Yeah, I'll start, and then Christophe can clearly go deeper. I guess we start with the mechanism. It is a combination of glucagon and GLP, and you mentioned the word balance, and we think that's really one of the most important elements that is underlying some of the potential differentiation. Unlike any of the other compounds in development that we're aware of, it is a one-to-one ratio, and so you're getting the direct effects of glucagon on the liver, you're getting the benefits of GLP on the metabolic side. Tom, you know, we've been talking for a long time in the MASH development space about that fact that it's a complex disease, it's multifactorial, that combination therapy is probably ultimately gonna be a good therapeutic strategy.
The fact to deliver combination therapy with one molecule is the exciting part of the excitement here, but also the specifics of what pemvidutide delivers, and maybe Christophe can touch a little bit about the mechanism and the data in more detail.
Sure. Yes, there's two parts, the glucagon that everybody knows and the GLP-1. It's really important to have this 1-to-1 ratio for this direct effect on the liver and the metabolic causes of MASH through the GLP-1. Where we differ is in the fact that with survodutide they have a very different ratio. It's close to seven to one so it's more focused on the GLP-1 and maybe less on the direct effect. What we have is the tolerability and on this chronic disease, which is specific to pemvidutide. We've shown that we have this EuPort domain linking the two peptide in order to deliver this one-to-one ratio, and that also has an impact on the delayed Tmax and the lower Cmax.
We have seen this in our phase II study, where actually more patients remain on drug. The higher the dose we give, the more patients remain on drug, and these patients really appreciate the treatment. We believe it's critical. It's very different than what we see with survodutide that has a very big issue on tolerability. A lot of discontinuation, I think they're like 23%-26% discontinuation. We've seen less than placebo rate of discontinuation, and we believe that all those two aspects, this balance ratio and that tolerability, will be well suited to treat patient chronically on the MASH, on the metabolic causes of MASH, and keep them for longer period of time.
Yeah. Really encouraging tolerability, certainly relative to the other incretin options that are in development. Yeah, I wanna dive in a little bit more on the clinical data. You had the phase II IMPACT study, six-month histology data, MASH resolution, excellent. Fibrosis improvement, strong trend, like narrowly missed statistics, but looks active, clearly active. Do you think with a longer time, I guess, like, what is the level of confidence that with longer treatment duration, you would have hit on fibrosis improvement in this study?
Yeah. In that phase II, the biopsy, the histology endpoint was at six months. I said before that when I was considering joining the Altimmune journey last year, first as a board member and then transitioning into the CEO role, that was one of the questions that I had. To me, the 24-week for this mechanism seemed optimistic, based on the mechanism, what we know about the time it may take, based on what we see around variability and placebo response in the myriad of different phase II studies out there, based on the fact that the two approved drugs missed on phase II, went a little longer in phase III, and hit on that endpoint. I think it was probably a little early to read.
Christophe can describe what we saw at 48 weeks, which again, was not on histology, but on non-invasives, where we clearly see continued improvement on the antifibrotic effect, and we think that 52 weeks is the right time to read out in phase III and that's how the study's being set up.
Yeah, I mean, we were happy with the 24-week data, and we went to the FDA with this data because they clearly showed the MASH resolution, which is a prerequisite to show this improvement on fibrosis. We also show good, very strong indications of an antifibrotic effect from the molecular cellular biology levels all the way to the clinical level. As we know, biopsies are very variable. There's a lot of challenges, and with our mechanism of action, as Gerry just said, it was probably very ambitious to try to demonstrate the statistically significant effect on the biopsy at week 24. In our week 48, we continue to see that improvement. We very strongly see the markers, the non-invasive test, going in directions that are very solidly antifibrotic.
We've looked at them in the ones that are relevant for histological changes, and they clearly show very strong differences. We are confident now that we can move with that 52 weeks data and of 52 week endpoint in the phase III, and that we should be able to demonstrate that antifibrotic effect then.
The other upside we'll look at in phase III, as a reminder, the 1.8 milligram dose was kind of the anchor dose that looked very strong, well-balanced, great tolerability, weight loss continuing in phase II. We will also test the 2.4 milligram dose in phase III, which gives us another potential upside opportunity on the efficacy side.
Yep, that makes sense. As you look through, and I'm thinking to the 48-week data and what you saw on the non-invasives.
Mm-hmm
In certain subgroup analyses, I guess, anything jump out there? Like, as we start kind of planning forward, like, are there certain subpopulations that appear to be responding better on some of the non-invasives than others?
I would say that for now, I mean, we're finalizing those analyses with our data right now, but it's fairly standard to what you see. It's standard to what you see with regards to the F2s, F3s, with regard to the genders, with regard to all these things, the type 2 diabetic patients. We haven't seen something that would be out of range here. It's a consistent pattern where we see efficacy first, very strong efficacy, not only on MASH resolution, but on the antifibrotic aspect. We see clearly the weight loss, and we see that good tolerability that in our mind is a key factor for this chronic disease.
Got it. Yeah, I wanna come back to the FDA feedback and alignment on the phase III, and maybe you could just elaborate on some of that feedback, plans for kicking that off, and then talk about the dosing too, 'cause you alluded to going to the higher dose here historically, but also I think introducing a titration scheme to get to that higher dose. Let's talk a little bit about that and sort of the implications for that.
Yeah. Maybe we start.
Yeah
With the titration because it is an important element. As a reminder, we did not titrate in the phase II study. All of the other injectable options being tested here have a very complex
Onerous
four or five or six or seven
Mm-hmm
Step titration process. We're looking at a much different approach, but we do think it's prudent and wise to titrate in a simple approach in our phase III.
The way to look at it is what we've learned from the phase II is actually we can have some upside even further on tolerability, even by going higher. Our 1.8 milligram dose, if we give it a very simple titration step to titrate, we can improve tolerability. That tolerability also is an upside for us in the sense that now we can test, it allows us to test that 2.4 milligram dose where we could see added efficacy 'cause we know that we're gonna have added weight loss and maybe some subpopulation responding even further to this higher dose and exposure. We believe that the very simple titration is actually that upside that will allow these patients. We know that one step is an easy one. You were asking about survodutide before.
It's a very lengthy stepwise approach that actually HCPs do really don't like. What we've tested is like how a one-step or a two-step in the case of the 2.4 would work with these HCPs, and it's a very easy things to do. They don't see that. Actually, they prefer having a better tolerability than just a very simple titration.
That makes sense. We're coming with a 52-week endpoint here, not unlike what Madrigal used for approval for Rezdiffra, but it is a shorter time point than obviously semaglutide for their approval. What was the, I guess, consideration on duration of dosing? Obviously, again, you saw the encouraging efficacy at six months. I guess for semaglutide, what do you think is added, I guess, in that last six months of therapy, maybe on their histology readout?
I think we get all of the benefits of the dual mechanism, right? I think we have the. We know that semaglutide took 72 weeks to read out. We know there are some mechanisms like FGF-21 that have been effective on histology at 24 weeks. We know we're bringing more than the GL-
GLP component because we're bringing the glucagon into the picture. That's a significant differentiation, we think, in the time to fibrotic effect versus those that might be looking at a 72-week endpoint. We look at all the 48-week data, and particularly those non-invasives on fibrosis and get comfortable that 52 weeks is the right timing to read out on histology for pemvidutide.
Yep, that makes sense. Can I ask you, I feel like sort of historical concern around the glucagon agonism has been glycemic control.
Mm-hmm.
particularly obviously in patients with diabetes. I guess, what did you see in IMPACT in that subgroup and, like, how do you get comfortable around that?
Well, on this, we are very reassured that actually we can maintain glycemic control, good glycemic control, both in the non-diabetic and in the type 2 diabetic patients. We also do not increase heart rate, which is something that you will see with a lot of the GLP-1-focused compounds. Some of these concerns seem to not be present, at least for what we've seen so far, and allow us to actually go all the way to this 2.4 milligram dose. Maybe that the ratio is also very important here. I think back to this, we're starting to understand better and better why it does matter and why on certain aspects or attributes of differentiation, that 1:1 ratio is critical.
I wanted to come back and dig in a little bit on the FDA feedback. I think you also got alignment on using AIM-MASH to help evaluate the changes in histology. Just talk about it. First of all, level set, like what is involved with AIM-MASH, and then how do you think this is gonna help you and potentially provide like a differentiated look on histology?
I mean, I'm happy to jump.
Yeah, go ahead.
We are right in the middle of putting all this together with the pathologist for the phase III. Clearly, this is the first trial that will implement this in the phase III. The company, PathAI, claims that this is improved variability. It's gonna streamline the process, so accelerate how the pathologist can look at this. If you understand this, basically the slides are put on the screen, and the system points to what the features are. Every single pathologist will point at this, but sometimes the pathologist will see something else or add to this. It's still the pathologist which is responsible for it. For us, we consider this, we're not powering differently.
We're considering this again as an upside that we could look at because this is if we can decrease that variability, decrease that placebo effect you can see in early readouts of MASH biopsy, you're gonna improve your endpoint. So it's all upside. We're trying to build our approach with a fairly conservative approach, but in the meantime, building on the upside that we'll be hopefully looking at at the end of the trial. Yeah. It's good to see the FDA make this step.
Yeah.
Towards the clearance on the tool itself. We've been talking for a long time about the challenges with biopsy. We found them very receptive. It was good timing. They had just cleared the AIM-MASH Assist tool. Overall, I think we get a good sense of what it might bring to the process. But as Christophe said, importantly, we're taking a conservative approach with powering, so opportunities for upside, along with all the accumulation of learnings about what can help on the consensus process, which pathologists, how they're trained, all of that in a really robust process that again Christophe and the team are landing now as we put the final details on the phase III plan.
It's great to see their willingness to incorporate this. Yeah, it should be very helpful, hopefully fruitful and give you a really robust look at the histology changes. I wanted to ask because you are. You know, the FDA has also signaled a willingness to consider non-invasives and regulatory path exclusively on non-invasives. I think directionally, everyone acknowledges we would like to move away from liver biopsy for a whole laundry list of reasons. But you recently engaged with the FDA, and so I wanna, I guess, get your sense of having gone through this process, kinda like what's your sense of where they are in the process of acceptance of the NITs. We've heard them make very overt statements and also take very, I think, like tangible steps towards it, but it seems like we're maybe still early to middle innings.
What's your sense?
The FDA was pretty clear. I mean, this is one part again, where clinical practice is ahead of what the regulators are. The FDA was clear around that it's premature to use the NITs right now. However, given that they've already moved with the AIM-MASH, given the pressure from the clinicians and the clinical researchers, it is not impossible that the FDA could be moving during the conduct of the trial to accept those NITs. We have built in the phase III in order to be able to address this, all the NITs that could be available and considered, in particular the ELF, the LSM, the liver stiffness, the VCTE, and we're trying to.
We could be switching or pivoting very rapidly in the case that they would consider this as an endpoint.
Interesting. Okay.
Yeah.
From a practical implementation standpoint, as we think about enrollment, like are we stratifying, I guess, by any of the NITs with the idea that maybe one of these could end up being like having that registrational path?
We are looking at F2, F3s on very specific criteria based on those NITs. Remember that the accelerated approval, the Subpart H, is based on biopsy so far, but we're collecting the NITs in this population as well. For some of the patients, sometimes you can have them, they're just F2, F3s based on the NITs assessment, or we believe at least they're F2, F3s on NITs assessments, and we'll take these populations toward the accelerated approval and then the long-term outcomes.
I think Christophe and the team have done a smart job. The study has two cohorts. There's the biopsy-proven cohort, and then there is the second cohort, which, as he said, will contribute both to the safety and the long-term outcomes, which is an NIT identified population.
Yep.
We should have a really interesting data set. If the agency evolves their thinking, I think we'd be in a good position. However, the study is designed with the primary endpoint at 52 weeks to be on histology at this point.
Yep, that design makes sense. Okay, maybe one last regulatory question. What is the sense of alignment, I guess, on the European-
Yep
side and yeah, how aligned are they with FDA?
Right. No, we definitely are having a global program, so we're definitely aligning with the Europeans, the EMA and the MHRA. We have alignment already with the FDA. We've done some homework, and we have a regulatory consultant working very closely with the EMA or MHRA. Our design and our setup currently should be very much aligned with those two agencies, so we don't expect anything much difference in our approach. That allows us to move with where we are right now and the design of the protocol as it is now.
Got it. That makes sense. We've talked a lot about the F2, F3 data and plans.
Mm-hmm.
How are we thinking about F4s, compensated cirrhotics?
We think there's potential for Pemvi in the F4 population. At this point, our focus is on the F2, F3. We'll continue to evaluate, and again, in a company our size, we will also wanna make sure with a major phase 3 to start this year that we're focused on the first priority, which is the F2, F3.
Yep, that makes sense. Gerry, you brought up we've been saying this for a long time. We've been talking about this for a long time, the move toward polypharmacy.
Yep
In general. How much have you generated preclinical data in combination with other mechanisms, so THR-beta or FGF-21 or like how are you, I guess, thinking about clinical development in a world where you have multiple approved classes of therapies, and then like how do you see this playing out long term?
Yeah, I think it's gonna be an important strategic question for all of the players in MASH. We clearly see an opportunity for Pemvi as monotherapy for certain patients, and we know there'll be a desire to consider combining different mechanisms together out there for different patient populations. Maybe Christophe wants to give a little bit about how we think about that and maybe some of the reasons why Pemvi might be a really good drug to consider in combo regimens.
Some of those patients will be multi-medicated. They will have a lot already of potential side effects. One of the things that pemvidutide brings to them is the opportunity to be, I call it, the agents of choice for them to be taken on top of an FGF-21 or resmetirom, for example, those kind of mechanism of action because of its very good tolerability and safety profile. You basically add efficacy as you see fit in your patients without increasing the burden of side effects, and I think that's quite unique. In general, you add more GLP-1 or even a GIP that creates more GI tolerability issues, discontinuation rates that go and/or we have also on the weight loss.
We have, for example, as we believe it for now, some lean mass preservation effect that if that's were to be really the case, it's important. FGF-21 have osteoporosis and bone issues. You don't wanna add muscle mass loss in that population. There are a number of aspect like this with pemvidutide that are quite unique that we believe could very much allow it to be an agent of choice to be combined with other therapeutics.
We'll look at that.
Yeah
do work on that consistently as we progress the program here.
That makes sense. I'm sure you've generated some market research. I'd like to hear kind of what the research suggests here. When we think about the incretin landscape as it relates to MASH, you have sema that's approved, so you know, kind of pole position in the space doesn't have anything beyond GLP-1, right? You know, some potential obvious advantages for a dual agonist or potentially even a triple agonist. Longer term, like how do you think the choice of incretin in MASH is gonna be driven among clinicians? Is it efficacy? Whoever achieves like the greatest fibrosis improvement at a certain time point, is it safety, tolerability? Is it potentially like less frequent dosing? Like what's the most important driver, you think?
I think we're learning a lot and some of this gets to your earlier question, Tom, around the patient segmentation. There will be the way that the physicians are starting to think about the market when there are multiple options beyond what is today is about patient segmentation. We know that there are specific patients, a lot of good portion of them, who will have tolerability issues on some of the other incretin therapies. We know that even today, as sema starts to get utilization in the MASH population, it's difficult to get patients to the target dose. We think that may also be the case with some of the other new combos that are being developed right now.
You might imagine a world where GLP monotherapy is appropriate as the first one for certain early patients. Many of those patients might need escalation. We think there might be in the middle a great opportunity for pemvidutide. Again, we do believe that if phase 3 reads out as we would expect, you're not gonna sacrifice anything on the efficacy side with pemvidutide, and you're gonna bring potential for a quality of weight loss, which might be really important if you think about the significant numbers of patients with MASH that are at risk of sarcopenia. We hope we'll be able to keep patients on therapy. This question around successful therapy in the real world relies on patients being on chronic therapy over a long period of time to get the benefit.
Again, we think that we have a real opportunity for differentiation there. I've always thought that the MASH market will grow up like a typical chronic class, where you'll have multiple mechanisms where you could have oral and injectable therapy, if you think about what the diabetes market looks like, for instance. There is a significant unmet need, and it's gonna be about differentiation, and that's where we feel we will be able to develop a really interesting data set in phase 3 to leverage with the market eventually.
Yeah, that makes sense. I want to shift gears and talk about you have two unique phase two programs in alcohol use disorder and alcohol-associated liver disease. Just kinda like level set us. What drew you to these indications and scientific rationale there?
Yeah. The headline and what drew us in was large unmet need and indications where we think the unique profile and mechanism of pemvidutide can impact the unmet need. That's what led us to AUD and ALD.
The mechanism of action is again very interesting for us because right now you can see GLP-1 addressing the craving, the reward system. We know that these patients already have some type of liver disease already in the AUD. ALD is kind of a more advanced form, if you wish, of it. Here we can target with our mechanism of action the liver directly, even if they have low levels of fibrosis, early fibrosis, for example, and we target as well the craving system. Those two combined are really important. The last point, again, and I'm coming back to that tolerability, especially in AUD. These patients don't feel they are really sick.
They are like you and I drinking a little too much, and they just want a kind of a drug that's not gonna start making them sick or sicker. This is one big advantage. For the ALD, the lean mass preservation is really important because this is where this population is at really high risk of sarcopenia. We have a really well set mechanism of actions to target this population, and it fits well with the entire liver serious liver disease perspective here.
Yep. That makes sense to me. You have an important readout coming up in Q3.
Yep.
from AUD, and
Yeah.
Help us think through endpoints and, like, what bar for success should be there? What does a good readout look like?
Yeah. We'll capture a slew of data, and maybe Christophe can quickly describe the
Yeah.
the multiple elements in there.
The previous drugs were approved on zero drinking days. The FDA has moved now on even WHO risk approach. We're taking all of this into consideration, but our endpoint is mostly the heavy drinking days. In this population, we've taken, I would say, a slightly, again, conservative approach because we haven't tested that population. Hopefully, the trial will show the benefit of it, and we'll be able to start thinking to be having discussions with the FDA on how to approach the next step based on this data.
What, I guess in your sense, like, what is a clinically meaningful reduction in number of drinking days?
Right. The way we've set that up is actually on average number of heavy drinking days, which is in the male more than 5, I'm being technical here, but more than 5 drinks per day or for female 4 drinks per day. We're looking at approximately just a 1-day difference between these two. It's that's kind of how we've powered the study to see that difference. We understand in that population there is a large placebo effect. We're also having that blood test, the PEth, phosphatidylethanol test that allows us to have a more objective because it's patient-reported outcome. It's a little. Patients tend to underestimate.
Underreport. Yeah.
That will give us a more objective read on exactly the impact of this.
What could be, assuming positive data, the next steps and, like, what does that pathway look like?
Yeah. We'll consider everything with the data in hand. We know there is a regulatory pathway on this indication, and we'll come back with the data and advise on next steps.
Excellent. Great. Well, unfortunately, we're up against time, but thank you to the Altimmune.