Hi, good morning, everyone, and welcome to the Altimmune session. I'm Annabel Samimy, Biopharmaceutical Analyst here at Stifel. We're pleased to have with us today CEO Jerome Durso, Chief Medical Officer Christophe Arbet-Engels, and CFO Greg Weaver. Altimmune has really solidified its focus in liver disease and cardiometabolic-based MASH and alcohol-related diseases such as AUD and ALD. We saw some very strong indications from the phase II trials in both MASH and AUD, and now you're starting your phase III in MASH with a rational design. First, why don't we get a quick overview of where you are? Jerry, maybe you can tell us what attracted you to Altimmune and where do you feel you stand today as far as these various liver diseases?
Thanks for having us today, Annabel. Glad to be on board. It's an exciting time for Altimmune. Really what brought me into the company was the asset pemvidutide. I think, as you said, real significant opportunities across a variety of different liver diseases. At the heart of that is pemvidutide. Really what we continue to see evidence of as the data emerges is a differentiated opportunity across MASH, and we'll touch a little bit around the emergence of our AUD data and the significant incremental opportunity that that creates.
I think, first of all, pemvidutide, because of its unique molecule, the dual mechanism, bringing glucagon and GLP on board in a way that seems to create great tolerability with an emphasis of keeping patients on therapy, we've seen from our clinical studies we think is really uniquely positioned across a variety of different liver diseases. Again, based on the data we saw in phase II, we've been heavily focused on advancing our MASH program and really transforming the company. As you mentioned in July, really exciting data in AUD from phase II, really we think the most robust data set in AUD, and now allows us to approach the next steps of the company with a real opportunity of a liver franchise here.
I think we're continuing to learn both from the clinical data and from the significant market research that Linda and the team are doing, that the proposition is strong with customers, is unique with customers, and really creates a lot of excitement here about the work ahead.
Great. Linda, I apologize, I forgot to introduce you.
That's okay.
As the Chief Commercial Officer. Okay, first on MASH. The landscape has obviously seen Rezdiffra and GLP-1s approved in the last couple of years, and perhaps soon some other stronger agents. So where do you think pemvi sits in this treatment landscape right now, and what could be evolving into a little bit of a broader treatment landscape?
Yeah. Maybe, Linda, you start on that one?
Certainly. I think what really gets to our benefits are the differentiation pieces, right? We've got the direct-acting liver effects, the metabolic activity, and MASH resolution early. We have a patient-friendly product that has great tolerability, and we've seen that evidence to date, with minimal titration, which is much different than some of the other agents. Along with this potential to not only show efficacy in MASH, but do it in a way where you have quality weight loss. We're looking to evaluate lean muscle mass preservation in the MASH population. Other people have demonstrated it in obesity, but we want to look at really the nuances in MASH. Then you couple on top of that the alcohol use disorder and the halo effect we've seen in the market research on MASH uptake.
When you know that when you look at it and see how important not drinking in MASH can be, it can actually really hurt the outcomes for patients who are being treated for MASH. Looking at the ability to reduce drinking, we'll be studying that with PEth testing, really gives us multiple shots of differentiation on goal to help a variety of patients.
Okay. There are a couple of other GLP GCGs in development, and GG Gs. Can you talk about pemvi in relation to survodutide or retatrutide and how you might be able to stand apart from that or even get share of voice in that more specific landscape?
Yeah, I'll turn it over to Christophe, but maybe a couple things on the front end of that. We continue to, again, be excited by the mechanism. For us, the mechanism matters, the ratio matters, and the molecule matters. All three of those together is really what we think separates pemvi from the other glucagon GLP combos that are in development. Christophe, maybe expand a little bit.
Sure. So pemvidutide is a 1:1 ratio glucagon GLP-1 dual agonist. Survodutide is actually a 7:1 glucagon to GLP-1, so it's mostly a GLP-1 with less affinity for the glucagon. You ask about retatrutide. This is mostly a GIP with 100-fold difference in the glucagon affinity, and this one is a suboptimal affinity for the glucagon receptor. What we've seen in survodutide is an effect that confirms the dual agonism and the effect that we see, the direct impact on the liver and also the added impact on the metabolic aspect, like weight loss. But we've seen also very large discontinuation rate in clinical studies. In the studies that were presented, survodutide showed close to one patient out of four that was discontinuing under the conditions of a clinical study when there is heavy supervision.
We are a little concerned that in the real world, this will be a real challenge for these patients. It's probably linked to the tolerability. We have an excellent tolerability that's inherent to the molecule, as Jerry was saying. This EuPort domain is designed to slow the delivery of pemvidutide, and that decreased the Cmax and delayed the Tmax as well. So what we've observed in our MASH trials is a really excellent tolerability and really keeping patients on treatment, which bodes well for efficacy readings in the phase III trial.
Is retatrutide also exploring MASH, or do you think that's going to be for a completely different population who needs severe weight loss or significant weight loss?
Mm-hmm. Our current understanding is that they're looking mostly at weight loss. They've explored very high and rapid weight loss, which may not actually be as suitable from what we hear from some KOLs. In the meantime, I think that they're going to be looking more into lower doses than what they've demonstrated so far. So I think this is where the direction is going.
You brought out the issue of the ratio. What do you think that the potency against the glucagon receptors are doing for you? What is it bringing exactly? What are the others not bringing?
We have a very strong affinity for both the GLP-1 and the glucagon receptor. It is in two decimals in the nanogram, in the EC50 for both of those in a 1:1 ratio. We are very strong in that matter. When you look at retatrutide, the data we understand is on the GIP side, they are pretty close to have similar potencies or affinities, EC50 affinities. For the GLP-1, it is a tenfold less, and for the glucagon, it is another tenfold less, so compared to GIP, seems to be 100-fold difference. What we have heard is that it might be a suboptimal level of affinity for the glucagon.
These molecule, I think we are all learning that these molecule can be very different and paying attention to those ratio and the type of molecule, not all GLP-1 are the same, not all glucagon agonists are the same. Putting those together, we feel that with pemvidutide we have a real opportunity to have a strong efficacy on the liver and on the metabolic causes in MASH or on AUD, as we have demonstrated recently.
Perfect. Yeah.
Annabel, as far as we're aware, there aren't any other balanced glucagon and GLPs in development. Again, we like the balance. We like the fact we're bringing the direct effect on the liver at a ratio that's relative in potency to the GLP side of the equation. Most importantly, the clinical data that continues to emerge points to a drug that is bringing along significant efficacy along with a tolerability profile, which we believe is going to be really important to these patients. Because, of course, in both of the areas where we're deep in study right now, they're chronic conditions where staying on therapy at the right dose is a key part of bringing out the benefit in the real world.
Okay, great. So what are the key features that you want to draw out of the phase II, and how is the PERFORMA study design for pemvi to achieve the optimal success and differentiation, and maybe even adapt to the changing landscape a little bit?
Mm-hmm. I can start with the data. Clearly, we've demonstrated a strong efficacy that was not obvious on the fibrosis early at 24 weeks, but that was kind of expected. Also in the AI-generated reads of those biopsies, we saw a very clear anti-fibrotic effect that was very strong both on the qFibrosis or on the LiverExplore. We confirmed this at 48 week with a continuous improvement between these two time points through the NITs, where we saw a very strong anti-fibrotic effect, and our biological markers were also very consistent with this. So we've learned here the importance of, and this was just with the maximum dose of 1.8. We've learned that through this experience, it is important to pay attention to the process on the biopsy.
We are implementing in our phase III the AIM-MASH Assist that decreases variability, which was validated this past December 2025. We hope that this will decrease this variability and make it more consistent between the pathologies. We've trained our pathologies. We've put together a system to monitor the consistency between these different pathologies. So we feel much more experienced and much more meticulous or rigorous in our approach to the biopsy reading. The other thing is, and the AIM-MASH Assist, obviously, is an added assistant to these pathologists that could really help us. In addition, we've learned that at 1.8 mg, we didn't plateau on the weight loss in the phase II, and that our 2.4 mg can have greater weight loss.
We've seen close to 15% in our obesity study decrease. We implemented an approach that is based on the 1.8 mg dose that we've seen in the phase II, but allows to test the 2.4 mg dose as an upside. We feel very happy about, and we are impatient to see how this dose will be behaving and how much more efficacy you gain. It's also a 52-week time point. We believe within that time point versus the 24, our data supports the fact that we should see a strong antifibrotic effect.
The tolerability and the new very simple titration, that monthly titration that we have a one step for the 1.8 mg or a two step for the 2.4 mg, we'll be able to bring these early first months or second months' GI events to their lowest possible for the patients, and even further improve the adherence to treatment that we've seen. Again, adherence to treatment and keeping the patients into the trial is also playing in our favor with regard to the potential efficacy and the outcome of the study. The way I tend to say that is we've built the phase III study in a conservative manner, but with a lot of upside that we would be able to appreciate at the end of the trial.
Okay, got it. Just a couple points of clarification. You're still going to have a three pathologist biopsy reading, correct?
Correct.
Along with the-
We have more than three pathologists
the AIM-MASH Assist. Yeah.
Because we have some backup pathologists, but the principle is to have three pathologists read, and then a consensus. They are all three reads with the AIM-MASH Assist, and then there is a consensus. We have trained them, and we have experience with that. We have tested this approach before the trial, and that shows a very nice consistency between the pathologists. We also have chosen some of the top pathologists that are in the world. Hopefully that will help throughout this study.
For the 1.8 mg to the 2.4 mg, is it a choice to move up to the 2.4 mg, or are there specific defined populations that move to the 2.4 mg?
No, there's two arms. There are three arms in the study, a placebo, a 1.8 mg, and a 2.4 mg. Obviously, the 2.4 mg was not tested in the phase II. We allow some patients to decrease, but we would like them to go back up to the 2.4 mg. The 2.4 mg arm is to try to get these patients to a higher dose or at least identify the ones that will be able to go to that higher dose. The 1.8 mg is very similar to what you've seen in the phase II. However, our powering is based on our phase 1.8 mg dose. As mentioned, the 2.4 mg should be an upside when we read the data.
Okay. The money question, what does success look like?
Well, success, well, first is achieving a positive trial with a good MASH resolution and antifibrotic effect and fibrosis improvement in this population. Then there will be many other aspects that we're going to start looking at, including the effect size, including who benefits the best, including the weight loss, the adherence to treatment, and discontinuation rate for us is also really important. We'll be looking at all these different aspects, and we want also to learn more about the type of weight loss. We've observed in our obesity study some evidence that we might be protecting the lean mass and preserve it with pemvidutide.
We're trying to study that in a more formal manner during the phase III and really connect this between the mechanism of actions, the impact on the weight loss, the quality of the weight loss, all the way to the impact for these patients on the functionality of these patients.
How are you going to measure the quality of the weight loss? Is it with DEXA scans or how are you measuring that?
We're going to look at the MRI-PDFF.
Okay.
We're going to have also blood biomarkers, and obviously, we're going to look at functional testing.
Got it. We did notice that as far as MASH trials are concerned, the phase II trial enrolled pretty rapidly.
Yes.
I think it was because of that weight loss component. Are you having the same experience with PERFORMA? What are maybe your timing expectations around this?
I am very proud of our team at Altimmune. It was about 90 days between the financing and the first patient into our studies.
The start-up, identifying the CRO, getting all the vendors, and starting contracting with sites. This was really an excellent, efficient way of starting the trials, and we continue to see interest in this trial for a few reasons. One, obviously, when you have pemvidutide and the weight loss, that is important. Also because of the AIM-MASH Assist, because we have designed also the way where PIs can recycle the patients to decrease the screen failure rates between the cohorts on biopsies and the cohorts on NITs within the same study. Those kind of feature in our design are really attractive for PIs, and so far, we have felt a really good enthusiasm to bring patients into that study.
Is there any more movement from the regulatory perspective on accepting NITs as the final endpoint or even for enrollment?
We haven't spoken since our end of phase II meeting on that topic with the regulatory agencies. We will hear, hopefully, a little bit more at the upcoming AASLD, where people are sitting on this, and if there is any movement. Our understanding so far is that currently nothing has been validated, but the design of the study would be ready if they were to change and validate any of those NITs endpoints very rapidly. We are ready for this, but we haven't heard anything to the extent that they would be changing their mind at this point.
Okay, great. Just the last question on MASH. Is there a particular part of the population that you're aiming for as the landscape evolves, like that's your priority segment of the population that you're looking for, or are you just looking more broadly?
Linda, why don't you take that one?
Yeah, I think for us, the population clearly that we're studying is F2, F3. There's emerging data that there are unmet needs related to folks who can't tolerate GLP-1 therapy over the long haul or are not getting the efficacy results they'd like to see. We also see ourselves, because of our tolerability and profile, very much a potential for our patients who have sarcopenia or at risk for sarcopenia because of the potential for lean muscle mass preservation, and that's not a small number. When you look at patients who need more metabolic improvements, weight loss, and even additional fibrotic improvements. We see places in the market where we could be, frankly, a first-line agent, and also have beneficial benefits to adding on to the holes that other agents have. We can plug those holes with our efficacy, and really, our tolerability comes into play as well.
I think the other dimension, which is going to be really encouraging as we look forward. As expected, as therapeutics have become available in the MASH space, the level of diagnosis, of concern for the patients, of action by the physicians, of support by the payers all go in a positive direction. As we anticipate bringing pemvi forward against those segments that Linda mentioned, we also see a market that's going to be larger by the time we launch than it is currently, and that, again I think it goes in the right direction for us.
I think a lot of the factors to date have been based on profiling whether the patient has obesity or overweight, and diabetes. We see an opportunity where other elements are going to be in the consideration pathway, whether it's the risk of sarcopenia, whether it's the drinking levels, et cetera. There's going to be a broadening of customizing that therapy for the patient that's in front of you.
Okay, while we're on the drinking, we might as well transition over to the RECLAIM trial in alcohol use disorder. Can you talk about what stood out there? You said it was the best in class that you've seen so far for alcohol use disorder, so maybe you can just give us a quick overview of what struck you as exciting.
Yeah. I think extremely encouraging data. I think the consistency of the impact on the drinking across a variety of different endpoints, including the two that are currently approvable by the FDA, gives us a real great option as we design a potential phase III. I think the consistency of the weight loss is, of course, beneficial in a population like this. I think safety and tolerability, no new elements emerged there. We did go titrate up to that 2.4 mg dose in this population. Again, the order of magnitude of the efficacy, both on the patient-reported endpoints and on the PEth, again, gives clear indication that the drug is sparing the drinking for a moderate to severe population that was drinking a lot.
Again, I think a lot of de-risking here in terms of how we think about phase III based on the consistency of the results in this population.
[inaudible]
What are the next. Oh, sorry, go ahead.
I was just going to add the exploratory also evidence some hints of some benefits on the liver through our FIB-4 data, which we'll be exploring in much more details and rigorously through the phase III.
Okay, great. What are the next steps for this AUD program, and how should we think about funding for it? What is, I guess, your preferred path of funding, whether it's a partnership or royalty or non-dilutive or dilutive balance sheet? How are you thinking about this program?
Yeah. So maybe just on the overall next steps. Again, really encouraging data that's been compiled. We'll have an end of phase II meeting with the agencies, which is going to be really important to align on the approach we want to take in phase III. All of that work, you would expect, is ongoing right now. Once we have clarity when the meeting will occur, we'll give some expectation around that. That'll let us size the phase III.
Again, I think we have a really unique opportunity to bring forth a pretty broad group of moderate to severe AUD patients that also include a group of AUD patients that have active liver disease, which is going to be really important based on our mechanism. That insight from the regulatory dialogue will allow us to size phase III, and maybe Greg can give a perspective on how we think about funding a potential phase III in this indication.
Yeah, thanks. Annabel, think of the balance sheet today as June 30, $519 million, which funds end to end on the MASH trial. Layering on top of the AUD trial, that's right, we are focused on the opportunity to use non-dilutive funding. That could be some combination of strategics or clinical trial financing through some royalty mechanism or something of that nature. I'm confident and encouraged by the feedback we've gotten from that contingent out there as we enter those discussions in the months ahead as we approach that end of phase II and feedback on the phase III, the scale of that. But looks manageable. I think you've seen the transformation of the company here between talent, resources, strategic focus.
Okay, great. Then, just how well defined is this population? I know there's many who won't own up to the fact that they have a disorder. So is the population well defined?
Yes. The population for AUD is very well defined. We have the criteria that's coming from the DSM-5. There is a validated regulatory path forward for this. We will, however, look also at the more advanced liver disease, liver impairment. It is part of the guidance for the phase III, and it is clearly a place where, for pemvidutide, we have an opportunity to also be very unique and not just address the addictive component of alcohol, but also address really the harmful effect of alcohol on the liver. This is an approach that seems to also be trending in the clinical community as we are hearing from KOLs.
Got it. As you mentioned, the ALD trial is also underway. How much overlap is there with AUD, and what are your goals for this trial versus AUD?
This is a good question. This is, yes, our ALD, we were very interested in looking because we capture also their drinking habits of how close they would be looking like our AUD population in our phase II. Obviously it is blinded data, not clean, but there is a lot of similarity in the heavy drinking between these two population. As expected, some are much more advanced with their liver aspect and some, the regular AUD may be a little less also. They may not even know about it. I think there is a continuum between these two population, and we seem to confirm this throughout the pattern of drinking that we see in both trial.
Okay. You are taking liver measurements specifically in the ALD trial, yes?
Absolutely. Yeah.
But not so much in the AUD, but maybe you capture that in the phase III trial.
We didn't take too much on the AUD phase II. In our phase III, we will be much more comprehensive in our assessments of the benefits on the, or the potential benefits of pemvidutide on the liver both in the regular AUD, the typical AUD population, as well as the more advanced liver or hepatic impaired, as called by ALD patients.
Great. Then I guess to wrap it up, is there any overlap between MASH and alcohol studies that we can draw any conclusions from one to another? Just to give us a bigger picture.
There is a lot of overlap between these two population. I think we know that the obese population tends also, in some percentage, a significant percent of them also add alcohol and vice versa. The alcohol population tend to also, just by the fact of heavy drinking and the calories intake, that you get to be also obese. There is much more a convergence, and we're going to have a product theater at AASLD that will speak about this with some KOLs because there is a lot of similar factors, both in the liver pathology between steatosis inflammations all the way to fibrosis, and also on the causes that are overlapping between the MASH population and the AUD, ALD population.
Great. Well, we're just about out of time, if not a little bit over. So thank you very much. Appreciate the color, appreciate the broad overview, and we're excited to see it continue.
We're excited as well, Annabel.
Yeah.
Thanks a lot.
Thank you.
Thank you very much.