All right. Good morning, everyone, to Jeffrey's London Healthcare Conference 2025. My name is Roger Song, one of the Senior Analysts covering SMID Cap Biotech in the U.S.. It is my great pleasure to have the next fireside chat with Altimmune, who have Vipin and then Christophe. Good to meet you here. Thank you for having us here. Absolutely. All right, so maybe Vipin, you can start with some elevated pitch and then to see what's the state of the union for Altimmune today. Yeah, so we are developing, as you know, we are developing a glucagon GLP-1 dual receptor agonist for MASH, for liver diseases, MASH, AUD, and ALD. It's a rationally designed molecule with a one-to-one ratio of GLP-1 and glucagon. We think that's very important, really, in order to drive the glucagon function. Glucagon works directly in the liver. There are no GLP-1 receptors in the liver. GLP-1 works more through the metabolic pathway, through appetite suppression and weight loss, whereas glucagon works directly in the liver. The idea is to combine two mechanisms in a single molecule to have both direct effect in the liver and combine that with the metabolic benefits of weight loss. It's also rationally designed to have a unique PK profile. We have a proprietary domain on pemvidutide called EuPort domain. What that does, that slows down the entry of the drug into the bloodstream. We have longer Tmax and lower Cmax. Really, the entry into the bloodstream is more gentle. That gives it a very interesting tolerability profile, a very favorable tolerability profile, which we believe is going to be very important. We have recently completed enrollment in a 48-week trial of pemvidutide in MASH. We recently presented 24-week data from that study. We're expecting 48-week data here in the fourth quarter before the end of the year. We also have an FDA end-of-phase two meeting scheduled based on the 24-week data. It's an in-person meeting again before the end of the year. We've got a lot of exciting news coming. We're looking forward to really designing our phase three program and discussing it with the FDA, which is happening right now. We are looking forward to 2026 to start our phase three program. Excellent. I think it is a very unique compound, pemvidutide, in the entire GLP-1 space. In a way, obviously, you are in GLP-1, but also you are hitting the glucagon nobody else is kind of designed for. Also, your program is now more liver-focused in the MASH with diabetes, with obesity. You have also other more liver-targeted ALD and AUD program. Let's talk each one this morning. Maybe focus on the MASH first. You mentioned, Vipin, you say you will read out the phase two, 48-week biomarker-driven endpoint and the weight loss. What do you expect to see and what would be considered as a good outcome giving you more confidence in this program moving to the phase three? Christophe, you want to take that? Sure. No, so we've had already very strong, I just want to remind you, our 24-week data, we were able to show very strong data on the MASH resolution. We were able to show numbers in the 60% of patients that were responding to the drug, which is in par with what other programs have seen after even all the way to 72 weeks. It was very exciting to see this already at week 24. We saw also very strong data on the fibrosis side, where at 24 weeks is quite remarkable in my mind to see such strong fibrosis. We were able to show this into confirming this with AI, with all the non-invasive tests. That was the basis for going to the FDA and being able to go only with very early data to the FDA. The FDA accepted this and granted us the meeting. On the 48-week data, I just want to remind you that we are not doing the biopsies at that time. We had determined to do the baseline and then week 24 biopsies. On the 48-week, we will look at non-invasive tests. These will be moving, as you may understand, some of them move very early in the progression with the treatment, some move a little later. For example, we had great MASH resolutions. The non-invasive tests related to the fat in the liver, fat content, et cetera, will be continuing, hopefully continue to improve because we had seen a weight loss that was quite substantial, but was not plateauing yet. The patient should be continuing to see the benefits of the metabolic effect. Some others were hoping to see, for example, on the liver stiffness, on the fibrosis with the FibroScan, some continuous improvement there. We are excited. We cannot wait to see the data and see how this will be, just confirming the strong information we had at week 24. Excellent. Chris, as you mentioned, this is not biopsy endpoint because I'm still clarifying with the investors that this is not biopsy, another biopsy endpoint. With that being said, you say the NITs non-invasive testing can be very indicative for the biopsy endpoint, how this will continue to evolve to show even greater treatment. Just can you remind us what type of the NITs you are really looking for, can kind of keep modeling the correlation with the biopsy result, particularly for the fibrosis part? This is the questions between the NITs and the biopsy is a place where the scientific and the clinical community is ahead of the regulatory agencies. Biopsies have risk. They have the bias of the histopathologist treating. There is a lot of aspects there that are making it more difficult to interpret, et cetera. It is obviously the part of the burden for the patient is substantial. The clinical community has been pushing regulatory agencies towards using non-invasive testing. Among those, they are different. There are two sets of non-invasive testing. There is the blood-based, like the ELF or some of the other, the FIB4, et cetera, type of blood testing. Then you have the imaging part, which is more like the FibroScan and that kind of test. We believe that the FDA is, there was a recent discussion at the AASLD meeting in Washington, D.C. We believe that the regulatory agencies are clearly looking into those. They haven't yet landed, to our understanding, really how to, there will be probably a combination of blood-based testing and imaging. That's what we understand. When we meet with them, we will have that more. This information. One important point is that in our phase three design and the phase three program that we're having, we're going to be prepared for both alternatives. Establishing the accelerated approval based on biopsies, but as well, we will collect all the non-invasive tests that will allow us, if the FDA were to move during the time of the execution of the trial towards clearly using this as an endpoint, and that could become an upside for what we're doing with pemvidutide. Got it. I just wanted to clarify that in our 24-week, as well as the 48-week trial, we're looking at a whole series of NITs. It's not just, it's really half of them are more markers of inflammation, and the others are markers of fibrosis. As you know, when you defat the liver, the first thing that happens is the inflammation goes down. The early markers, the early changes you detect. We've already maxing out in terms of the improvement in those markers early on. The fibrosis markers improve after the inflammation is taken care of. If you look at the totality of the data, we're seeing across the board, all of the NITs improving, moving in the same direction. That's what tells us that the inflammation is improving and the fibrosis improvement has begun as well. Excellent. That's a great point. My specific question is exactly this one: which NIT endpoint can be more correlated with the fibrosis? Any specific number you want to see, okay, 24 weeks is this and 48 weeks is getting better, and then this will correlate even greater fibrosis, the treatment effects? Sure. I'm not going to give you a specific number. We are actually working on trying to see from our 24-week data and what we're going to see on the 48 weeks, what is the predictability of this. The NITs have been already well established to correlate with the improvements in fibrosis. We do expect to see, for example, the liver stiffness. It's directly correlated to fibrosis. We do expect to see some benefits. We have seen, and we presented this at AASLD, some clear biomarkers that are looking at the balance between the fibrogenic and the fibrolytic and pemvidutide, PRO-C3, and CTX. When you look at this ratio, we have a very strong fibrolytic benefits that we can bring with pemvidutide. We'll continue to look at those markers, and they will be translating into the things like liver stiffness, et cetera. These are, and even on the histopathology now with AI, we have very strong data already at week 24 suggesting the benefits of pemvidutide on the fibrosis in these patients. Yeah, excellent. As you read out those data, it will be very helpful for us to know those modeling and then how this correlates with the biopsy because we do not have the biopsy data, but you have those endpoints that potentially can predict the biopsy. That will be very helpful. Obviously, you will prepare that for FDA as well. Another component of the readout is also weight loss. I think just to set the stage, you absolutely see the weight loss benefit. It is not plateauing. At the 48-week, what should we expect to see? Because it is not an obesity trial, we should not benchmark you to obesity, number one. Number two is it is also not the highest dose you have. It is not like you have to be semi-like kind of weight loss or what is your expectation for the weight loss? Right. The weight loss is a very important aspect of pemvidutide. We have had prior studies all the way to 48 weeks when we show clearly obesity-type weight loss that was in the range of other compounds. Interestingly, this weight loss never reached a full plateau. There was still possibility for improvement. In our MASH program, we do not even use the top dose, as you mentioned, and we do not see a plateau at week 24. The weight loss, however, so we hope to see a continuation of that improvement, but potentially there may not be even a plateau at week 48, giving additional benefits on the chronic treatment for the patients with MASH. The very important aspect of the weight loss, it is not just weight loss with pemvidutide. What we see is a weight loss, and we've shown this in our obesity trials, is a weight loss that we call it with quality weight loss, which preserves the lean mass. Why is that important? It's because most patients with MASH or the patients as we are studying other steatosis liver disease like AUD or ALD, most of those patients are aging. They are post-menopausal women. They are andropausal men. They are in their 50s, 60s. You don't want these patients to lose their muscle mass. To a great extent, our weight loss basically is very similar on the preservation of the lean mass of what you would see with diet and exercise. This is very comparable to that. We believe that this is a very important attribute of pemvidutide, the benefits for this population. It will avoid the risk of sarcopenia in some patients and all the complications you can see with lean mass that would be lost too much of an extent. That is something that we have benefits on the week 48 data. We will see some additional weight loss, and we hope to see again that very important lean mass preservation that is unique to our compound. Got it. Okay, great. Moving forward, right, this is the 48-week. Also, simultaneously, I think Vipin just said you are preparing in-person meeting with the FDA for the end of phase two meeting and then to design the phase three. What will be the ideal outcome out of that meeting for the phase three design, particularly when we talk about the unique feature of pemvidutide, many different aspects, and then how you incorporate those novel endpoints to the phase three, maybe increase the likelihood of success? We always seek with FDA and regulatory agencies, and we're going to meet with the FDA. After with the EMA, we always seek to find alignments on the design of our program. We try to design our program to the most efficient way. We have more specific questions on some details of the design. Clearly, we would like to have a good understanding of where they will be going with the NITs. That's something they have not disclosed completely. There's still some debate, but how close are they? We know on the AI for the biopsy reading that they're pretty close to accept this since the Europeans have already accepted that. I think on the NITs side, it will be important for us. We will be able to better understand which of those NITs they're going to be really focusing on, what combination potentially of NITs they would be focusing on, and then helping us to maybe gain even more efficiencies in our phase three design and build upon that. Yeah, I just want to emphasize that our goal is to have a flexible design so we can incorporate all of the measurements, all of the NITs that we are talking about, the AI-based reading of the biopsy. Initially, there may be both a pathologist read as well as an AI-based read. If FDA changes to AI, then we will be ready to switch at that point. Same thing with NIT. We will collect all of the data. If along the way, FDA takes away the requirement for biopsies and goes to NIT-based endpoint, we will be ready to incorporate that in our design of our phase three program. We want to maintain that flexibility. If FDA changes those requirements, we will be right there. Really, that's the agreement we want from the FDA as well. Got it. A couple of quick specifics. One is, would you try to increase or incorporate the high dose into this phase three? That is up for discussion. Yeah. We are looking at the best approach there in order to gain the maximum efficacy. Just one point on this that is very important, I believe, because the tolerability, as Vipin was, that's intrinsic to the molecule itself, that EuPort, that delayed Tmax, that decreased Cmax leads to very good tolerability. We have in our phase two, the 24 weeks, we have low nausea rate. We have a discontinuation rate that is really at the low dose, basically it's zero. At the highest dose without titration, we had a discontinuation rate that's half what we've seen with the placebo. This is not just by chance. I believe that just the molecule, the way it is designed, and what makes it really important. Other products, we've seen it was reported at AASLD, vary between discontinuation rate between 6%-20% or more. This will be some aspect that is really, really important in defining the dose and how we use to we can push a little further. There may be some subpopulation that could benefit from a little higher dose. How we do this, these are some of the discussions we'll have with regulatory agencies, and we'll finalize all these designs at the end. Going forward, tolerability is going to be very important at AASLD. There was a lot more discussion about tolerability than there has been in the past because MASH is a chronic disease, and if people don't stay on therapy, then you really can't help them. You want, as we've seen with GLP-1s, for instance, 60% of people are not on drug after six months. Very significant drop-off. That's not going to help. It takes that long to really even get the efficacy. It's really important to have tolerability profiles so the patients stay on medication in the chronic setting. Got it. Okay. We definitely want to talk a little bit about your pipeline, the ALD, AASLD as well. Before we do that, just lastly for MASH. We know MASH space is evolving along with the Incretin. We have semaglutide got approval, but you also have other mechanisms developing in this indications. How do you think pemvidutide can fit into this? Because you have the component of incretin. Maybe people will think, okay, you are another tirzepatide or semaglutide or even retatrutide. And then on the other side is you also have very much kind of the liver component like FGFR, et cetera. Two questions. One is which target population you think is the best fit for the pemvidutide? The other one is maybe the pricing part, how you will lean towards which angle of the pemvidutide. I'll take the first part. Yeah. On the population, we like to say we're not GLP-1s. We're not the different GLP-1s. GLP-1s don't have a receptor. There's no receptor for GLP-1 on the liver. It treats indirectly MASH, and it takes time. There are all the associated tolerability issues in the chronic disease. Things like this make it much more difficult. With the glucagon, we are a liver-targeted product that helps with the really focused impact on the liver, the defatting and the fibrosis, as we've shown very rapidly already at week 24. This is the specificity here that we can bring, and that separates us. We are having not only a direct impact on the liver, but by adding that metabolic aspect that complements the underlying kind of cause of the disease. Imagine you defat your liver. Now you have your impact. You decrease the fibrosis. You don't want the factors that are contributing to the inflammations to the fibrosis to be still present. By treating the metabolic part of the disease, we are able to do that. That helps us position the product in a very favorable place where in one compound, you have those two mechanisms, and you have a complete answer to your problem for the patients with MASH. Vis-à-vis the FGF21, again, they have a direct impact on the fibrosis, but they do not directly impact the metabolic aspect. In addition, they do have issues with the agonism of the FGF21 and the potential impact on osteoporosis, which is something when you look at the demographic, these populations are in their 50s, in their 60s, et cetera. This is not something you would like to have. There is clearly a positioning where we could be a first-line therapy for patients with MASH. Because of the tolerability profile, if some subpopulation need additional impact on some or an additional, for example, an FGF21, because you have a very advanced fibrosis in your liver, you might be able to combine it because you're not going to increase or add multiple side effects to your patients. Actually, with the tolerability we have, you're just going to take a little more risk for more advanced patients based on this. On the pricing, Vipin more focused on that. Yeah. As you laid out the different mechanisms, Roger, there are two different classes. There are the mechanisms that produce weight loss and indirectly work on MASH. It takes a lot longer to get there than their direct-acting mechanisms. What we like about pemvidutide is it provides a very broad spectrum because we have both weight loss and fibrosis improvement and very fast-acting drug within 24 weeks, as we have shown, 60% MASH resolution already, fibrosis improvement taking place, and weight loss all happening in just 24 weeks. It is only going to get better with 48 weeks and beyond as you keep treating these patients. Really, the value proposition here is to have two synergistic mechanisms that are showing multiple benefits: MASH resolution, fibrosis improvement, weight loss, and tolerability. You combine all of that together, that's a very compelling, very differentiated profile from any of these other drugs. We can start with, as Christophe mentioned, as a first-line therapy for F2, F3 because of both weight loss and MASH resolution and fibrosis improvement. We go all the way to F4. We can also combine it with other mechanisms because of the tolerability profile. I think all of the possibilities are out there. As you know, there have been a number of recent transactions done around FGF21s, but every single one of the companies that have acquired those assets, they're looking to add a metabolic component. That's exactly what we have done. We fit really well within the paradigm of treating the whole disease, not just the liver, but also the weight loss component, which 80% of the patients with MASH would benefit from losing weight. It is the synergistic effect of both of these mechanisms that we think would be highly attractive to patients, to physicians, as well as to payers. Got it. Yeah, great. We're running out of time, but I think I still want to touch maybe a minute on the ALD, AUD part because this is also another unique opportunity and then leading to the potential partnership opportunity because this is a real full kind of liver portfolio. Can you just spend a minute on that? We'll be wrapping up. I mean, on the AUD, ALD, we're very excited because we just completed the enrollment of our AUD study. We have our ALD study that is continuing to be on track. These are diseases that are very similar. I mean, the AUD patients have fatty liver. They have also the direct impact on the liver. The ALD do have some fibrosis. With the GLP-1 side, we clearly target the reward system and the craving. It is also timely because of the post-COVID era, there are a lot of patients that are interested in increasing their alcohol consumptions. They're also happy with a little bit of added weight loss and the right type of weight loss with the preservation of the lean mass. Most importantly, in a population like this, these patients or these people are pretty healthy otherwise. In general, they want a drug that's going to be very well tolerated. Our AUD had a lot of enthusiasm. The trial went on really fast, and the ALD is continuing. We think that we have here an opportunity to more than just targeting the MASH population, but targeting additional indications that will be very complementary to our entire portfolio. The key is that for both of these indications, again, we are taking advantage of the dual mechanism of action. It's the synergy that helps us because these patients will benefit once again, not just by reducing cravings for alcohol intake, but also improving their liver health. The patients are actually worried about their liver. That's one of the things they think of. If you tell them that you have a drug that will improve their liver health, that's very attractive. You might lose some weight on top of that. That's a complete package again. Excellent. Okay, great. Thank you for the time with us this morning. Thank you, everyone, for listening. Thank you. Thank you.