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Hi, good morning, everyone, and welcome to the Altimmune Session. I'm Annabelle Samimi, Biopharmaceutical Analyst here at Stiefel. We're pleased to have with us today CEO Jerome Durso, Chief Medical Officer Christoph Arbett-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. And, you know, we saw some very strong indications from the phase two trials in both MASH and AUD, and now you're starting your phase three in MASH with the rational design. So first, why don't we get a quick overview of where you are? Jerry, maybe you can tell us what attracted you to Altamune and where do you feel you stand today as far as these various liver diseases. So thanks for having us today, Annabelle. Glad to be on board. So it's an exciting time for Altimmune. Really what brought me in to the company was the asset pembidutide. And I think, as you said, real significant opportunities across a variety of different liver diseases, but at the heart of that is pembadutide and 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, Pembedutide, 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 two, we've been heavily focused on advancing our MASH program and really transforming the company. And then as you mentioned in July, really exciting data in AUD from phase two, really, we think the most robust data set in AUT, and now allows us to approach the next steps of the company with a real opportunity of a liver franchise here. And 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 as a chief commercial officer. But OK, so first on MASH, the landscape has obviously seen RISDifera and GLP-1s approved in the last couple of years and perhaps soon some other stronger agents. So where do you think kind of sits in this treatment landscape right now and what could be evolving into a little bit of a broader treatment landscape? Yeah, maybe, Lynn, do you start on that one? Certainly. I think, you know, what really gets to our benefits are the differentiation pieces, right? We've got the direct acting liver effects, the metabolic activity and mesh resolution early. We have a patient-friendly product that has great tolerability. 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 in obesity, but we want to look at really the nuances in MOSH. And 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 and MASH can be, 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 pest testing, really gives us multiple shots of differentiation on goal to help a variety of patients. Okay. Great. So there are a couple of other JLPGCGs in development and GGGs. Can you talk about PEMV in relation to servodetide or retitrutide 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 Christoph, but maybe a couple things on the front end of that. We continue to, again, be excited by the mechanism. And for us, the mechanism matters, the ratio matters, and the molecule matters. And all three of those together is really what we think separates PEMV from the other glucagon-GLP combos that are in development. Christophe, maybe expand a little bit. Sure. Sure, so PEMVIDUTIDE is a one-to-one ratio glucagone GLP-1 dual agonist, and when servodutide is actually a 7 to 1 glucagon to GLP-1. So it's mostly a GLP1 with less affinity for the glucagone. You asked about retratrudide. This is mostly a GIP with a hundredfold difference in the glcagone affinity. And this one is a suboptimal affinity for the glycagone receptor. What we've seen in servodutide 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 onthe metabolic aspect like weight loss. But we've also seen very large discontinuation rate in clinical studies. studies. And in the studies that were presented, servodutide showed close to one patient out of four that was discontinuing under the conditions of a clinical study when there is heavy supervision. So 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 U-port domain is designed to slow the delivery of pemvitutide, and that decreased the C-max and delayed the T-max 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 three trial. And is RET and TRU-TIDE also exploring MASH, or do you think that's going to be for a completely different population who needs severe weight loss or a significant weight loss? 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 KOL. 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. So 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? And what are the others not? So we have a very strong affinity for both the GLP-1 and the glucagon receptor. It's in two decimals in the nanogram and the EC50 for both of those in a one-to-one ratio. So we are very strong in that matter. When you look at ratatridae, the data we understand is on the GIP side, they're pretty close to have similar potencies or affinities, EC50 affinites. For the GLP-1, it's a tenfold less. And for the glucagon, it'S another tenfold S. So compared to GIP, seems to be a hundredfold difference. What we've heard is that it might be a suboptimal level of affinity for the glucogon. So these molecules, I think we're all learning that these molecules can be very different, and paying attention to those ratios and the type of molecule, not all GLP-1 are the same, not All-Glucagon agonists are the same, and 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've demonstrated recently. And Annabelle, as far as we're aware, there aren't any other balanced glucagon and GLPs in development. So 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. And 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, there are 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 two and how is the performance study design for PEMVI to achieve the optimal success and differentiation and maybe even adapt to the changing landscape a little bit? Well, I can start with the data. Clearly, we've demonstrated the 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 antifibrotic effect that was very strong, both on the Q fibrosis or on the liver explore. We confirmed this at 48 weeks with a continuous improvement between these two time points through the NITs, where we saw very strong antifibrosis 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 have, to pay attention to the process on the biopsy. We're implementing in our phase three, the AMASH assist that decreases variability, which was validated this past December 25. 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 AMASH assist obviously is an added assistant to these pathologists that could really help us. In addition, we've learned that at 1.8 milligram, we didn't plateau on the weight loss in the phase two, and that our 2.4 milligram can have greater weight loss. We've seen close to 15% in our obesity study decrease. So we're implemented an approach that is based on the 1.9 milligram dose that we've seen in the face two, but allows to test the 2.4 milligram dose as an upside that we feel very happy about and we're impatient to see how this dose will be behaving and how much more efficacy again. It's also a 52-week time point. We believe within that time point versus the 24, and our data supports the fact that we should see a strong antifibrotic effect. And then the tolerability and the new very simple titration, that monthly titration that we have a one step for the 1.8 or two step for the 2.4, we'll be able to bring these early first month or second month's 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. So we've built, the way I tend to say that is we've build the phase three 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. So, just a couple points of clarification. You're still going to have a three pathologist biopsy reading, correct? Correct. So we have more than three pathologists because we have some backup pathologists, But the principle is to have three pathologist reads and then a consensus. They're all three reads with the AMASH assist, and then there's a consensus, and we've trained them, and we have experience with that. We've tested this approach before the trial, and that shows a very, very nice consistency between the pathologists. We also have chosen some of the top pathologists that are in the world. So hopefully that will help throughout this study. And then for the 1.8 to the 2.4, is it a choice to move up to the 2.5 or are there specific defined populations that move to the 2.0? No, there's two arms. So there are three arms in the study, a placebo, a 1.0, and a 2. 4. Obviously, the 2 point 4 was not tested in the phase 2. We allow some patients to decrease, but we would like them to go back up to the 2.4. So the 2-point-4 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. And then the 1.8 is very similar to what you've seen in the phase 2. However, our powering is based on our phase 1.80 milligram dose. So, as mentioned, the 2.4 should be an upside when we read the data. Okay. So, the money question, what does success look like? Success, well, first is achieving a positive trial with a good match resolution and anti-fibrosis 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 the weight loss the adherence to treatment and this continuation 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 pemvudutide. And we're trying to study that in a more formal manner during the phase three and really connect this between the mechanism of actions, the impact on the weight loss, the quality of the weight lost, 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? No, we're going to look at the MRI, PDFF. We're going have also blood biomarkers, and obviously we're gonna look at functional testing. Got it. So just, you know, we did notice that as far as MASH trials are concerned, in the phase two trial and rolled pretty rapidly. And I think it was because of that weight loss component. So are you having the same experience with Performa? And what are maybe your timing expectations around this? So I'm very proud of our team at Altimmune. It was about 90 days between the financing and the first patient into our studies. the startup, identifying the CRO, getting all the vendors, and starting contracting with sites. So 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, as when you have Benvidutide in the weight loss, that's important. But also because of the AMASH 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 cohords on NITs within the same study. So those kind of features in our design are really attractive for PIs, and so far we've 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 from the moment? We haven't spoken since our end of phase two meeting on that topic with the regulatory agencies. We will hear hopefully a little bit more at the upcoming ASLD 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 needs and points very rapidly. So 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. So 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 populace that you are 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 sarcopena 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, so 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. So as we anticipate bringing PEMV 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. And 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. So while we're on the drinking, we might as well transition over to the reclaimed 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. Yeah, so 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 three. 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 milligram dose in this population. So, again, the order of magnitude of the efficacy, both on the patient-reported endpoints and on the PATH, again gives clear indication that the drug is sparing the drinking for a moderate to severe population that was was drinking a lot and again i think a lot of de-risking here in terms of how we think about phase three based on the consistency of the results in this population so what are the next oh sorry go ahead i was just going to add the exploratory uh also evidence some hints of some benefits on the lever through our FIP4 data, which we'll be exploring in much more details and rigorously through the phase three. Okay, great. So 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? and how are you thinking about this program? Yeah, so maybe just on the overall next step. So again, really encouraging data that's been compiled. We'll have an end of phase two meeting with the agencies, which is going to be really important to align on the approach we want to take in phase three. So all of that work you wouldn't expect is ongoing right now. Once we have clarity when the meeting will occur. We'll, you know, we'll give some expectation around that. That'll let us size the phase three. 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. So that insight from the regulatory dialogue will allow us to size phase three. And maybe Greg can give a perspective on how we think about funding a potential phase three in this indication. Yeah, thanks. Annabelle, think of the balance sheet today as June 30, 519 million, which funds the end-to-end on the MASH trial. Layering on top 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 two and feedback on the phase three, the scale of that, but it looks manageable. And yeah, I think you've seen the transformation of the company here between talent resources strategic focus okay great and then um just how well defined is this population um 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 is is is uh for aud is very well defined uh and we we have the criteria that's uh 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 uh liver impairment it's part of the guidance for the phase three and uh it's clearly a place where for pemvidutide we have an opportunity to also be very unique and not just address the the the addictive component of alcohol but also address really the harmful effect of alcohol on the liver. And this is an approach that seems to also be trending in the clinical community as we're hearing from KOLs. Got it, got it. And as you mentioned, the ALD trial is also underway. So how much overlap is there with AUD and what are your goals for this trial versus AUD? This is a good question. So 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 two. And now obviously it's blinded data, not clean, but there is a lot of similarity in the heavy drinking between these two population. And 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 so i think this is uh there is a continuum between these two population and uh and uh we seem to confirm this throughout the pattern of drinking that we see in both trial okay and you're taking liver measurements specifically in the ald trial yes absolutely yeah and but not so much in the aud but maybe you can fact fact capture that in the phase three So we didn't take too much on the AUD phase two. In our phase three, we will be much more comprehensive in our assessments of the benefits or the potential benefits of pemphidutide 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, great. And 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 populations. 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. So there's much more convergence. And we're going to have a product theater at ASLD 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, Annabelle. Thanks a lot. Thank you very much.