All right. Good afternoon, everyone. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name is Tom Smith. I'm one of the Senior Biotech Analysts here at Leerink. It's my pleasure to welcome our next company to the stage, Altimmune. Happy to be joined up here by CEO Vipin Garg and CMO Scott Harris. Gentlemen, thanks for joining us. Thank you. Thank you for having us. Certainly an exciting time in the metabolic space. Altimmune's advancing their GLP-1 glucagon dual agonist Pemvidutide in both obesity and MASH. A lot to talk through. Maybe Vipin, if you could just kick us off here with a brief overview of Altimmune for those in the audience who may be less familiar with the story. Yeah, absolutely. As you mentioned, we are developing a GLP-1/glucagon dual agonist called Pemvidutide. It's unique. It's been rationally designed to have a one-to-one ratio of GLP-1 and glucagon. It's really ideally suited for indications where you're looking for a direct effect in the liver, as well as weight loss. In addition, Pemvidutide reduces the number of risk factors for cardiovascular disease. We are really excited about this molecule because it's really pipeline in a product. You can develop it for multiple indications. We have recently completed enrollment in a phase II-B MASH trial. That data readout we're expecting here fairly shortly in the second quarter coming up of this year. We are very excited about that. We've also completed a phase II obesity trial. We'll talk more about that. Finally, we've recently received clearance from the FDA for two additional INDs, two additional indications for Pemvidutide. We will discuss those at our upcoming R&D Day here in two days on Thursday, March 13. Looking forward to it. That's great. Yeah, thanks for the intro there. I guess first on Pemvidutide, you alluded to the one-to-one agonism between GLP-1 and glucagon. Maybe you could just talk about, I guess, what drove the decision, like that selectivity profile, and then how that ends up comparing to some of the other GLP-1 glucagon dual agonists that are out there, things like Survodutide? Scott? That decision came out of a series of studies that were performed by Richard DiMarchi and Merck when he was associated with that company. They looked at different ratios of GLP-1 and glucagon. They determined based on animal studies that the one-to-one ratio was optimal for maximizing the effects of glucagon while maintaining glycemic control. We've carried that forward since then. Since that time, we've now had over 500 patients in completed studies. We'll add a couple hundred more to that with the recent studies that we're completing. We had the end of a phase II meeting with the FDA where that safety experience was reviewed and FDA agreed with the design specifically of the molecule that glycemic control was being maintained while the glucagon effect was being maximized. We distinguish ourselves from other molecules in the field by having the highest amount of glucagon. We think that drives this differentiation. It drives this effect on liver fat reduction, on serum lipids, on preservation of lean mass. These are all glucagon effects. Again, we think that we have the most potent dual agonist in development with glucagon. That's great. OK. Yeah, let's dig in a little bit on the MASH side of the story. We have a very important readout coming up here rather imminently in Q2. I know you guys have completed a phase I- B study in presumptive MASH. Maybe you could talk about, I guess, the data that you generated there, what gives you confidence as you went about designing the phase II-B study. Then start to tie in, I guess, some of the data that we've seen from Survodutide, which now advanced to phase III, as you mentioned, more of a glucagon effect with your compound. What are your expectations here as we start to think about the phase II-B? In that study, we took patients not with biopsy-proven MASH, but with MASLD. The definition was a high liver fat content. In this study, it was 10%. In that study, we saw a very dramatic reduction of liver fat at 24 weeks, which is the time point that most drugs are compared. We actually had a 76% reduction in liver fat. That's class-leading among the drugs that are still, as we know it, in MASH development. We also saw those effects at 12 weeks. In fact, we even saw signs of it occurring at six weeks. Not only potent, but also rapid. That speed indicates the potency of the molecule. We also had a number of other readouts in that trial that we could talk about later in our discussion today. Specifically in designing the MASH trial, it's liver fat reduction which drives the biopsy effects. That's been shown repeatedly in studies. Not only MASH resolution, but fibrosis improvement is driven by the degree of liver fat reduction. The greater the liver fat reduction, the better effects you have on these endpoints. We felt very good about going into the trial with a likelihood of success. We found that there was a dose-response plateauing at the 1.8 mg dose. Even though the 2.4 mg dose might have offered greater weight loss, for the efficiency of a phase II trial, which is meant to be smaller, more efficient than a phase III trial, we topped the dose at the 1.8 mg. We also have the 1.2 mg dose, which allows us to look at a dose-response, which conspicuously has been absent in many readouts in MASH trials. You worry about the biological plausibility without the dose-response. We have those doses in there. We are not including the 2.4 mg dose, but we certainly have the opportunity to add that in the phase III program because what differentiates us here is not only the MASH effects, but the weight loss as well, which makes us unique. We looked at that liver fat reduction, and we decided that we were in the potent class of MASH agents. What do we mean by that? The drugs that have direct effects on the liver. In our case, it's glucagon, that component of the molecule, with the FGF21s also in that class of potent direct-acting agents, which also have rapid readouts. They had readouts at 24 weeks that were successful with liver fat reductions that were less than what we've seen. We felt very comfortable with reading for 24 weeks. We found that it was a great opportunity to differentiate us from the incretins that had failed even at 72 weeks in the Semaglutide, original Semaglutide phase II study. Three times longer, the same number of patients failed. These drugs are now reading out with a much greater number of patients at 48 and 72 weeks. They would not imagine trying to read out at 24 weeks. We differentiate from the other incretin drugs on the basis of potent MASH effects that are readable, Tom, at week 24. Now we face off against the FGF21s. What do we offer there? Weight loss. None of these drugs have any meaningful weight loss. If successful in our readout, and we can talk about the assumptions and the power, we would be the first incretin agent to read out successfully in 24 weeks, and the first drug of any class to have both potent effects on MASH at week 24, but also weight loss. Now, with regards to your third question, which was Survodutide, that molecule has much less glucagon in it. Our ratio, as you mentioned, is one-to-one. Their ratio of GLP-1 to glucagon is eight to one, meaning they have, if you would, one-eighth the amount of glucagon. They get good effects on liver defatting. That is due to their glucagon effects. To do that, they have to go to much higher doses. They have to be much more aggressive with dosing to see that glucagon effect. The price they pay is for tolerability. As you know, they have very high dropout rates, even at their lowest dose, which is representative of the fact they're pushing the doses to the extreme at the expense of tolerability. They had to titrate over 20 weeks to see that. They had 12 titration steps, something we couldn't imagine at two of our doses in our trials. In fact, in our upcoming MASH trial readout in the second quarter, we have no dose titration at all. Also, with regards to Survodutide, we went to the FDA with a full portfolio of our safety information. They looked at that, and they said, we don't see a safety signal. We agree with you that you have glycemic control. We agree with you that you don't have any cardiac signal. You don't have a meaningful increase in heart rate. You don't have any arrhythmias that we're seeing. We know with Survodutide, they were asked to do something which is inefficient in a phase III drug development program, which should take their 6,000 patients to commit 5,000 to studying cardiac safety. What that implies to us is that a signal was seen in the discussion with the FDA, and FDA wanted more information. I would emphasize that we were not asked to do that. Even comparing to Survodutide, just on the efficacy parameters, we have greater liver fat reduction, and we think also greater potency. That's great. Maybe building off of some of that, where we're calling out the sort of the safety tolerability, just remind us, I guess, what you saw in the phase I-B MASH experience. Then on this decision to not titrate, obviously suggests like a good amount of confidence in safety tolerability and not needing to kind of stepwise increase the dosing there. Just kind of walk us through, I guess, the rationale behind the dose selection in the phase II-B. Yeah, the dose-response in obesity is different from the dose-response in MASH and liver fat reduction. We think liver fat reduction is a great biomarker for MASH endpoints. We saw the liver fat reduction and many other endpoints plateauing at the 1.8 mg dose. To us, it meant there wouldn't be good efficiency by using the 2.4 mg dose in that trial. That contrasts with obesity, where the more you give, the better. I'm sorry, I didn't capture the second part of your question. Yeah, just you mentioned the lack of dose titration, which I think, yeah, would be quite differentiated from a lot of other incretins that are out there. Just talk through a little bit of the dose selection rationale and why you don't need that titration. It relates to the medicinal chemistry. It's the lipid side chain that gives the drug longer half-life. That drug is specifically organized to be polar on one end and act very much like a surfactant. What it does is that it aggregates the way micelles would form under the skin and slowly releases into the bloodstream. What differentiates us is the slow release into the bloodstream. It's the time, it's the peak concentration that drives all the side effects and probably even some of the safety, like heart rate. Our drug does not peak until 70 hours after dose administration. Instead of getting a peak, we get a hill, a soft hill. With other drugs, we're seeing peaks that are occurring at 14 hours or similar to that, which results not only in tolerability issues, but safety issues as well. Based on that, we felt that we could administer the drug without dose titration. In almost all of our studies, we have not titrated at the 1.2 or the 1.8 mg dose. If we recall, at the 2.4 mg dose, we had a short titration of four weeks. That is short in comparison to the 16-20 weeks used with other compounds. We would say, with comparable safety data and tolerability, that we have the best tolerated drug in the class. Now, moving ahead, we're doing some modifications of dosing. As you know, in our obesity program, we've talked about titrating for a slightly longer period of time. We're not titrating in the IMPACT trial, which is the MASH biopsy trial, but that is something we could do in phase III. One thing that we didn't do in our MOMENTUM obesity trial is we did not allow for dose reduction. We had not seen adverse event discontinuations of any sort in earlier trials. Other companies have had as many as 30% of patients who have dose reduced, or they stopped dosing before they got to the upper dose because of intolerability. We thought to, as we go into phase III and improve the tolerability of the compound in the Prescribing Information, that we would allow dose reduction. We have done that in the IMPACT program. There is currently no dose titration in the phase II study, which is in contrast to most other incretin studies. We are allowing for dose reduction if needed. Exactly. OK, understood. Just to reemphasize, in our phase I-B MASH trial, there was actually very good tolerability and very low discontinuation rates. The data was very clear that we did not need to have dose titration on top of reducing dose. We believe that is going to work out really well in the MASH patient population. Yeah, I would add to that that we saw in our MASLD, or if you would, our MASH trials and diabetes trial, very low adverse event discontinuation rates. We saw low adverse events in general. In the diabetes program, for example, we had no zero adverse event discontinuations at all at any dose. Even at the 1.8 mg dose, we had no nausea and vomiting. That's unique among incretin drugs. The moral of the story is that when you're in disease populations like MASH or diabetes, people report lower adverse events, and they have lower rates of adverse event discontinuations. The bottom line is now that we're going into a MASH readout, where approximately 50% of the patients could have diabetes. Up to that, we don't know yet because we haven't seen the demographics. Also, the fact that they have a disease MASH, we think a very, very good tolerability profile will be seen. Great. Let's talk about the design of IMPACT a little bit more. It is, I think, very uniquely designed, certainly amongst the incretins, but even kind of beyond that, looking at that 24-week paired biopsy time point. If you could elaborate a little bit on how you powered the study, what you're expecting in terms of treatment effect, and your expectations here as we head into the top line data in Q2. It's difficult to pick an actual treatment effect because the placebo response varies so much from study to study. An example being with the same placebo, excuse me, treatment effect of 20 weeks comparing 30% - 50%. That's very different comparing 7%- 27% in terms of the power and the conclusion. In the first example, the improvement over placebo is 60%. In the second example, it's four-fold, right? That also drives the statistical power. There are a lot of moving parts here that make it very difficult to say what the treatment effect should be. If you hit statistical significance, that's going to be very meaningful. Now, we're not going to hit statistical significance with a 5% difference. We've designed the trial to have a lower placebo response rate because we've learned from the experience of other trials how to get the placebo response rate down. The principal way of doing that is to reread the biopsies at the end of the trial and avoid the bias that occurs when pathologists know the sequence with which they're reading biopsies. For example, early in the trial, they're going to upgrade the severity to allow the patient to get into the trial. Later on, expecting the patient's going to get treated, they downgrade the severity. A patient with no change in the biopsy can have an improvement simply because of the time when the biopsies were read. This probably accounts for the 20%-30% placebo response rates that have been seen in other trials. When you reread the biopsies, the experience has been in the 7%-12% range. That's going to drive statistical power. That may also bring down the actual absolute treatment effect. To get statistical significance is the major difference here. I also say that we're getting then the placebo response by using three readers and what's called the mode read method. Importantly, we're scrambling all the biopsies so that the pathologist rereads the biopsies without having any idea of when the biopsy was done. Yep, that makes sense. Yeah, one thing I would add, Tom, in terms of our expectation here, if we are able to show statistically significant improvement in fibrosis combined with weight loss, we will clearly set a new standard for treatment of MASH. I mean, that would be the new standard because there's no other drug that can do that. We have drugs that have direct effect in the liver, fibrosis improvement at 24 weeks. We have drugs that have weight loss, but not this combined both effects in the same drug. That is really what we're trying to get going here in terms of the next phase of the trial. Yep, that makes sense to me. Have you implemented, I guess, plans to evaluate the biopsies using AI or machine learning to give you more of like a quantitative scale of the actual fibrosis changes rather than the pathologist interpretation of what you're doing on the biopsies? Yes, we will do that. The primary readout that we'll have in the second quarter will be based on the pathologist's reads. OK, got it. So that is a subsequent analysis that we can expect at some point in the future? Yes. OK, great. Maybe if you could just take a step back, thinking about the MASH landscape here. I mean, today we have Resmetirom that's approved. We have Semaglutide most expected to be approved towards the end of this year, probably. And then a number of other kind of late-stage treatments. I thought you framed it quite well. You could have potentially a very unique data set and potentially set the standard here in terms of weight loss plus histology benefit. Like, how are you guys thinking about how this market shapes up over the next three to five years? As you said, it's good news that we have a drug already approved in the market. We're seeing that that drug is doing very well. That's a good sign. It's got a very modest effect. It's very clear that there's a lot of room for improvement, particularly if you combine direct effect in the liver with weight loss because that's really the complete solution for treating MASH. You want to treat MASH, and you want to take away the reason in the first place that resulted in MASH, which is obesity and overweight. By combining these two effects, we would be, you know, even with other drugs coming on the market, we think we're going to be the treatment of choice. Why wouldn't you want to treat both of these conditions at the same time? Again, we will set a new standard in terms of treating MASH. It's really, think of it as MASH with obesity. That's really the treatment, that indication that we are going after. These patients, people with MASH, 80%-90% of the subjects are overweight or obese and will benefit from losing weight. We are combining these two things. Think of it as MASH with obesity. We're treating MASH and obesity at the same time. Right, OK, that makes sense to me. Maybe last question on MASH, just to bring it back to the IMPACT study and I guess your expectations. Is it a requirement that you show statistically significant improvement on fibrosis in this phase II-B study to warrant advancing it into a phase III program? Is it something you need to evaluate sort of totality of the data showing MASH resolution alone? Obviously, you can get approved in the US, we think, on the basis of MASH resolution alone. How are you guys thinking about the minimum requirement out of this phase II-B study? Yeah, I think it'll be based, Tom, excuse me, on the totality of the data. Yeah, but based on everything we know, we are very confident that we should hit both of these endpoints. I mean, again, we've talked about we have the best-in-class liver fat reduction. That's really the driver of MASH resolution, of fibrosis improvement. We should hit that. Clearly, we should hit MASH resolution based on everything we know. Weight loss, we have already produced a significant amount of data to show that we're getting very, very significant weight loss after 24 weeks of treatment. Understood. OK, yeah, let's switch gears and talk about obesity. You have results from the phase II-B MOMENTUM study. Maybe if you could just sort of hit the highlights of that data set, and then we can talk through some of the recent regulatory interactions, potential for phase III, et cetera. Right. That was a 48-week trial in patients with obesity and overweight. The drug was given for 48 weeks. At the 2.4 mg dose at the end of 48 weeks, we hit 15.6% weight loss. Most importantly, the trajectory of weight loss was still steep. Had we continued dosing out to, say, the 72-week time point at the Resmetirom trial, we would have had very competitive weight loss. Importantly, all three doses were potent. Even the lowest dose, which was the 1.2 mg, which was given without dose titration, still yielded 10% weight loss. As a drug given without titration, which has an adverse event profile similar to placebo, very attractive in primary care. Remember, obesity is going to move into the primary care prescribing space. It has to be to be a $100 billion indication. This is a drug that can be administered without up-titrating through inactive doses to get there. It does not have to be reimbursed with each step separately. You give it. You do not have to titrate or have your physician extend or follow the patient. Now, it was not only positive in terms of the weight loss, but the other parameters. In patients who came into the study with elevated LDL, we had a 21% reduction of LDL cholesterol. We even saw that effect in patients taking statins. It opens up the whole opportunity to use weight loss to drive better LDL reductions. As you are aware, 30%-50% of patients who take statins fail to achieve their LDL goals for a variety of reasons. To combine it with the desire of the patient to lose weight to drive additional weight loss, we now have a pattern of synergy, which when we described to the FDA, they were very excited. We also saw 80% of patients normalizing their liver fat, something that we would expect. In addition, we also saw class-leading preservation of lean mass. We did an MRI sub-study of 67 subjects. We showed that of the total weight loss that was realized, only 21.9% was attributable to lean mass. By comparison, Semaglutide was 40%. By the way, in their Prescribing information, the association of that lean loss with higher rates of bone fractures of women in the elderly is four to seven-fold. That was very notable. Survodutide was about 38%. Tirzepatide was 26%. Finally, the ratio historically reported with diet and exercise was 25%. We've actually beaten pharmacologically diet and exercise, which is really exciting. We've designed a phase III program around these parameters. We could talk about that with time. Each of the pivotal studies addresses one of these described attributes of Pemvidutide. Yeah, that's great. Yeah, let's talk about the phase III design because in November, you engaged with FDA. You have some regulatory feedback. Maybe just talk about that feedback. This all came in proximity to the FDA's updated obesity guidance. I guess, what's the level of alignment between the feedback you received in November and obviously the updated guidance documents for obesity? The alignment was incredible. We've joked internally that they were writing the guidance as they were meeting with us. The guidance reads very much the way the meeting went. For example, we came in and said, this is not a drug designed to lower hemoglobin A1C. However, we will have an adequate number of diabetics in the program so that you can assess safety. They agreed. That was reflected in the guidance. We were told, importantly, that we had no safety signals. That's extremely important. We were told specifically we didn't have a cardiac safety signal. We were specifically told that we did not have to conduct a cardiac safety trial. All of our trials, the four trials, accounting for 5,000 patients, are efficacy trials. We had a very, very interesting discussion with the agency about lean mass preservation. It's reflected in some of the language in the guidance. They asked us how we expect to get the information in lean mass into Section 14 of the Prescribing Information because in obesity drugs, you're used to seeing weight loss, waist circumference, blood pressure, lipids, and heart rate. How do you incorporate lean mass? The conclusion was, this is very exciting. We increasingly recognize the importance of this. We're seeing these morbidities. We're seeing fractures. We're concerned about loss of function in the elderly population using these drugs. Let's have further discussions and find a way to get this into the Prescribing Information. Great, that makes sense. In the VELOCITY program that you've laid out, it does seem like you're enrolling or targeting a pretty broad swath of patients. I think you kind of specifically called out patients with comorbidities, high LDL, liver fat, sarcopenia. Maybe just talk about how broad do you think you can go with this program and how the basis for that is the data that you've generated so far in MOMENTUM? This was an innovative program. We didn't come in with STEP 1, STEP 2, STEP 3, STEP 4, SURMOUNT-1, two, three, four. We know what that template looks like, what that boilerplate looks like. We came in with an original innovative program where each pivotal trial highlighted an attribute of glucagon: LDL reduction in the presence or absence of statin. That's VELOCITY-2. Liver fat reduction as a risk factor for cardiac disease. VELOCITY-3, lean mass preservation's effects on function, rates of bone fractures. VELOCITY-4. The FDA called this program refreshing and innovative because they were not seeing a repeat of what had been given to them before. It was addressing new concepts. Most importantly, each of the studies reflected an attribute of glucagon. Most importantly, the FDA confirmed the safety profile of the compound, which is a tremendous platform for going forward with all of our studies in the future. That makes sense. That actually cuts across all our programs where we are trying to treat not just obesity in general, but actually comorbidities of obesity, so serious diseases with obesity. You'll see that even as we talk about the additional indications, it's the same theme that we are developing. Because of the dual mechanism, we are trying to capture these both benefits at the same time. Disease conditions where patients will benefit by improving their liver health, but also losing weight at the same time, that's how we are focusing on it. That keeps the obesity indication alive in this specialized patient population. Got it. That makes sense. I guess in tying all of that together, could you just talk about how you're thinking about next steps and advancement as it relates to business development and partnerships? I think you've talked about a partnership for obesity would be ideal. Just how you're thinking about partnering across the broad opportunities that you could go after with PEMVI? Yeah, we're moving full speed ahead with the MASH program. We're actually preparing for our end of phase II meeting as we speak. We think we can have that meeting on the back of the 24-week data. Our plan is to move into a MASH phase III program on our own. With obesity, we've been very clear that we're looking for a partner. The only way we'll move it forward from here is to have a partner. The whole landscape is changing in obesity. The pricing pressure is very much downwards. People are already discounting these drugs. Whereas if you go after a serious disease condition with obesity as a comorbidity, that's a simpler route because you have pricing flexibility. You're really treating that serious disease. Losing weight is an added benefit, a desirable outcome, but it's an added benefit. That's really how we are looking at it. Understood. Can you, I think an increasing focus here, sort of like non-clinical, but key to thinking about scaling this up, has been focus on manufacturing and supply. How are you guys manufacturing today? How are you thinking about scaling that up for future clinical studies and commercial? Yeah, we are working with world-class CDMOs who are very well known in the space. They're working on other programs. Right from the very beginning, we are all set. We have plenty of material to do phase III trials that we are talking about, even any additional studies, as well as launch the drug. As we are moving forward, we have relationships with commercial manufacturers that we will need down the line when we commercialize the drug. OK, we have clinical supply that's secured. We're secured, we think, through phase III. And then commercial. Early commercialization. Early commercial. OK, got it. That's great. Unfortunately, we're up against time. We'll have to leave it there. Looking forward to the R&D event a couple of days from now. We'll stay tuned to the Altimmune story. Thank you. Thanks for the invitation. Thank you, guys.