Hi there, good morning and thanks for joining the Altimmune Session. I'm pleased to have with us CEO Vipin K. Garg and Chief Medical Officer Scott Harris with us today. As you all know, Altimmune has a GLP-1/GCG glucagon dual agonist being developed for MASH, which ironically is a one stop shop also for weight loss with the benefit of more liver targeting than the indirect [Sema]. I'm just going to open up the floor to you first and then we can rapidly go into Q and A right afterwards. Vipin, go ahead, give us an overview to get us all on the same page here.
Yeah. Annabel, good morning and thank you for having us this morning. As you mentioned, we are developing a GLP-1/glucagon dual agonist. The idea is to combine direct acting liver effects of glucagon with the benefits of GLP-1. It's really two mechanisms. We are combining liver effects with metabolic effects. We recently had a readout from our 24-week phase II data and that looks very encouraging. Extremely positive data, class-leading MASH resolution at 24 weeks. Fibrosis improvement well on its way, improvement in anti-inflammatory markers. Everything we looked at, NITs, even from looking at fibrosis improvement using AI-enabled histological assessments, everything is pointing towards very rapid and strong activity of the drug in both having a direct effect on the liver as well as weight loss. We showed very robust weight loss of approximately 6% at 24 weeks. The weight loss is still continuing.
As the treatment continues, the weight loss will continue to improve. Excellent tolerability, which is very important in any therapy, particularly in this class of therapy. Excellent tolerability in spite of no dose titration. Some important features of the molecule, we think it's really a complete package. It's a multifaceted approach to treating MASH, not just treating the liver, but the whole body. The benefits on serum lipids, blood pressure, all of those things we believe combined together are important for treating MASH.
Excellent. As you said, taken in totality, this data were actually quite positive. MASH resolution, fibrosis biomarkers lined up. Not the traditional fibrosis endpoint, but everything else aligned up properly. Weight loss, CV biomarkers, everything. Maybe you can sort of opine on how you think about this traditional fibrosis measurement and whether you know how to think about that as far as where regulatory agencies are going and where the field is going and how is the FDA going to be looking at this traditional biofibrosis histological endpoint versus the totality of the data, which was actually quite positive for you. What are we missing here as far as you getting credit for that profile that you actually have?
Scott, do you want to.
Yeah. Thanks, Annabel. The effects that we saw in MASH resolution were rapid and class-leading, and speed is very important here. You know, as Vipin said, the totality, the readout was extremely positive. Regarding the fibrosis improvement, we saw excellent response on the NITs, and when we applied an AI algorithm, we saw excellent responses as well. The activity of the compound in fibrosis is quite clear. We're also quite clear on the fact that had we biopsied at week 48, we would have seen positive results there. The MASH resolution endpoint is sufficient for approval in the U.S., but we also think that we have potent effects on fibrosis as well. The NASH CRN scoring system is categorical. That's where all of the outcomes data is based.
We could be moving towards an outcomes analysis in the future based on continuous fibrosis improvement, which is something that pathologists can't see. Based on the fibrosis improvement that we were seeing on the AI, there was an ongoing antifibrotic effect, and we would clearly have met the criteria for a stage change had we gone longer in treatment. As Weilman mentioned, we were extremely happy with the readout, and it was a very positive readout, and that we would hit all of those endpoints at a later time point.
Okay, can you just go back to the AI-enabled histological assessments for fibrosis? Who is using this measurement now? How validated is it? How comfortable is FDA with this? It almost seems like it could potentially be more accurate than just, you know, biopsy with three readers of one select piece of tissue from your liver, which may not necessarily reflect the entire liver. How are agencies starting to look at this AI-enabled feature here?
Right. Annabel, Europe has already approved AI-enabled methods for reading the biopsies. The proposal has been sent to the FDA. The company that is providing these analyses, which is PathAI, has informed us that they expect the FDA to act on their proposal in the fourth quarter of this year, right around the time of an Interphase II meeting. We think that'll be a positive interaction based on the AI reads. We've made European basis of approval, and if FDA acts accordingly, which we hope they will, then we will have met FDA standards as well. It's very clear from the totality of what we know about AI is that it's much more accurate than the human eye. We think this is the readouts of the future.
We have excellent results in AI reading, and we think the FDA will be very positive when it reviews the PathAI package in the Fourth Quarter.
Okay, that's good to know. They'll review in the Fourth Quarter. Do you know when the response might come?
We can only say approximately in the Fourth Quarter. I don't want to do the dates, especially when the commitments are to another company. We've been advised that the company expects the FDA to act on this. Going into that end of phase II meeting, it is possible that we already have FDA action that would have basically established the fact that we had a positive readout by their standards as well on fibrosis in this study.
Okay.
Yeah. Annabel, I just want to point out that our strategy is to really focus. Our base case is that we will go in with a fibrosis-based, with a biopsy-based endpoint. There are a number of potential upsides beyond that. If the AI becomes accepted by the FDA, clearly we'll be ready to pivot to that eventually. If we go all the way to NIT-based endpoints, we'll also incorporate that into our phase III program. As you know, we have already capped all of the NITs in our phase III program. That'll continue as we go to phase III. We'll have extensive data on NITs, so it doesn't matter which way the FDA eventually goes. We'll be prepared to leverage those changes in the regulatory protocols.
Okay, great. Before we get into expectations moving forward, can you talk to us a little bit about what you've learned of the tolerability profile and how that might give you flexibility in dose selection going forward? You mentioned a couple times the tolerability was good, but how much flexibility does this give you? What else can you do as far as dosing here?
We'll give you the street a total impression after speaking to the FDA. Obviously that's going to be part of the discussion. I would emphasize that in the phase III trial, we have the lowest rates of adverse event discontinuations of any drug in MASH development and certainly better than the entire incretin class. That was achieved without dose titration. We have a lot of optionality here. Should we decide to continue to straight dose pemvidutide, which we think is very attractive, or adding titration, that decision can be made with the FDA at a later time point. I think it's very important to realize that speed is important here. In our readout in IMPACT at 24 weeks, we were seeing rapid effects. As we said, at 24 weeks we saw the best-in-class MASH resolution even compared to compounds reading out to 72 weeks.
In fact, when we look at our non-invasive tests, we saw evidence of early change in the NITs, which we think are class leading as well. Physicians and patients are going to want to know this going into treatment. Physicians don't want to wait 72 weeks to see if a drug is working and patients don't want to wait that long as well. We think that early efficacy is going to be extremely important. Remembering that without titration you can see those effects much quicker as opposed to all the way out to 72 weeks, and also not knowing if you're going to get to that titrated dose as well. We don't know, for example, with semaglutide how many patients will get to the 2.4 mg dose and how long it will take. Remember the 10% of F3 patients progress to cirrhosis each year. Speed is important.
The assessment of how fast the drug is working is important. Physicians treating these patients and also with the lower adverse event discontinuation rates, people are going to stay on therapy. We know that with other GLP-1s there's a high discontinuation rate. We'll put that all together in terms of the final target product profile and that discussion with FDA will take place in the fourth quarter as we planned.
I think that's the most important point. It's really important to keep patients on therapy for them to get better ultimately if they don't. It's also important for patients and payers to see benefits as early as possible so they can actually be motivated to stay on drug and ultimately benefit from the drug. The weight loss component is something that they can see very quickly in a few weeks after treatment begins and that motivates them. I think that's really important from both payer as well as patient perspective.
Yeah, we actually heard that loud and clear on our payer panel this morning. The biggest issue is that patients are not staying on therapy past three months, and payers do not want to pay if patients are not going to be staying on therapy because they never see the clinical outcomes. I think that's going to be an important feature of your drug to keep these patients on drug. You are going to be releasing 12 month data in the fourth quarter. What would your expectations for the NITs be? Can you essentially straight line expectation for response, and if you do indeed see continued improvement, how would that factor into your phase III design? Are you going to be looking at both a 6 month and a 12 month measurements? Are you sticking with the 12 month measurement? How should we think about all of this?
Yeah, I want to start by saying that as we saw at only 24 weeks, are very potent, very impressive compared to other compounds reading out at later time points, and we expect those NITs to grow the exact trajectory. It's a bit difficult to predict, but based on those 24-week NITs and based on what we think endpoints would be in those NITs in phase III in consultation, Annabel, with experts, we think that we met the FDA basis of approval on what we think would be a NIT endpoint at only 24 weeks, and that's only going to grow with time over 48 weeks. We're extremely optimistic about the prospects of approval in NITs and how we would do. Again, to your point, these NITs are going to grow over the course of time.
We'll use that to help inform this treat in the anti-fibrotic and MASH resolution effects and what we would have had with a biopsy endpoint had we had biopsied the patient in week 48.
We’ll see continued weight loss, as I pointed out earlier at 24 weeks. It’s very robust weight loss, but there’s no plateauing. The weight loss is still continuing, and we’ve shown that before as well. As we go from 24 to 48 weeks, there should be additional weight loss, which is also very important.
Okay, that's great. Is there any kind of definition of success that you have in mind, or is it just continuation of improvement?
We expect continuation of improvement.
We think.
Metrics ready and it's only going to get better.
All right, going back to this question. When you think about the phase III trial and designing it for that speed of effect, do you expect to look at both a 6 and a 12 month measurement? Where are you trying to align with FDA? What do you know they will already allow? What is your ask of them? How should we think about these discussions and how you sort of design that phase III?
Thank you, Annabel. With non-invasive tests, unlike a biopsy, you can monitor a patient in time and also the speed of the effect. Based on discussions with a variety of experts in the area, we think the FDA is going to want a trial that goes 52 weeks in duration. Whether we assess the endpoint earlier or not, I think the FDA is going to want to see a 52-week endpoint and 52-week safety. To your point though, the NITs can show an earlier response and we think speed here is really important. This drug works quickly. We saw reductions in liver fat comparable to week 24 as early as week 12, and we have data that the effect is starting earlier than that. We saw ALT improvements that were statistically significant as early as week four.
All across the board, the NITs are moving in the right direction very quickly. The bottom line is that we'll have that early data. Whether we report out on it early or not remains to be seen, but we'll certainly have that and be able to show the time course in support of what we think is a very rapid effect, which is going to be very meaningful to patients.
Got it.
The only thing I would add, Annabel, is that our ask to the FDA is really to go in with a very flexible design because we expect things to change over the course of time. The FDA is considering perhaps going away from the requirement for biopsies, for instance. We want to build that flexibility into the protocol. If these changes take place, if the FDA agrees to an AI-enabled histological assessment of the biopsies, we will incorporate that in the protocol. We will have all of the NITs as well as AI-enabled histological assessments, depending upon how the landscape changes over time, and we'll be ready to take advantage of that. The way we are designing the protocol is to build on the flexibility.
The base case assumption is that we'll start with biopsies, but eventually the requirement for biopsies will go away and we'll be able to pivot to a non-biopsy trial, and all of those features will be built into the phase III program. Flexibility is the key so we can take advantage of any regulatory changes.
Let me just very quickly, Annabel. Flexibility, not only in the NITs, but the computer-based reading. We think both really make our trials more efficient. Higher probability of success, quicker demonstration of efficacy, lower number of patients, lower costs in the studies. We're very optimistic about both potentials and our ability to pivot to either of those, should we get that agreement from the FDA.
Okay, great. Now I'm going to pull back a little bit, bigger picture here. The recent Roche acquisition of 89bio reminded us that, one, large pharma has not lost interest in MASH, in fact they are interested in it. Two, that an incretin combined with liver targeting agents are the way to go. I think Roche has every intention to try to work with FGF21s and their own GLP-1s to try to come up with some kind of combined treatment, so that aligns with your program. I guess my question to you, and you may or may not be able to answer this, but what are investors missing and what is a potential partner missing here? Have you seen increased interest, partnership interest here, just given the activity that we're seeing here?
Yeah, that's a great question, Annabel, because there is this focus now on combination therapies, combining liver-acting agents with more metabolic effects, GLP-1s with FGF21s, THR-β and the like. Everybody's focusing on those. That's exactly as you pointed out, that's exactly what we bring to the table, both a direct active acting agent in the liver as well as weight loss. We think, why would you want to use two molecules if you can accomplish that same goal with a single molecule with good tolerability? That's what we bring to the table. I completely agree with you that the large pharma interest in MASH is coming back. Everybody used to be in the MASH field 10 years ago. People sort of went away from it, but they're coming back now, particularly after the success of the launch of Rezdiffra. Semaglutide is approved now.
The market is going to open up and people will pay attention to the space. We think combination therapy is the way to go. We are very well positioned as we look to the future.
How have strategics responded to your data? We know how the street responded to the data. Rightly or wrongly, have strategics had a different approach to your data?
Yeah, I mean, we can't really go into the specifics of that, but all I would say is that we're looking at every option, and strategic discussions are very much part of that.
Okay. All right. I guess one other market item, Sema was obviously just approved for MASH. You have similar weight loss. The advantages obviously are that you have a faster impact on the liver for MASH. Now, when you think about the market and how people stay on drugs, or if they stay on drugs, reimbursement, cost, this is going to be positioned as a MASH drug, which could potentially get a higher price point than, say, a Sema, even though it takes longer. How do you balance price and the fact that Sema now has a MASH indication? Maybe it's not as fast of an impact, but they do get the weight loss, they do eventually get MASH improvement. Everything else kind of improves if they stay on the drug. How should we think about all of this in terms of pricing yourself as a MASH drug?
Yes. Look, as you know, price is the function of value that you bring to the table. If we look at the two approved drugs in MASH space, Rezdiffra and semaglutide, Rezdiffra is more for later stage treatment of later stage patients, whereas GLP-1 or semaglutide will likely be used in earlier stage patients. What we need is a drug that actually spreads, covers both of these bases and really allows a broad spectrum treatment of most of the patients. It has a bigger footprint. We think pemvidutide fits that because we've got the weight loss benefit that GLP-1s alone are relying on, but on top of that, we have direct effect in the liver. We should be able to treat F1, F2, F3, all the way to F4.
That's really the advantage of the drug that the doctor doesn't have to really think it's very hard to diagnose these patients. They're not doing biopsies on them. Based on just NITs, they have to guess as to how advanced the patient is. If they can have a drug that they feel confident that will sort of have a multifaceted treatment of the disease, really doesn't matter whether it's F2, F3 or F4, they feel confident they can treat all of these patients. That would really expand the market. With semaglutide, the effects, it takes just too long to see the effect, 72 weeks. I mean, that's just not acceptable in this patient population because they will progress to cirrhosis if you don't treat them and have the treatment effect early enough. That's where the advantage, the value proposition of pemvidutide will be.
Got it. When you think about other mechanisms in the space, say FGF21s, and a number of companies contemplating these combinations of either GLP-1s or FGF21s or THR-βs, how do you position yourself here exactly?
We have got both of these benefits in a single molecule. I mean, that is really the attractiveness of pemvidutide. We have both weight loss of the metabolic effect and direct effect in the liver. That's exactly what other people are trying to do by combining two different therapies. It's easier said than done. When you combine two different therapies, you're dealing with two different sets of tolerability issues, titration issues. Even the PK profile can be different from one molecule to the other. They'll basically have to be prescribed as two separate drugs, which, you know, we think it's much better to do that in a single molecule that can deliver both. Both of these benefits.
Great. That's depending on which time. This is something that's also uncharted territory for you. You seem to be blazing the trail there. Do you want to just briefly give a quick overview of your intentions here?
I'm sorry, Annabel, I didn't hear your question. Scott, did you hear the question?
The ALD and AUD. Sorry. Okay, just briefly.
I want to remind you that we have Fast Track status for alcohol use disorder. We're the only company that has it. That trial is ongoing. It's going quite well right now. We do expect to have a readout on this trial in the second half of 2026. Enrollment's going well. Steady conduct is going well. The endpoints have been established by the FDA. We think the probability of success here is really quite good. We think this is a very attractive profile on AUD. The ALD study has just gotten going. It's a little hard to predict what the timeline will be on that. We're using the same endpoint of VCTE. We've got statistical significance of unmash. We think it's the best endpoint for the disease, and we're highly confident about success in that program as well.
Okay, great. I guess last question. Pursuing obesity or are you happy with a backdoor strategy through MASH?
I wouldn't call it a backdoor strategy. We've been very clear the value proposition is much greater. Going after MASH and other diseases, treating obesity or people losing weight would be an added benefit, but not the main driver of the treatment. That's really how we're looking at the market. Rather than competing in the obesity space, we're going after high value or more difficult to treat diseases. Obesity is the root cause of many of these, so we're treating multiple comorbidities. The benefit of a multifaceted approach of treating a full person rather than just one narrow segment of the disease is really going to be the value driver here.
Got it. Positioned to run that phase III trial with the cash with your balance sheet?
Yeah, we are continuing to improve our balance sheet, and we're looking at every option as to how to fund the entire phase III trial as we move forward.
Okay, excellent. We are out of time, but thank you for that overview. I think it was very helpful to clarify a lot of the points there.
Thank you for having us again.
Thank you.
I appreciate it. Thank you.