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I think we can get started. Hi, everyone. I'm Ellie Morel . I'm one of the biotech analysts here at UBS. Very excited to have Altimmune here with us for a fireside chat. Joining us from Altimmune is Vipin Garg, Chief Executive Officer, and Scott Harris, Chief Medical Officer, who just joined us from coming down Mount Kilimanjaro after quite the adventure. Thank you both for joining us. Maybe just to start off, can you give us a high-level overview of the company and some of your recent progress?
Absolutely. Well, thank you for inviting us. Altimmune is developing a GLP-1 glucagon dual agonist for obesity, for MASH, we're looking at other metabolic diseases as well. As you know, GLP-1s, everybody's talking about them, sort of the next frontier in treatment of obesity. As this market grows and evolves, there will be need for additional mechanisms of actions. And that's exactly what pemvidutide is designed to do. By combining GLP-1 with glucagon, GLP-1 is for appetite suppression, and glucagon is for energy expenditure. So by combining these two features, we believe we can have a more efficient way to lose weight, but also additional benefits at treating comorbidities of obesity. Because glucagon has a direct impact in the liver, we're having a reduction in liver fat, really metabolizing fat faster. And that's going to have benefit on serum lipids, as we'll talk about the data.
We're seeing that from all of our studies. Not only are we able to get significant weight loss, but patients are getting class-leading reduction in triglycerides, in LDL cholesterol, in liver fat, and so on. So we believe that by combining these effects, we'll be able to address some of the comorbidities of obesity much better than GLP-1s alone.
Absolutely, and there's a lot of talk, and we'll talk about obesity as well as MASH, but just in terms of the MASH space around having a direct effect on the liver, particularly potentially a direct anti-fibrotic effect. Now, there's been a lot of discussion around the incretins and the effects of weight loss, which can benefit MASH, but something that I know we've spoken about in the past is some of the potential effects that glucagon could have specifically on the liver, so could you elaborate on this and where you see some of the metabolic benefits on the liver?
Scott.
So in time, again, study after study, the one factor that predicts MASH resolution and fibrosis improvement, which are the endpoints in a MASH trial, is the reduction of liver fat. The more liver fat reduction you have, the higher the likelihood of hitting those endpoints. And we have class-leading liver fat reduction. So with regards to the incretins like tirzepatide and semaglutide, those are GLP-1 and GIP, and those agonists do not have direct effects on the liver. Their effects on liver fat are entirely mediated indirectly through weight loss, so the effects are slow. For example, at 24 weeks, we had 76% liver fat reduction. With semaglutide, it was about 30%-35%. So you'll get there eventually, but the effects are slow. And consequently, when trials were done, they had to be done over much longer durations.
You'll notice that with semaglutide in the ESSENCE trial, the study duration was 72 weeks. That's even longer than the tirzepatide duration of 48 weeks. Also, the effect is very modest. If you look at the trial design, instead of using the number of patients that you would have seen in the resmetirom trial, they increased it substantially. Because if you have an effect, you can show statistical significance if you go long enough and have enough patients. Fast forward to pemvidutide, we believe that we have one of the most potent drugs, if not the most potent drug for MASH, based on liver fat reduction and the fact that in animal studies, we've actually seen a direct anti-fibrotic effect of pemvidutide that's independent of that liver fat reduction. So we have two shots on goal here.
And we are actually reading out that study not at 72 weeks or 48 weeks, but at 24 weeks. And we think that that earlier readout, the ability to hit stat-sig at 24 weeks, will be clearly representative of the potency of the drug. Now, other drugs have hit 24 weeks fibrosis improvement, like the FGF21s. And they have liver fat reduction in the range of about 65% at 24 weeks. So we beat that right from the get-go. So we believe that we have a better chance of hitting that fibrosis improvement endpoint at 24 weeks. But in addition, we have something that they do not have, which is body weight loss. And body weight loss is a huge motivation for patients with MASH.
In our trial, which is called the IMPACT trial, which we'll read out on the second quarter, that trial enrolled probably faster than any other MASH trial to date. And the reason was that patients who came to the trial wanted to lose weight. We think that tells you about the market appeal of the drug. And lined up against the FGF21s, people who want to lose weight would choose pemvidutide. So we'd be the only incretin agent to read out at 24 weeks on any endpoint. Plus, we'd be the only agent at all to have both effects on MASH and weight loss at 24 weeks. So we think that when we get to NDA, we may have the best drug in development for MASH.
Yeah. Very interesting study, and before we go more into some of the specifics on the clinical data and what you've seen so far, just going back to this mechanism, you mentioned that you think it could have an independent effect on fibrosis in the liver, but then also we see this very potent effect from glucagon in terms of specific liver fat reduction. Tell us a little bit more about what you think the biology behind this is?
On the fat side, it's clear that glucagon inhibits liver fat synthesis and also accelerates beta-oxidation of fatty acids. We saw, for example, in one study, the ketone body production, which is representative of fatty acid breakdown, went up by a factor of six, not to what you would call ketotic ranges, but clearly a very healthy fasting range. And that's the very nature of glucagon, to basically shift body metabolism from burning carbohydrate to burning fat, which is very beneficial, not only in terms of overall metabolism, but we think is the underlying mechanism for the lean mass preservation that we're seeing, because the substrate to synthesize carbohydrates is muscle breaking down to amino acids. We're not exactly certain of what the effects of glucagon are on fibrosis. It's known that glucagon is anti-inflammatory.
In the liver, for example, when livers are harvested for liver transplants and they're transported from one site to another, they're packed in glucagon to preserve them before they're put into the recipient. So we think that there's something analogous to that.
Interesting. And a question that's come up in the space around glucagon has been around safety and tolerability. We've seen some data from survodutide and MASH. Maybe what's your perspective, high level, on the safety tolerability profile of glucagon?
Right. Well, as you're aware, Ellie, we just recently completed a very extensive end-of-phase 2 meeting with the FDA. And in that meeting, they see all of your data. They see all of the completed studies, the study reports, and they actually see the raw data as well. And no safety signals were identified in that discussion, whether it be cardiovascular or anything else. And in fact, they complemented us on an innovative program. We can talk more about the actual studies in a minute and told us agreed with our plans to go with four efficacy trials. So we believe that that's very strong confirmation of the safety profile of the compound going forward, and it's what we've reported in every trial to date that we've PR'd on. And the FDA agreed with that impression.
You've highlighted sort of the balance between GLP-1 and glucagon with your molecule. Can you talk about sort of why that matters and specifically how your molecule compares to survodutide?
Right. So survodutide has a ratio of GLP-1 to glucagon of eight to one. So it's much more heavily biased towards GLP-1. Our molecule is one to one. We believe in the potency and the value of that glucagon effect. And this molecule is designed to give the maximum amount of glucagon, yet maintain glucose homeostasis, which we've done repeatedly in all of our clinical trials. And the FDA actually agreed with that. So as you're aware, we're not lowering hemoglobin A1c. There are other drugs that can be used to do that. But in the obesity population, only 20% of diabetics, of patients with obesity or diabetes, and half of those are well controlled. So in a well-controlled diabetic population or non-diabetic population, this drug is absolutely ideal. But we're not seeing deviations in glucose control that would raise any concerns about safety.
In fact, in our pivotal studies, we're including a number of diabetics in order to further show the safety of pemvidutide in a whole variety of patients.
I think on the surface, there was some reaction to some of the survodutide data and thinking that some of maybe the high discontinuation rates or some of the tolerability had to do with the glucagon component. Why do you think that's not the case?
No, the tolerability rates were probably what you see with GLP-1-based agents. They were predominantly gastrointestinal nausea and vomiting. Now, regarding that, the adverse event discontinuation rates that we saw in that trial were typical for phase two. They were just shy. They're about 19%. I'm talking about adverse event discontinuation rates. If you look at the tirzepatide phase two program, it was 25%, and the semaglutide program was 30%. And across the board in recent phase two readouts, or for survodutide, retatrutide, etc., we've seen similar phase two adverse event discontinuation rates. The philosophy of phase two is to test what you can do with your drug and then make modifications. And we've seen this with the semaglutide program and the tirzepatide programs, where in their case, they adjusted the dose titration. They got those adverse event rates down. Now, we have tremendous optionality here.
For one thing, in that trial, we had a rigid dosing regimen that did not allow people to dose-reduce. We are doing that going forward. We think that's going to make a huge difference. And in addition, in our phase 3 program, we've elected to extend the titration of the 2.4 milligram dose to eight weeks and to titrate it, the 1.8 milligram dose, for four weeks. And we think the combination of the dose reduction and also the allowance for dose titration, that the adverse event profile of pemvidutide will either be class-leading or very competitive. I want to emphasize that that 1.2 milligram dose, which produced a 10% weight loss, had adverse event discontinuation rates similar to placebo. We think it's an excellent drug for primary care because docs can prescribe it without titrating up to it.
In other words, you start with an approved dose of drug, which is not the case for semaglutide or tirzepatide. You go through phases of non-approved doses, and it also produces 10% weight loss. And we're not intending to titrate at that dose. We don't see the need for it. And we see a very, very big opportunity in primary care at that 1.2 milligram dose. In reality, what docs do is they start the lowest dose. They see how the patient does. If you're not getting enough weight loss, they increase it to 1.8. And then if there's not enough weight loss with that, after several weeks, they go to 2.4. This titration regimen we use in clinical trials is artificial. It's not used in clinical practice. And in reality, it's stepwise increased to 1.2, 1.8, 2.4.
We want to emphasize that we intend to get all three of those doses approved in our registration program. That's important, and that will contrast with drugs and other sponsors that have unapproved doses in their titration regimen.
Yeah. The other thing I wanted to point out is that pemvidutide has a unique PK profile because of the modification of the molecule that's been designed in the molecule, the EuPort domain that we use in building the drug itself. It not only extends the half-life and protects the drug from proteolysis, but beyond that, it has other benefits. It's got lower Cmaxes compared to other drugs in development or approved drugs, as well as higher Tmaxes. So the entry of the drug into the bloodstream is slowed down. So a lot of the tolerability or even safety issues are driven from Cmaxes, a quick peak in the concentration of the drug. If you can lower that, if you can reduce that Cmaxes and extend the Tmaxes, you should see improved safety profile. And that's exactly what we are seeing.
Just to emphasize the point, I mean, we believe that pemvidutide is the most best tolerated drug out there in terms of an incretin-based therapy because all of our data so far was without titration and without dose reduction, and in spite of that, our profile was very similar to existing compounds. Going forward, our goal is to get each one of the three dosage approved, 1.2, 1.8, and 2.4 and that gives a lot of flexibility. The physician can start the patient on an active dose at 1.2 and then increase it as necessary if the patient needs to lose more weight or they need more activity from the molecule.
Absolutely. And there's certainly a lot of different development avenues between obesity and MASH. So I want to maybe delineate in terms of which trials we're talking about. But maybe first, before we dive into the clinical development strategy and the data you've seen, just high level, how do you think about the prioritization? I mean, these could theoretically be very different price points on the market.
Absolutely.
Also different cost structures for developing and commercializing.
Yeah. And it's becoming clear that the first generation of drugs for MASH are really setting a very low bar. They're statistically better than placebo, but really very modest effect. If you look at even Rezdiffra, that's already approved, and compare that to semaglutide and tirzepatide, very modest effect. So there's a lot of runway there. There's a lot of opportunity to improve. If you have a more potent drug, which we believe we have, you should get much better, much faster effect and much longer. The benefit itself compared to placebo should be much greater. So that's what we hope to show. I think we are very nicely set up in MASH. The market is developing. There are companies ahead of us that are building the market. And if we come behind them with a better molecule with more potent activity and safety profile, that would be highly desirable.
So that's really the strategy in MASH: to go full speed ahead with MASH. We're going to move forward with that. For the obesity, our strategy remains to continue to seek a partner. And because, again, that's a huge market. In the end, to commercialize that drug effectively for obesity, we're going to need a partner. So we've decided that we'll continue to look for a partner for obesity. But for MASH, full speed ahead. We can progress MASH on our own. And you make a good point. I mean, ultimately, the best way to treat MASH is really to have both direct effect in the liver as well as people losing weight at the same time. So if we can bring that combined benefit, that should actually be priced much more premium to just obesity. So we'll have to evaluate that as it develops.
But we're very excited about both of these opportunities. In addition, we think because of the glucagon benefits of the molecule, there's opportunity to develop pemvidutide for additional indications. And we are also looking at that. We're planning to file our first up to three INDs by the end of this year. And we'll talk more about that when we got clearance from the FDA to move forward.
Since it's a readout that's coming up next year in the second quarter, let's talk about the design of your phase 2b in MASH.
The trial is 190 subjects, and the randomization is 2 to 1 to 2, placebo 1.2 milligrams and 1.8 milligrams. So if you look at the sample sizes of the two primary treatment groups, the placebo and the 1.8 milligrams, that's about 76 per arm. That's very robust for a MASH trial. We've seen successful readouts with sample sizes in the 50s and 60s. So we've invested more subjects than in other trials in order to have a greater probability of success. The treatment duration is 48 weeks, but we're actually, as we mentioned before, reading out the endpoints at 24 weeks. And also, as I mentioned before, this will be the first incretin agent to read out in a biopsy endpoint at 24 weeks.
Yet we're following all subjects for 48 weeks to look at their biomarker responses, their safety, and also their weight loss at the end of 48 weeks. We're very happy with the way the study has gone. As I mentioned before, it's been one of the fastest enrolling studies in MASH. We think that speaks to the attractiveness of the compound and commercial potential, and we're on track to read out the study in the second quarter of next year.
What's the reader methodology that you're using? I know there had been some modifications towards the end around rereading. Can you walk us through the reader methodology?
Right. So we have a number of advisors in the program, and we've also benefited from seeing how other companies have done that and what's benefited their readouts and decreased the variability of the biopsy results. So one of the things we did is we've given very clear instructions to the readers on how to interpret the biopsies. What is a ballooned hepatocyte can differ very greatly in the eyes of pathologists, how to read fibrosis. So giving them clear rules will decrease the variability, and we've seen that as well. We are also advised that there can be a drift in the way pathologists see the biopsies over the course of the trial and that there might be some bias early on when they're enrolling patients.
They know they're trying to make eligible for the trial, and then efficacy at the end, there's a tendency to underread the biopsy early on and overread it later, so the way that you deal with that is you take all the biopsies at the end of the trial, you shuffle them, and you give them back to the pathologist in a blinded fashion. And with that, experience has shown that's the best way to look at the biopsies. We instituted this. We had originally intended to read out in the first quarter, and then we decided to implement this, and with the time that was involved to do that, we made the very slight adjustment to go back into the second quarter to allow that process to unfold.
Makes sense. And something that I don't quite understand, but it seems like we've seen in a handful of the trials of the weight loss medications in MASH is a higher placebo rate. What are your expectations for your trial, both on MASH resolution and fibrosis from the placebo?
I wouldn't say that deals directly with the mechanism of action. I think it probably deals more directly with how the biopsies are read. For example, in the ESSENCE trial, if I recall correctly, the placebo response rate for fibrosis improvement was in the low to mid-20s. My understanding is that they did not have a consensus panel read with that similar to what we're doing, or they didn't reread the biopsies. So consequently, how rigorously you read the biopsy controls your placebo rate. And if you don't do it, we think not the drug mechanism, but the mechanism. The readout determines your placebo rate.
Interesting. Any color on some of these statistical assumptions?
The most important part here is that we had stat sig at 24 weeks. That itself is going to be very meaningful. Companies and analysts have said, "Try to align up the treatment responses," but there would be no way that a drug like semaglutide could hit stat sig at 24 weeks. It just wouldn't happen, so it's a very, very clear statement of the potency of the compound to be able to do it, and as I mentioned, we'd be the first incretin to be able to do that at 24 weeks.
If you wait for 72 weeks or 48 weeks, the effect size will be even greater. If you can already hit statistical significance at 24 weeks, if you project out to 72 weeks, you should have significantly higher effect than the drug that is just barely hitting statistical significance at 72 weeks.
Absolutely. Let's talk about the clinical data that we've seen so far from pemvidutide, specifically walk us through the trials that you've already run and what we've seen in terms of weight loss as well as safety tolerability.
Let me focus on the MOMENTUM trial because it's the largest trial that we've completed to date. As you know, the MASH trial is 190 subjects, but it's currently ongoing, and we're blinded to those results. In the momentum trial, the 2.4 milligram dose, at week 48, we had a 15.6% weight loss. The trajectory of weight loss indicated there was a lot more weight to lose. If we had gone to the 68 to 72 weeks of the tirzepatide and semaglutide trials, we would have seen very competitive weight loss with that. We saw a very prominent reduction in serum lipids in patients with elevated lipids. At baseline, we saw a 21% reduction of LDL cholesterol. We saw that effect preserved in patients who were taking statin therapy.
As you're aware, there's a big unmet need in the statin treatment population because only about 50% of patients actually hit their LDL goals. So if you have a therapy that's a weight loss therapy, very attractive to patients since compliance with statins may not be ideal. To combine the two together to get a synergistic effect to drive down LDL cholesterol, that would be very attractive. Actually, the FDA made a comment. They found that was a very attractive proposition. That's actually the design of VELOCITY-2 , our second pivotal trial in the pivotal program to look at LDL cholesterol reductions in people who have elevated LDL at baseline, a subset of which are already taking statins.
Although not in the MOMENTUM trial and previous trials in patients with fatty liver or MASLD, we saw a 76% relative reduction in liver fat with over 50% of subjects actually achieving normalization. These are really excellent statistics. On the safety side, the adverse event profile was typical for a phase 2 compound. We believe that with the dose reduction and the dose titration that we've talked about, that this compound will be extremely competitive, if not class-leading on safety and tolerability by the time of that readout occurs. As Vipin mentioned, we were in the same range as other compounds in phase 2, despite not effectively allowing dose titration or dose reduction. The mere fact that we could keep up with the other compounds despite those restrictions really talks to the tolerability of the compound.
Great, and then maybe just turning to the recent interactions with the FDA and potential designs for phase three and obesity. Yeah, just walk us through some of the recent FDA feedback.
As I mentioned before, an end-of-phase 2 meeting is a very extensive meeting with the agency. You put all of your data out there. We had 521 completed subjects. We actually have 190 in the ongoing MASH trial as well. They take a look at the data for all of the safety of the compound. They dig in. They have the primary data, and they tell you what they think. What they told us is that they did not see any safety signals in the compound. They did not give us any specific safety directions. They agreed with our proposal to go with four pivotal studies oriented towards efficacy. Those studies will comprise 5,000 subjects. It aligns with the FDA guidance on obesity for the number of exposures needed for one year. The first of the study will be the largest study, VELOCITY-1 .
It will be a study in non-diabetics, very similar to the STEP other SURMOUNT trials. And that will be a weight loss study in non-diabetics. But the other two, three studies will have diabetics in them. As I mentioned, VELOCITY-2 is looking at subjects with elevated LDL cholesterol at baseline. VELOCITY-3 is actually a study in patients with fatty liver. Fatty liver is known to be associated with cardiovascular comorbidities and represents ectopic fat in the body, which can deposit in many other tissues in the body. So the treatment of MASLD is extremely important. And then VELOCITY-4 looks at lean mass preservation, but it also focuses on function in subjects, particularly the elderly and individuals who are more apt to the morbidities of lean mass loss, such as individuals with sarcopenia at baseline.
Yeah, one of the things that's noteworthy about the design of the trial is that right from the very beginning, we were not trying to duplicate what other obesity trials have done in the past because of the mechanism. We wanted to bring out and leverage the benefits of glucagon. So it was unknown to us would the FDA agree to that, would buy into that strategy as opposed to doing similar trials as have been done with tirzepatide and semaglutide. It was refreshing to see, and they actually complimented us on that. That's really where we think the obesity field is going. Going forward, there's going to be a lot more emphasis on treating multiple comorbidities of obesity, and different mechanisms are going to be required to achieve that goal.
Incretins or GLP-1s and GLP-1 GIPs are excellent at treating diabetic patients with obesity because they're addressing a very important comorbidity of obesity diabetes. But they're not really addressing as effectively serum lipids and dyslipidemia and liver fat. That's where glucagon comes in. So we think that's sort of the next set of comorbidities that we need to address, and that's exactly what pemvidutide is designed to do.
Yeah, I think that absolutely makes sense in terms of a potential development strategy. You've mentioned that you wouldn't bring obesity forward on your own. How should we think about the timing around a potential partnership? Are you waiting for the MASH data?
Obviously, MASH data. Let me just back up and first say the end-of-phase 2 meeting is an important, very important value-creating milestone for de-risking milestone for pemvidutide, for Altimmune, and even for our potential partners. So we'll see how that plays out as people become, as we expose them to the design of the trial. Now the program is all set. Now we know what needs to be done and what would it take to get the drug to registration. So I think that should help going forward. But beyond that, our strategy hasn't really changed. We'll continue to seek a partner centered around obesity, but we're going to move full speed ahead with MASH. We think we can develop that on our own. And that's why we're looking at these additional indications as well. Those are also indications that we can develop and even commercialize on our own.
So our goal is to continue to create value. And ultimately, it'll be good even for a partner to see that progress, and there may be even more interest in as we bring together all of these additional indications.
Yeah, and let's talk a little bit more about some of those additional indications as well that you think you can develop on your own.
Right. So again, the focus is to leverage glucagon, both combination of GLP-1 glucagon. So these are all obesity-related indications. We'll still look at obesity as one of the endpoints, but the focus is going to be on comorbidities of obesity. We've not gone out and talked about what these indications are. We're waiting to complete our FDA interaction. As I said, we plan to file first up to three INDs this quarter. We'll get feedback from the FDA, and then next year, we'll prepare. These are all going to be phase two type studies. So we're going all the way back to one of the benefits of having this end-of-phase two meeting is that the safety profile of pemvidutide is all set at this point. Even for MASH, that should help us, but even for these additional indications.
So in the first half of next year, we plan to file additional INDs, and we'll discuss more as we have more information.
Great and with AASLD this weekend, and we'll be getting the first phase 3 readout from a GLP-1 in the space. What are you looking to see in terms of some of the full data from the ESSENCE study, and I guess also anything else that we should be focused on at AASLD?
The initial readout for the ESSENCE study came in exactly as we would have predicted. The effects were modest. They were helped by the fact that they dosed for as long as 72 weeks. The longer you dose, the better the effect. Vipin brought that out. And also, they overpowered the study, the number of subjects in the study. If you have a small treatment effect, if you have enough subjects, you'll be able to show it, whether it's clinically meaningful or not. Look, we think it's in advance. We think that with GLP-1 agents, because of their indirect effects in weight loss, treated long enough, you're going to see these effects. But they would not have seen these effects at 48 weeks or 24 weeks. So consequently, the effects are there.
But when you combine a GLP-1 with a direct-acting mechanism, you have much greater potency in the liver, much greater effects in fibrosis. So we believe that with pemvidutide, we can treat all phases of MASH, not only the early phases where you want to get weight loss, but the later phases where you need to reduce fibrosis. So we think that we could take all comers and that we're not pigeonholed into any one phase like a GLP-1 like semaglutide might be. We can go all the way up to F4.
In terms of a cash runway perspective, remind us sort of where you stand from that perspective.
Yeah, so we just announced that at the end of third quarter, we had approximately $139 million. That's sufficient cash to go well into the first half of 2026 and really achieve all of these milestones. Obviously, the MASH data readout would have been completed by that time. Even the additional indications that we are talking about, we'll be able to initiate them and have data on some of them by that time.
Great. And yeah, with that, I think we can close it out. But thank you both so much for joining us.
Thank you for having us.