Good afternoon, everyone. Welcome to our Piper Sandler Healthcare Conference. It's day two of our conference. My name is Yasmeen Rahimi. I'm a senior biotech analyst here at Piper Sandler. Altimmune is one of my companies dear to my heart, as I was one of their first covering analysts, and I've really seen this company transform when it was like maybe a $2 stock or like it.
$20 million market cap.
Yeah, $20 million market cap. So it's been a pleasure working with you guys and watching this tremendous progress. 2025 is a very big year ahead of us. Would love to spend time, and obviously in a very hot therapeutic area of metabolic disease. I think the area that I would like to comment and start off with is really, you got the alignment with the agency in regards to your pivotal programs in obesity and metabolic syndrome. You're currently in the middle of conducting a phase 2b study in MASH that's going to read out in 2Q. And you also recently, on your earnings last month, noted that you're filing three additional INDs.
Up to three.
Up to three. So maybe that's a good place to start, because I think investors were asking us, could you walk us through what are indications for which a glucagon GLP-1 agonist makes sense? And what is the sequence of these IND filings and what type of indications you're potentially contemplating and why?
Let me start the question, then Scott, you can pick it up. So in terms of, I mean, we're not going to be able to go into the specifics of the indication that we are thinking about going into. We are exploring them. We are expecting to file our first IND before the end of the year. So we should have alignment with the FDA sometime in the first quarter on that, and then we'll be able to talk about it. That would be the first indication. Again, as I said, we will file with exploring up to three new additional indications. But the whole program, the way we are looking at it, and even from the obesity perspective, if you look at our end of phase II meeting and our trial design, they're all designed to leverage the benefit of glucagon. So GLP-1 is there, appetite suppression.
But what else can we bring to the table by adding glucagon to GLP-1? And that's really what the driving force is here. That's where we believe what's special that we bring to the table. So think about, in terms of new indications, they're all centered around benefit of glucagon, liver, lipid metabolism, things like that. That's all we can say at this point, but Scott can provide you a little more color and perhaps tie it back to the four different trials that we've agreed to with the FDA on the phase III program, because I think that also provides a window into what we are thinking about in terms of where glucagon will play.
We didn't copy or mimic the previous sponsors that had gone into the FDA. As you're aware, Lilly and Novo and other sponsors have done a step one, a step two, step three, step four. We felt it was important to anchor the program with a step one type study, a traditional study not in diabetics. But the other studies have diabetics. But instead of repeating the two, three, and four pattern, we picked study themes that highlighted the benefits of glucagon, things such as lipids, the LDL lowering properties of glucagon, which is the focus of VELOCITY-2 , the second trial, reduction in liver fat, which is VELOCITY 3. And then the fourth is preservation of lean mass. And the FDA was very enthusiastic about this. With regards to the second indication, it's recognized that many patients who are taking statins do not achieve their LDL targets.
As much as 30% of subjects or patients cannot tolerate statins. So the question is, how do we get there in terms of population health? We have data from our MOMENTUM study showing, first of all, that we had greater than 20% reduction in LDL with people who came in with elevated levels at baseline. But we also importantly saw the effect in people who are taking statins. What that tells you is synergy in therapies to drive those goals. In addition, motivation, LDL cholesterol is silent. People don't feel it. There's a question about motivation behind the LDL lowering therapy use behind statin use. But one thing that is guaranteed is that people want to lose weight. So the FDA saw this as a way of getting patients to drive their lipid reductions by getting weight loss therapy. And again, this is unique to compounds that have glucagon.
This cannot be achieved with other therapies such as GLP-1 monoagonists or GLP-1 GIPs. With regards to the lean mass, the FDA called this an innovative trial. They were enthusiastic about it. They wanted to see these trials done, and we're going to be looking at lean mass preservation, but also function, which is extremely important. We've also identified populations such as individuals coming into the trial with sarcopenia. About 20% of people with obesity actually have lower muscle mass than they would have if they have ideal body weight. The explanation for that is that they get resistance to their own insulin because of their obesity, but it's the insulin that maintains their muscle mass, so consequently, they have less muscle mass as an obese person, paradoxically, than they would have if they were ideal body weight, so consequently, that's a population that's really primed for studying.
You're probably aware that in the semaglutide label, it warns against a higher risk of fractures in the elderly and in women. So this is also a prime population. And it's the kind of study that FDA wants us to conduct.
Team, on the VELOCITY studies, when do you plan on kicking off the VELOCITY studies? What is going to be the sequence of the four, as well as the capital needs to conduct them and bring them to the finish line?
Right, so we've been very clear about the obesity program, that our goal there is to secure a partnership. We're working on that. We have no plans to initiate those studies on our own, at least not at this point. We're going full speed ahead with MASH. We think that's something we can create. The value we can create there is significant with the appropriate investment, so stay tuned. We'll obviously update, but we're getting ready for phase III. Everything is, we're not waiting around, but we're getting everything ready for phase III, and we're moving full speed ahead with MASH and as well as these additional indications.
Okay. Team, let's spend the rest of the time on MASH because the data is expected in 2Q. I think that we have done, given that enrollment completion was announced, and I think we did, and it's a 24-week duration, and I think it takes about 10 to 12 weeks of analyses. Do you think it's sort of fair to predict timing could be sort of a little bit into the back half of 2Q? So I don't know what your thoughts are. Biopsy analyses, some companies analyze them all at the end. Some of them analyze them as they go. Could you talk about sort of the time frame for completing all those?
Yeah. So we are doing a re-read of all the biopsies. We believe that's the right thing to do in order to reduce any placebo effect, any bias in sort of reading in the reader at the beginning of the trial. So these, obviously, they were all read at the beginning of the trial, but there'll be a re-read of every biopsy at the end of the trial. So that adds some extra time. But we're very comfortable saying that we'll have data in the second quarter of next year. We're not being very precise in terms of the timing within the quarter. It's hard to predict that, but we feel very good that we'll have the data in the second quarter. Scott, maybe you can talk about the trial design and what we are expecting.
The trial consists of 190 subjects. They have to have F2 or F3 fibrosis to be in the trial. The primary readout for the trial will occur at 24 weeks. It's important to recognize that to get statistical significance with an incretin-based agent at 24 weeks would be unique and a first, with tirzepatide reading out at 48 weeks and semaglutide reading out in 72 weeks. Semaglutide in their smaller phase II trial could not get significant statistical significance with 100 patients per arm, which is a very large phase II study. But when you take a treatment effect and you put 400 patients per arm, you can certainly achieve that kind of goal, but they would not be able to achieve that readout at week 24.
Also based on the tirzepatide data, and what's really driving this is the level of liver fat reduction, which is very modest compared to the drugs that have direct acting agents. Very unlikely they would read out at 24 weeks with statistical significance as well. To achieve statistical significance at 24 weeks, it's doable if you have an agent that works directly on the liver. In the example of that or the FGF21s, we've seen three compounds, all FGF21s, with successful readouts at 24 weeks. The reason is they have very strong liver fat reduction, which is the primary driver of the MASH effects. If you don't have the direct effects in the liver, if you're mediating your MASH effects totally by weight loss, you're waiting a long time to see those effects.
It really questions whether you're going to see those effects in more advanced populations like cirrhotics, because the effects are mild compared to the FGF21s. The liver fat reduction with the FGF21s is in the range of about 60%-65%. And again, there's a strong correlation between liver fat reduction and MASH success, fibrosis improvement. We have 76%. So simply based on that comparison alone, we should be in the category with a successful 24-week readout and also differentiate immediately based on that point from all the predecessor incretin trials in NASH. But we beat the FGF21s because of one significant factor, is that we have weight loss. And they don't have weight loss. And we had one of the fastest enrolling trials to date in MASH. It was because we offered patient weight loss. It's like the statin effects.
You give them weight loss, the patients come in. This is going to be a big market driver when the drug is approved. And this weight loss is going to significantly differentiate pemvidutide from the FGF21s and provide the complete solution for patients with MASH.
Thank you. Could you maybe talk about two aspects of the execution? One is how you're handling, how is biopsy handled in the study? That's part one. And then part two, what happens to patients that discontinue treatment? How is that statistically analyzed?
Right, so in terms of the biopsies, we've benefited greatly from being a follow-on to many trials. We've seen in the past high placebo response rates. We know how to deal with them. It's all based on how you read out the biopsies, and we haven't gone specific on exactly how we're reading the biopsies. We have mentioned, though, that we are doing a re-read, but we have benefited from all of the previous panel discussions and adjudications that have taken place, and we'll provide the details about that when we read out the trial, but the expectation is that we're doing at least as rigorous approach as any other company to date.
It's a dual reader?
It is a panel reader. Yes.
Okay. Panel.
Yes.
Okay. And then the dropout.
So there are different ways that you could look at the data. You're probably familiar with that. You've seen companies only reading out on their completers. You've seen some companies reading out on all of the patients, what you might call an ITT, where any patients who do not have a biopsy are treated like the way the FDA would treat it as a non-responder. And then you've seen that with tirzepatide, they did something called multiple imputations, where they in a sense estimated or modeled or computed how patients would have done had they had the biopsies if they didn't have one. So we're going to provide data on all three at our readout.
Okay. In terms of dose titration, up titration, and down titration, how does the IMPACT study differ from the MOMENTUM study, and what is the criteria to go up and down in doses?
So there is in MOMENTUM study, sorry, in IMPACT study, we're only taking two doses, 1.2 and 1.8. There is no dose titration on either one of those two doses. However, we are allowing dose reduction, which we didn't allow in the past. So that's gone very well. All we can say at this point is that we're very pleased with what we have seen. Obviously, enrollment is complete at this point. So we're very happy with the tolerability profile that we are seeing.
Is there a certain discontinuation rate that you think is acceptable that you hope to be achieving in the study?
Again, as I said, we're very happy with what we are seeing, and obviously, it would be breaking the blind at this point to start talking about data that we will talk about at the end.
Okay. I think the question at the top line data or close to the top line data will also come, given that you have two different doses. How should we be thinking about histological response, both across NASH resolution and one-point improvement of fibrosis across the dose? Should we expect a dose response in both endpoints? Is it too small to detect that? I'd love to get your thoughts on it.
We've seen the dose response in all of our trials, and we would suspect between the 1.2 milligram dose and the 1.8 milligram dose that we would see that dose response. That 1.2 milligram dose is extremely attractive for obesity because it's not titrated at all, and it has an adverse event profile similar to placebo, meaning the docs can just prescribe it without titration and not worrying about the patient coming back to get titrated, so we thought it was worthwhile to study this dose in MASH. In terms of the 2.4 milligram dose, it's something that we could always address in phase III, but all of our data pointed to the fact that the dose response for MASH, liver fat reduction, was all plateauing at the 1.8 milligram dose. It's different from weight loss, and you would suspect the two different effects would have two different dose responses.
We elected just to go up to 1.8, but we could easily add the 2.4 milligram dose in a phase III program.
And depending upon the data, once we see from phase IIB, we may actually choose to get two doses approved for even for MASH because that gives flexibility to physicians to start the patient at the lower dose, see how they're doing, and then move them to the higher dose.
Team, I think with the ESSENCE data that recently came out on semaglutide in MASH, it's been really clear that Novo is communicating their commitment to build a market in MASH. And I think we have seen all of us sort of the launch of Rezdiffra. So how do you view the market evolving and how pemvidutide will fit into the MASH landscape? And who would be the ideal patient?
That's a great question, so I mean, as you know, both Rezdiffra and now we've seen the ESSENCE data, the effect size is fairly modest. So there is really, this is a low bar in terms of a more potent drug to come on the market. We are very happy with how things are playing out. I mean, clearly, there was a few weeks ago, there was quite a bit of discussion. Are we going to need medication for MASH at all? Is the GLP-1s going to just sort of take care of that? It appears, while GLP-1s might have a role, they're not going to have the kind of effect, kind of potency that you're going to need for all of the phases of MASH patients, and that's where we come in with a more potent drug, as Scott said. This is a complete solution for treating MASH.
The best drug to treat MASH is what people are already talking about, combination therapy, something that has direct effect in the liver combined with weight loss. Well, that's exactly what we have. Rather than using two separate drugs, in one drug, we have both of these mechanisms. And that's the best way to treat, eliminate the cause of MASH, obesity, and treat directly in the liver. So we think we're very well positioned to be a major player in MASH once we get our p hase 2b data.
And how soon post the phase 2b data, could you engage with the regulatory agency to discuss pivotal design? That's part one and part two, I guess. How important is the sign-off of the phase III from MASH as part of your dialogue with potential partners?
Actually, let me back up. The sign-off on phase III for obesity was an important de-risking event for the program, not just for obesity, but for the drug itself. Because really, that's the first time the FDA has a comprehensive look at the safety profile of the drug. And we got clean bill of health on that. So they haven't asked for any additional safety study. That cuts across. That's not just obesity, cuts across all of the things that we are talking about regarding pemvidutide. So that gives us a lot of confidence. In terms of your first question, what's the plan? Our plan would be to go to the FDA as quickly as possible after completion of 24-week study of top line data. Even though the study will continue for another 24 weeks up to 48 weeks, we don't think we need to wait that long.
That's just a safety endpoint. And we'll provide that data to the FDA. So we want to move as quickly and as aggressively as possible to start the phase III program for MASH.
Yasmeen, I would add to that that that end of phase II meeting, which was affirmation by the agency of the safety of the compound and also the efficacy, is acceleration for all of our programs. It puts us in a faster position to execute an end of phase II meeting on MASH now that we've done the end of phase II meeting on obesity. So the timeline has been accelerated by having that obesity end of phase II.
Okay. Team, for investors, I think it's pretty clear that glucagon, I think, has a direct effect on the liver and a high POS to show differentiation in the MASH study and the fact that you can get efficacy in NASH resolution and fibrosis as early as 24 weeks, could be very profound and establish best-in-class. The question that comes up within investor discussions are the differentiation within the class of glucagon. Would love for you to kind of reflect. I think the only other compound that's ahead of you in development is slightly ahead, at least in MASH and phase III, is survodutide. So how does it differ? How does, based on the data, you could compare and contrast? And obviously, this is a tremendous big market. There could be multiple players, but.
The differentiation is twofold, at least. Number one, the tolerability profile of survodutide does not appear very good. They have the highest adverse event discontinuation rates of not only MASH drugs, but also incretins. They're seeing adverse event discontinuations even at their lowest doses of greater than 20%. And they're extending their titration to a minimum of 24 weeks. And they've even announced as long as 32 weeks. Contrast that with a drug, which in our two doses in our MASH trial are not being titrated at all. The second thing is that we were given a clean bill of health on safety by the FDA. We were not asked to do a safety trial, whereas in the survodutide program, they were. We don't know what that was about, but it says something about the FDA's opinion of the safety of the compound.
Because ordinarily, with the other incretin programs and ours, they've let the programs proceed only with efficacy trials.
The other thing I would add to that is a major difference between pemvidutide and survodutide is that we have a lot more glucagon. So if you believe in glucagon and the effect of glucagon, that's where you want to go. Pemvidutide delivers a lot more punch in terms of efficacy, and we see that. If you look at their lipid data, serum lipid data, pemvidutide does much better, even though they're both glucagon because they have 8:1 ratio, biased towards GLP-1. So there's a little bit of glucagon there relative to our pemvidutide, [which] has significantly higher level of glucagon.
Then, fast forward post IMPACT. You meet with the agency. You get the sign-off on the registrational studies. What is the vision beyond that? I think in terms of the VELOCITY studies, you're waiting for a partner to finance it. But it's the same asset for obesity as well as MASH. So how are you thinking about, obviously, is your strategy really focused on partnership discussions post this data or focus on raising enough capital to conduct MASH and sort of keep VELOCITY in the back burner until approval?
Yeah. So let me just say this first, that everything we are doing, we will be reading out on obesity as well on weight loss endpoint. Because MASH patients, we want to show that even the other indication that we are talking about, they're all obesity plus something. So essentially, every indication will be so we will be moving that ball forward. But as we have said before, that we are going to focus on MASH internally. We are fully prepared to fund it and raise the capital necessary to do that. It's a much smaller program and actually is much more powerful in terms of the mechanism of action. So for obesity, it's obesity with lipid disorders. That's how we've designed our program. So again, it's not your standard obesity protocol, but it's more focused on fixing the comorbidities of obesity.
For MASH, it's liver dysfunction with obesity with weight loss. So in every situation, we're actually bringing the obesity advantage or the weight loss advantage of the drug to the forefront.
Okay. And team, is there any evidence for glucagon's effect in cirrhotics? Because upon the data from IMPACT, how are you thinking about expansion potentially in a cirrhotic population?
It's something we've taken a very careful look at. And I want to emphasize that we think we can succeed in that population. We think it's the total solution for MASH, not only the early F0s, the F1s. As you're aware, that population mainly succumbs to cardiovascular disease. But we think that we not only have a potent metabolic effect, we think we also have a potent antifibrotic effect that will do very well in the F4 population. I should mention that we have preclinical data showing that pemvidutide is directly antifibrotic. In addition to its effect to lower liver fat as a way of being antifibrotic, it also appears to have a direct antifibrotic effect in animal models where there's no liver fat.
Great. Well, team, we've come to the end of the Fireside Chat. Thank you so much for a great discussion, for being part of our conference, and very much looking forward to 2025. So let's thank you for having us here.
Thank you.