Hopefully everyone got in who wanted to today. We're going to kick off our second session of day one of the Citizens Life Sciences Conference. My name is John Wallabin. Pleased to have Altimmune joining us here, CEO Vipin Garg, and CMO Scot Roberts. Scot, this is kind of the farewell tour. We're sad to see you go. What is it, about a year's time?
Next February.
Next February. OK, so we've got you for a little bit longer.
Right.
Thanks for joining us, guys.
Thank you for having us.
For folks who are not as familiar with the story, can you tell us just at a high level what you're working on at Altimmune? Then we'll dig into the details.
Sure. Thank you for having us. At Altimmune, we are developing a GLP-1 glucagon dual agonist for multiple indications. Our goal is to leverage the dual mechanism of pemvidutide, our GLP-1 glucagon dual agonist. The idea is to use the drug where we're looking for benefit, direct effect in the liver, and benefit of weight loss. For instance, we are developing the drug for MASH. We have phase IIb data coming out soon. We'll talk more about that. Just really think about MASH as MASH with obesity. 80% of people with MASH have obesity, and they'll benefit from weight loss. You need a drug that's working directly in the liver, and people are losing weight at the same time. All of the indications that we are developing are liver-focused.
The benefit in the liver, we are able to take advantage of glucagon and then combine it with GLP-1. Therefore, we leverage this dual mechanism of action in all of our indications. We'll talk more about that.
Can you talk a little bit about the history of this class? Because you guys were early to the game with GLP-1 glucagons, at least in the SMID Cap biotech space. Pharma looked at it years ago, kind of fell out of favor. Now coming back, and now we're seeing Lilly had great data from their triple agonist with, we can talk about the importance of glucagon to that. Novo just licensed a triple agonist. We're going to have data from you guys, Merck, this year. Why is there a resurgence? What have we learned over the past, call it, five years about the importance of having glucagon as an ingredient component?
Yeah, I mean, if you look at the history of obesity, metabolic space, people are realizing that it's not just about weight loss, how much weight loss you're getting. It's going to be more about comorbidities in addition to weight loss. That's really where multi-agonism comes into play, because you're trying to influence dual mechanisms or multiple mechanisms at the same time. I think it's a validation of the glucagon mechanism that multiple companies are now looking at it. There's no question, for instance, GLP-1 receptor. There are no GLP-1 receptors in the liver. If you want to have direct effect in the liver, you need glucagon. The liver is loaded with glucagon receptors. It's really validation of that fact. More and more data that's coming out about glucagon shows the benefit of glucagon, not only in the liver, but serum lipids, for instance.
It is really more of a cardiometabolic drug that produces weight loss and improves the overall health of these patients. That is really going to be important going forward. The whole obesity space, just the weight loss space, is really going to be one segment, but there will be significant need for additional mechanisms to really treat the patient holistically.
It seems counterintuitive to have a glucagon agonist to help with weight loss in people who may have diabetes, prediabetes. Can you talk a little bit about how you walk that fine line?
Sure. Scott, do you want to take that?
Yeah, just a first comment, Jonathan. We have two Scotts in this suite suite of Altimmune.
Yeah, sorry.
It's OK. I didn't want anyone to think that Scot Roberts or Chief Scientific Officer was leaving. The glucagon itself had been vilified for many years because GLP-1 makes glucose go down and glucagon acutely go up. What we learned from a number of studies is chronically you give glucagon in these animals, and probably in humans as well, the glucose goes down. Now we're seeing a shift in the paradigm here, where type 2 diabetes is no longer recognized as an endocrine disease, but a disease of obesity. Insulin is now recognized as being bad for diabetics. Type 2 diabetics, it increases fat deposition, weight gain, insulin resistance, and leads to a vicious cycle, whereas you break that with glucagon. There's been a lot of focus on treating blood sugar in diabetics. That's because the GLP-1 space grew up in diabetes.
It is recognized also that diabetics do not die of their blood sugar. They die of their lipids. They die of their liver fat. They die of cardiovascular disease. Pemvidutide is designed to be glucose neutral, in that it has an even balance of GLP-1 and glucagon. We see we have maintained glucose homeostasis across all of our studies. We had an extensive end-of-phase two meeting for obesity with FDA in November of last year, and they agreed that we have maintained glycemic control. We are accomplishing exactly what we set out to do, maximize the effects of glucagon, as Vipin described, yet do that while maintaining glucose control. That is exactly what we have done here. We think that the way we have designed the molecule to maximize the glucagon effect while maintaining glycemic control is optimal.
It has class-leading effects in liver fat reduction and also excellent reduction in serum lipids, things that you don't see with GLP-1s and GIPs.
Before we jump into the ongoing study and the next steps, can you talk about the data you've generated to date? Because for a phase II asset, you've been in a lot of patients. What have you seen so far? Just give an overview about the attributes that look attractive for pemvidutide.
Sure. When we went to the FDA, we had over 500 subjects. That's quite a lot of subjects in phase two. Now that is exposed to pemvidutide. Now with the completion of the IMPACT trial, we'll have over 700. We have quite a bit of a safety database here. As I've mentioned, we went in front of FDA, and they confirmed the safety profile of the compound, not only for glycemic control, but cardiovascular safety as well. We've had no imbalance or increase of arrhythmias. We've had no major adverse cardiovascular events. The safety profile of the compound has been firmly established in the prior studies that you've mentioned. We conducted a phase two obesity study. With that, we achieved 15.6% weight loss at 48 weeks. However, the trajectory of weight loss was still steep at that 48-week mark.
Had we followed patients out to the 72-week time mark of tirzepatide, we would have been very comparable. In patients who had elevated lipids, LDL at baseline, we saw dramatic reductions. We saw a 20% reduction of LDL cholesterol. FDA looked at that and said, wow, you've got synergy with statins here, because the same effect was seen in patients taking statins. We know that only 50% of patients who take statins achieve their LDL goals. The FDA recognized the potential for synergy here. In our MASLD studies, we've seen class-leading reduction of liver fat, 76% at 24 weeks, the highest among any drug that's now in development for MASH. On top of that, in our obesity population, we also saw class-leading preservation of lean body mass, which is extremely important in obese individuals.
We know that with drugs like semaglutide, we're seeing as much as a 40% loss of lean mass. Or let's rephrase that, that 40% of the weight loss is lean mass. And that's been associated with morbidities like hip and pelvic fractures in elderly men and women. These are very important attributes that I think we brought out in our current program going into our IMPACT phase II readout this quarter.
Can we talk about the IMPACT design? Because the MASH field's learned a lot with a lot of failures early on about how to find the right patients, how to measure, how to read biopsies. Can you talk a little bit about, and then also you guys have talked a lot about dosing titration. Can you talk about patient selection, endpoints, and dosing and scheduling in IMPACT?
As you mentioned, we've learned a lot from the prior studies. This has really helped us be at the top of our game here. The study was designed to have 190 subjects. The primary comparison is the 1.8 milligram dose to placebo. The study has more patients than other phase two studies that have had successful readouts, and also based on the fact that we think we're going to have a higher treatment effect based on the liver fat reduction, which is the primary driver of the endpoints in MASH, we think we have a very highly powered study. As you mentioned or inferred, we are rereading all of the biopsies based on the learnings from other studies.
It's been recognized that in studies, that if you just simply read biopsies in the beginning of the trial, knowing that they're baseline biopsies in the beginning, that creates bias. Those biopsies are upgraded in severity. That effect is lost later in the study. It may even be pushed; the readings may even be pushed to less severe grades, because pathologists think that they're reading post-treatment biopsies. A placebo patient with absolutely no biological change can actually have a placebo effect. They can get a response on these endpoints. We've seen that in prior trials, where we're seeing placebo response rates between 20%-30% in studies in which the biopsies are not being reread. What we do is we take all the biopsies at the end of the trial. This is what we're doing right now. You scramble them. You give them back to the pathologist.
They have no knowledge of when the biopsy is being done. That immediately takes away that bias. Based on that, when you look at studies that have done that, we see readout placebo rates of 7%-12%. Big difference. You control your placebo response. You increase your chance of statistical significance. We are very bullish on the readout. We think we have a better treatment effect. We have a larger study. We think the study is better powered. We think we have control of the placebo response.
Have you guys said what your assumptions are for MASH resolution and fibrosis improvement responses, your powering assumptions?
The key endpoint that people are focusing on here is fibrosis improvement, right? As I mentioned before, if you look at the assumptions and study power, our chances of hitting statistical significance on fibrosis improvement are high.
What are kind of your thresholds for successful, or what's clinically? Because you guys are reading out earlier than most other trials too.
Right.
For evidence.
If you look across the studies, the numbers are all over the board. It depends on the placebo response rate. We see 50% versus 30%. We see 27% versus 7%. If you have statistical significance, that is what is really meaningful. I want to emphasize the fact that if we have stat SIG on these endpoints at 24 weeks, we will be the first incretin to have accomplished that goal. All the other incretins, which work more slowly, indirectly in the liver through weight loss, take 48 weeks-72 weeks to see their effects. We have direct effects in the liver. That is the glucagon component. Think of it like an FGF-1 having direct effects. We have sufficient potency, unlike other incretin agents, to be able to read out successfully in these endpoints at week 24.
Compared to the FGF21s, we bring something they don't bring, which is extremely important, which is weight loss.
Yeah, how should we think about weight loss in a MASH metabolically deficient population? Because you did see lower weight loss, fair quality, in your phase Ib MASLD study, and that was the presupposition along with the Hispanic population. What have we learned since then about what to expect in MASH patients in terms of weight loss for this class?
Yeah, it's not so much about just the magnitude of the weight loss, really combining these two benefits, direct effect in the liver with weight loss. Think of it as MASH with obesity. Now, we know 80%-90% of people with MASH, the reason they have MASH is because of overweight and obesity to begin with. We are treating both the cause of the disease, a serious disease, as well as directly we are treating that disease. That's really the benefit of combining GLP-1 and glucagon. Really, 80%-90% of the patients will benefit from losing weight. We will be the only drug that in a single molecule will show that benefit, combining that benefit of MASH resolution, fibrosis improvement, and meaningful weight loss.
Based on all of the data that we've generated today, we're very confident that we should see meaningful weight loss that would benefit these patients.
I haven't thought about this before. I'd be interested in how you guys think about this. You're going to have the—you're hitting the liver hard early, but then you're also having the benefit of the body weight reduction over time. The other semaglutide, tirzepatide, they see their effects longer because they're seeing the benefit of the weight loss, which lags. How do you think about hitting glucagon early, but then seeing continued weight loss? We're never probably going to do a serial biopsy study, but do you think that would continue to have a compounding effect over time?
We will continue to also see glucagon effect over time. Yeah, we agree with you, because we have seen that in other studies where the longer you treat these patients, the better the benefit, even without weight loss. Now you combine two of these effects and continue over a period of time, 72 weeks and beyond, you should see significantly more effect. That is what Scott was saying, that if we show statistically significant improvement in fibrosis and meaningful weight loss at 24 weeks, that effect is only going to grow with time.
Look, actually, can you talk about your normalization of liver fat? Because can it get better than normal?
Clearly.
When we talk about 76% relative reduction of liver fat, which is class-leading, what's also class-leading about our results is that despite starting with the highest liver fat content at baseline of any study, we had the highest rates of liver fat normalization. We had a greater burden to carry to get from 23% down to 5%. We achieved that in over half the subjects. That's something other studies haven't done.
Perhaps it's just giving more time for fibrosis to clear and the pathways to heal themselves.
You have that effect at 24 weeks because of the glucagon effect. As Vipin mentioned, we know in other studies that those endpoints improve over time. We know in a recent study comparing 24 weeks to 96 weeks, the effects of fibrosis improvement doubled. Now, we think we can have an even better growth of our effect than that, because not only do we have the continuing glucagon effect, same as the continuing FGF21 effect, but also we add on top of that the benefit of weight loss, which continues to grow over time. That weight loss is very important for many reasons in differentiating our product. First of all, patients see MASH as a silent disease. When they come to get treated, they want to lose weight. We saw that in our study. This study enrolled faster than any other study out there.
The reason is that patients wanted to lose weight. It shows that investigators and patients were happy with the study. That is also going to drive the commercial aspect of the compound. Given the choice between a compound that produces weight loss with MASH effects like we have and one that does not have the weight loss, the patient will choose the drug with weight loss. Also recognize the fact that MASH patients, up until they hit F4, die predominantly of cardiac disease, not liver disease. They die of the lipids. They die of the liver fat. It is very important to have movement in these areas, a lot of which are driven by weight loss, and really to have meaningful effects in the MASH population.
I forgot to ask this. Are you guys including F1 patients in IMPACT?
No. [crosstalk] It's going to be F2, F3. We think we're going to have approximately a 50/50 split between F2 and F3.
Which derisks phase III even more for you guys.
Exactly.
Can we talk about tolerability for a minute? Because that's also the big hang-up with the GLPs as well, as patients have tolerability issues, can't stay on long term, probably some mix of cost, price, and tolerability in the real world. Can you talk about pemvidutide's tolerability profile and how you think that compares to the field?
I can tell you specific to this trial, Jonathan, we're watching things like discontinuations, adverse event discontinuations, and the like. We have to know about them because they get reported to us. I would just simply say from 10,000 feet that we're very happy with the way the trial is going. MASH patients tolerate adverse events better than other populations. Diabetic patients in particular, and you know that MASH patients, 50% of them are diabetic. In our diabetes study at 12 weeks, we had no adverse event discontinuations. In fact, at the 1.8 mg dose, which is the key dose that we have in the IMPACT trial, we didn't have a single patient reporting nausea, 0%, or vomiting.
It means that going into this trial in patients with NASH, 50% of whom will have diabetes, we're probably going to have a very good tolerability profile manifested by the frequency of GI adverse events, but more importantly, adverse event discontinuations due to that intolerability.
Talking about interpreting these data sets, it becomes complicated when we hear about things like dose reduction or dose maintenance. You guys have no titration or slow titration, but is there any flexibility in dosing in your trial, like others have shown, that might make their profiles look better than they actually would be in a more rigid design?
If you look at all the other studies, 30% of patients are either reducing their dose because they can't tolerate what they were given, or they didn't achieve the dose that they were targeted to achieve, 30%. Had they been forced rigidly up to those doses, we would have seen very high adverse event discontinuation rates. By allowing this in these other trials, they've gotten their adverse event discontinuations down to low numbers. We made that transition in going from our obesity study to this study. In this study, patients can dose reduce for intolerability to stay in the trial. It's only going to add to that excellent profile that we anticipate.
You have a 1.2 and a 1.8 milligram arm?
Neither are dose titrated.
Yeah, so then if you're starting at 1.8, you can drop to 1.2, but if you're 1.2, that's.
You go to placebo.
Go to placebo, OK. You said blinded discontinuations look very good.
Yeah, we can't give you specifics, but we can say that from 10,000 feet, watching the progress of the trial, it's going extremely well. We're really happy with what we're seeing today.
In data coming this quarter, everybody's asking when, and people are asking, could it come today? I was like, it's a busy morning. I hope not, but maybe. You talk about the biopsy reading. When we look back at trials, you have everyone. Can you talk about the reading methodology for your biopsy readers? You talked a little bit about dropping that placebo rate, but how difficult is it to be sending biopsies to multiple pathologists? Do they have triplicate reads of baseline and end-of-treatment biopsy for 100 and some odd people? It seems like that would take quite a long time.
As we mentioned, when we announced the rereading of the biopsies, we pushed the readout back to the second quarter to accommodate that whole process. That is what led to the shifting of the trial readout from the first to the second quarter. We have a very good handle on it right now. We are at or near the completion of the rereads, and we should be moving to read out this quarter. I think we are very firm in our belief that we will read out this quarter.
What data will you be giving us in the top line?
Obviously the primary endpoints, Jonathan. That's a dual endpoint of MASH resolution or fibrosis improvement. Also important key secondary endpoints like weight loss, changes in liver fat, the noninvasive tests such as Fibr`oScan, ELF, Enhanced Liver Fibrosis Scale. We'll also have a readout on adverse events, discontinuations, demographics, and glycemic control.
Not to hold you to anything if you say it today, but we also see sometimes NASH and fibrosis improvement or two-step fibrosis improvement. Do you guys think you'll have that available as well?
We'll eventually have those tables. Whether we have them for the readout, we'll have to see.
All right. I want to ask two big picture MASH questions. How are you thinking about what we're seeing with Resmetirom's launch and what that could mean for pemvidutide long term? What do we know about incretin use in MASH today? Do you think that semaglutide's official approval in MASH will change that at all?
There is no question that losing weight is a beneficial thing for treating MASH. There will be some of that use. I think one thing is clear, looking at Rezdiffra, that just GLP-1s alone or the incretins alone are not going to be able to address this market. We are going to need a direct effect in the liver. I think that is now firmly established, which is good for all of the other agents that are more direct acting in the liver, including pemvidutide. We think that is really a very encouraging sign that Rezdiffra is doing well and continues to do well. As you know, Rezdiffra has no benefit in terms of weight loss. It is purely working in the liver. Same thing with FGF21. We think if you combine these two effects, you have an even better chance of succeeding.
That really puts you in a prime position in terms of why would you use two drugs, GLP-1 and a direct acting agent in the liver, if you can accomplish that same goal with a single molecule? That is really the value proposition here. When physicians hear about this profile, they really get excited about the drug because now they can completely, this is really a full complete solution for MASH, not just fixing half of the problem, but even taking away the cause of the disease itself. We think that really speaks well to the future of pemvidutide.
As we're bumping up on time, I wanted to just give you an opportunity to talk a little bit about the two other indications that you'll be pursuing with pemvidutide. Can you talk about those indications, next steps, and the potential opportunity?
The rationale for the indications are compelling. GLP-1s suppress alcohol cravings. With regards to alcohol liver disease, it's a disease of fatty liver. The histology is indistinguishable from MASH. When I trained as a hepatologist, we used to call this nonalcoholic steatohepatitis because these patients we accused of being pocket alcoholics were actually not. It was clear that when you have excess fat in the liver, it drives inflammation and fibrosis. The histology, the pathological findings look the same. For AUD, it's quite clear that that will progress to ALD. We have a drug that not only reduces the cravings, it also heals the inflammation, the ALT elevations that's seen in these patients. With regards to ALD, that's a fatty liver disease. Between MASH and ALD, we've accounted for the great majority of liver transplantations that have been done in the United States.
Our goal, our vision is to own that space. We plan to own the fatty liver space because we have the drug that can do it.
OK. We'll be getting an update from you guys, your first quarter earnings next Tuesday, I believe. Can you remind us of kind of your year-end 2024 cash position? Historically, you guys have announced data with your earnings calls as well. Maybe what should we look forward to next week?
We will give you a full update next week. Again, as Scott mentioned, we are very comfortable saying that we will have data in the second quarter. We are not providing any more color than that. Stay tuned. We will provide a full update next week.
If you remember cash position and runway that gives you, we got the important data coming 2 Q.
Yeah.
How are you expecting the balance sheet ?
At the end of 2024, we had approximately $132 million, which is sufficient cash with all of the milestones that we're talking about, including the two new indications into the second half of next year.
OK.
We're in a good position, and we'll continue to monitor and be prepared for the next steps in development of Pemvidutide, particularly as we look forward to the phase three program.
Perfect. As we just ran over time, Vipin, Scott Harris, thank you for joining us. We have.