To the third annual H.C. Wainwright BioConnect Conference. I'm Patrick Trujillo, Senior Healthcare Analyst at HC Wainwright. It's my pleasure to have the management of Altimmune with us, President and CEO Vipin Garg, and CMO Scott Harris. Welcome to BioConnect once again, and it's a pleasure to have you with us, and it's always great to catch up on the pipeline. I think maybe first we'll start with pemvidutide, just some background on pemvidutide and how it came to be part of the pipeline.
Yeah, thank you for the invitation. Excited to be here. As you know, pemvidutide is the GLP-1/glucagon dual agonist that they're developing for metabolic diseases, for liver diseases, for obesity. If you think about what's happening in MASH, you know, MASH is our data that's coming out very shortly here by the end of this quarter. If you think about MASH, there are really two different types of drugs being developed for MASH. There are metabolic drugs like GLP-1s that sort of improve obesity and indirectly affect MASH, but there are also direct-acting agents like FGF21. What we are doing with pemvi is really combining these two effects in one molecule, both weight loss as well as direct effect in the liver. Think of it as MASH with obesity.
About 80%-90% of patients with MASH have obesity, so they'll benefit from weight loss, and there's a lot of discussion out there about combining FGF21s with GLP-1s or combining different drugs with different mechanisms. We're doing that in a single drug. We think that gives us a significant advantage, and if we are able to show statistically significant improvement in MASH resolution and fibrosis improvement at the end of 24 weeks and show meaningful weight loss, we'll be the only drug that can achieve that. Scott, you want to talk a little bit more about pemvi?
Yeah, pemvi itself is designed to maximize the effects of glucagon. It's glucagon that drives the direct effects in the liver. What you get is a really potent reduction of liver fat, a potent reduction of serum lipoproteins. That's because there are glucagon receptors in the liver. You don't get that with GLP-1s. You don't get it with JIPs. So those drugs do not have very meaningful effects on, say, LDL cholesterol. Any effects that they have on liver fat are indirectly through weight loss. If you don't get weight loss, you don't get the effects in the liver, and those effects are slow. Those drugs have to read out at 48 weeks-72 weeks. We have glucagon in our molecule, which puts us in the category of having direct effects like the FGF21s. That allows us to read out at 24 weeks.
That will mean that we're in the direct-acting agent class of drugs that can read out at 24 weeks with rapid effects. That's important with MASH. Some of these patients are on the verge of developing cirrhosis. Speed is potency. We distinguish from the FGF21s because they don't have weight loss. To maximize the effect of glucagon, we go on to a one-to-one weight ratio by design. If you give glucagon alone, you have problems with glycemic control. You balance it with the GLP-1, and a 1:1 ratio, you maintain that control. We've shown repeatedly in our studies and with the FDA when they evaluated our End of Phase II Briefing Package for obesity in the fall of last year consistent control of blood sugar. Amongst the agents in development that have GLP-1 and glucagon, we have the most potent glucagon because we have the best ratio.
Others have ratios that are heavily biased to the GLP-1 and have much less of those glucagon effects.
Can you tell us where are we with MASH and drug development in MASH? Where is the unmet need in MASH?
Right now there is one approved drug. Its effects are relatively modest. However, the uptake has been very great, which says it's a huge unmet need. MASH has now risen to being the leading cause of liver transplantation in the United States, and the prevalence of it is growing every year because it's growing with the obesity epidemic. There is a need for many drugs, and there is also going to be diversity in needs. It's often forgotten that patients with MASH, up to the time they develop cirrhosis, Patrick, actually die of the cardiovascular disease first. A drug that only treats the fibrosis and the end stages of the MASH inflammatory process misses the fact that you have to treat the metabolic effects at the same time.
We have the upcoming phase II-B trial IMPACT. This is in MASH. Can you tell us about the design of IMPACT? What was unique about this design, the 24-week readout, and kind of your expectations around its readout?
Sure. As you started by saying, the 24-week readout for an incretin is unique. We're going to be the only incretin that's able to even consider reading out at 24 weeks because of the glucagon effects. One of the other unique features of the trial is that we're trying to control the placebo response, which is endemic in MASH trials. We're seeing in some MASH trials placebo response rates that exceed biological plausibility, 20%-30%. It's because of bias in the reading of pathologists. One of the biases is that early in the trial, they upgrade the severity, knowing that they're reading baseline biopsies, trying to help the sponsor with enrollment. That effect goes over the course of the trial and, in fact, even goes in the opposite direction because they think they're reading treatment.
You can have a placebo patient with no biological effect having a response simply based on the timing of the biopsy. How do we address that? We take all the biopsies at the end of the trial. We scramble them, de-identify them by time of biopsy, and read both the baseline and the end of treatment at week 24 at the same time. In studies that have done this, they've seen placebo response rates that are controllable, much lower in the range of about 7%-12%, 13%. If you control your placebo response, you get what we're trying to achieve, which is statistical significance. If you lose control of that, you lose your control of the statistical response.
If successful, what do you see as the key differentiators for Pembe relative to the GLP-1s, relative to the FGF21s?
For one thing, we're going to be more potent than any of the incretins. Then compared to the FGF21s, we're going to have weight loss. When you think about that combination, it is the complete solution for MASH. We don't think there's going to be any drug out there that really offers that profile. We think that with a successful readout, we'll be the best-in-class drug for MASH based on those two important attributes. The other thing about the drug is that it's easy to administer. Those drugs in the IMPACT trial are being given without bis-titration. That's unique among the incretins, which are titrating out to 24 weeks to maintain tolerability. The molecule is designed to enter the bloodstream slowly and avoid peak effects that drive intolerability.
By the way, in some molecules, also drive heart rate increases that we're not seeing because of the rapid introduction of the drug into the bloodstream. Slow onset, lower peak, take the peak and round it up and make it go over a longer period of time. We are unique in the fact that we can actually simplify therapy for primary care as well as for hepatologists and endocrinologists by allowing a drug that does not need to be bis-titrated.
I think this benefit of combining direct effect in the liver with weight loss is very important. We've already seen that in our trial itself. It was much easier to recruit in our trial than other MASH trials because losing weight is very attractive to this patient population. They can't see their liver, what's going on inside the liver, but everybody can see that they're losing weight, and these patients do want to lose weight. We think from a compliance perspective, there will be a major advantage when the drug reaches the market.
Right. And so this 24-week readout timeframe, how do regulators view this? And would you have your End of Phase II meeting after the 24-week readout, or do you have to wait for 48 weeks?
Yeah, no, we plan to have our End of Phase II meeting after the 24-week readout and even before the 48-week data. You know, our primary endpoint is 24-week biopsy readout. There is no biopsy readout at the 48-week. We'll be able to supplement that 48-week data when that becomes available and really be ready to execute a phase III program early in 2026.
Just to be clear for the audience who are not familiar with, the primary endpoint of the trial, which is the biopsy, is set at week 24. We're treating patients for 48 weeks. What do we get from that? We get 48-week weight loss, which is important. We also get the non-invasive test throughout the trial. You can use the non-invasive test to help predict the growth of the response over that period of time. That's going to be extremely important as well.
What are your expectations around weight loss, both in 24 weeks and 48 weeks?
This drug has a weight loss profile very similar to semaglutide at 48 weeks. Now, we believe that if we were to follow the drug beyond that, we would beat semaglutide because if you look at the weight loss curves that were generated in our MOMENTUM obesity trial, the trajectory of weight loss is still very steep at the end of the trial. We think we would have beaten semaglutide, which was plateauing at week 48. I think that roughly we'll be in the same range. Now, recognize that we did not go into this trial with our best weight loss dose. The dose-response for weight loss is different from the dose-response for MASH. With MASH, we found it was plateauing at the 1.8 mg dose, and we felt for efficiency in this trial, phase II, we would only dose up to 1.8 mg.
However, for phase III, now we're building the target chronic profile. Even though we wouldn't see additional MASH effects, we would be able to add to the weight loss by going with the 2.4 mg dose. That's what we're looking at doing in phase III.
Do you have to titrate at the 2.4 mg?
There's a short titration at 2.4 mg, but there's no titration at either of the two doses, which is 1.2 mg and 1.8 mg in the IMPACT trial.
Just timing for IMPACT, what are we looking at in terms of timing?
We need data readout this quarter, as we've said, so it's very soon. The quarter is coming to an end quickly, so yeah, looking forward to it.
Are there any other questions from the audience on IMPACT? I think then I'd like to talk about obesity, the obesity strategy. Maybe you could talk about, you mentioned obesity at the outset. Maybe you can talk about the data that you've generated so far, MOMENTUM, what was MOMENTUM, and I guess what's the status of this program?
Sure. I'll take the first part of all that, and we can talk about the status because it relates to a long-term business discussion. This was a phase II trial. It was 391 patients. The dosing was 48 weeks. We had three doses of pemvidutide, the 1.2 mg, the 1.8 mg, and as I mentioned before, the 2.4 mg versus placebo. Non-diabetics, again, treated for 48 weeks. No titration at 1.2 mg or 1.8 mg. Very short four-week titration at 2.4 mg. It's 1/6 the titration duration of other drugs in this space. At 48 weeks, we saw the highest dose, 15.6% weight loss. As I mentioned before, if you look at the curve, there was a lot more gas in the engine at 48 weeks. I think we would have been very comparable to, say, tirzepatide after 72 weeks of treatment if we'd gone out.
What we also saw was very potent effects on serum lipids. In patients who had elevated levels coming into baseline, we had statin-like effects with a 21% reduction. In fact, we saw these effects even in patients taking statins. As we eventually got to the FDA to discuss the program, and maybe I'll delay response to that question directly about the meeting that we had, they were very excited because they saw synergy with statins. You know, with statins, only about 50% of patients get to their LDL goal. A lot of that is compliance. They said, "Wow, this is a great way to get to LDL goals by driving the compliance with LDL-lowering therapy by weight loss," same as Vipin said. Our trial was one of the fastest, or IMPACT trial was one of the fastest or only MASH trials to date.
Patients came in the trial because they wanted to lose weight. We also think that speaks to the commercial profile of the compound when it is out there competing with other drugs. For the TAM, you know, people are going to come in and say, "We want the weight loss," and it is going to replicate what we saw in enrollment in IMPACT. Now, one other key finding that we saw in the trial was that we had class-leading preservation of lean mass among the incretin agents. If any of us try to lose weight in this room, about 25% of that weight is lean mass. With semaglutide, they saw 40% in two trials, not just one, but two.
That has not really been explained, but it is worrisome because people who lose weight, especially elderly people and postmenopausal women, have a higher rate of bone fractures in the Select Cardiovascular Outcomes trial, meaning the rate of fractures was increased by a factor of seven in that population. That was actually put into the label. Preservation of lean mass and also bone mass is extremely important. We look at our compound, we are 21.9%. We are better than the other incretins, and we are actually even better than diet and exercise. We think that glucagon shifts metabolism away from pulling substrate from muscle for energy to fat. We think that is the mechanism that this happens.
Can you tell us, you know, what has been the perception among potential partners to the MOMENTUM data?
I can take that. As you know, we've talked about it quite a bit. Our plans are not to pursue a pure obesity indication on our own. We think that's the right strategy because really the market is going to change in obesity. Obesity is quickly becoming a race to the bottom in terms of price and flexibility. What we want to do, we want to treat serious diseases, serious conditions that result from obesity. Think of it as MASH with obesity. We're not giving up on obesity. We're treating a serious disease where people would benefit from losing weight. We've also added AUD and ALD to our portfolio. Again, very similar diseases where there is no treatment available. They're liver diseases. ALD is very similar to MASH, for instance.
60%- 70% of patients are obese and overweight, and the outcomes are very much worse if they're obese. If we can treat both of those things at the same time, we've got a much higher value proposition. That is the strategy we are pursuing. You know, if we find a partner who wants to develop new obesity indications, certainly we'll entertain that. On our own, we think we can take this program forward in MASH and these serious liver diseases, really provide a complete solution to liver and metabolic diseases where we're hitting two different mechanisms at the same time.
If all goes to plan, then you'd be able to bring this forward in MASH into phase III in 2026.
Yeah, we're full speed ahead in MASH. As we said, we're going to have End of Phase II meeting at the end of the year and start our phase III program. We've already started our AUD phase II study. We announced yesterday that's up and running. We expect to start our ALD phase II study in the third quarter. Multiple indications, all having the same theme of liver benefit, liver health improvement, and losing weight.
Can we talk a little bit more about AUD and ALD, just kind of what drove this decision to expand the pipeline to these indications and why these specific indications?
As we looked at the landscape in liver diseases where having a direct effect in the liver would be beneficial, it became very clear there is no approved therapy for ALD, for instance. Even for AUD, there are two or three drugs, but nobody really uses them. They're very old sort of legacy drugs, not very effective, very poor compliance. Very critical on that medical need in both of these areas. We felt that the combined GLP-1 glucagon mechanism had special advantages we could leverage in developing these drugs at relatively modest expense over and above our MASH program. We've got a very large safety database. We're trying to figure out how to leverage everything that we've already created. You know, we've got 500 patient safety database.
Nobody going into a MASH program, phase III program, has that kind of safety database. We can leverage that for AUD and ALD and really expand the market share for the drug.
How quickly do you anticipate these trials to enroll, and when do you think you might see your initial data readouts?
Let's see how the enrollment goes. We're just starting the AUD study right now. We think, you know, definitely by the end of next year, but it might be sooner, depending upon how quickly the study will enroll. There's really no competition out there for these types of trials. We think we're going to enroll it pretty quickly, particularly, again, the attraction of losing weight. A lot of these patients need to lose weight. We think we're going to be doing, you know, having data next year on AUD and ALD.
AUD, what's kind of the key endpoint? What do you need to see here? Is it sort of reduction in heavy drinking days, or how are you thinking about the endpoints?
For everyone's knowledge, there is a guidance in developing an alcohol use disorder, AUD. That is well said. The guidance is the risk program, right? They tell you what you need to do. We know there are three primary endpoints that it will accept. The one announced about a month ago is going to be the easiest, which is a two-level reduction WHO risk score, which actually measures the amount of alcohol people are taking as opposed to heavy drinking days. What is their level of average drinking? That is a lot easier to hit. There is also an endpoint for reduction of heavy drinking days and total abstinence that are actually harder to hit because they require none of those. In phase II, however, you explore with lower sample size. You use easier endpoints.
We're actually counting the number of heavy drinking days, but we'll measure the other as well. We see a significant reduction, which I think we will, based on all the data we've had, and we've had some really great animal data showing that we can talk about. We think we'd move into phase III relatively rapidly.
Can you frame for us just the final profile that eventually emerged for pemvidutide? We have a MASH, you know, approval and MASH, the level of overlap between obesity and MASH. If you have these additional indications, how large are each of these relative to each other? How big is the opportunity in AUD and ALD, for example?
Yeah, so I mean, the good thing about these three indications is that there's a lot of overlap in terms of the mechanism, in terms of the value proposition. You're treating two different things at the same time. It is very similar. They're all diseases that the outcomes are worse in people with obesity and overweight. You want to lose weight. That's a beneficial effect. You also want to improve the overall metabolic health. Something we haven't talked too much about today is the benefit we are seeing from pemvidutide in terms of serum lipid reduction and improvement in serum lipid. That benefit is very important in all of these indications. You can actually price them relatively close, very similar. Obesity is a different, you know, condition where pricing, you know, flexibility is there.
In all three of these, lack of treatment, the pricing flexibility, there is an additive. That is a very large market opportunity. MASH itself, just the patients with MASH with obesity, even if we just focus on those, that is the bulk of the MASH market. I mean, 80%-90% of the market is those patients. Same thing with AUD and ALD. AUD is about 28 million subjects, patients that need to be treated in the U.S. Only 2% of them are today taking a pharmacotherapy. Very large opportunity, unmet need. ALD is smaller. Obviously, AUD leads to ALD. Very critical condition. You combine all three of them together, very significant opportunity.
You're just thinking about the biomarkers and some of the changes you've seen in the prior studies. Can you talk about some of the more meaningful ones, maybe, you know, whether it's serum lipid reductions or others that you think maybe provide a read through to this upcoming IMPACT study?
I think probably the most potent one is the level of liver fat reduction because there's been a very clear association between that and the MASH endpoints, both MASH resolution and fibrosis improvement. Studies, time and time again, have shown that. Among all the compounds in MASH development right now, we have the highest liver fat reduction, which gives us the greatest confidence about the treatment effect. Alongside that, we see other inflammatory and fibrotic markers. There's an imaging technique known as CT-1. We have the best results in that as well. Time and time again, we're seeing evidence of successful readout on the non-invasive tests. We think that should convey the MASH readout that's coming up.
Just in terms of CT-1 and FibroScan as emerging biomarkers, how does the FDA and other regulators, how do they view the biomarkers?
We're encouraged to look at them. They're very much in favor of biomarker responses. Holistically, they look at everything together. They're going to be making the decision about approval based on the biopsies.
For MASH.
For MASH. And then just in terms of sort of MASH treatment guidelines and reimbursement frameworks and just in the context of these non-invasive biomarkers, how should we expect sort of the reimbursement landscape to evolve, especially as more treatments get approved?
The good news is that there is no biopsy required to treat these patients. That's already a win for the whole MASH field. These biomarkers ultimately, what we're trying to do with pemvi is really have a broad spectrum in terms of the doctor doesn't have to precisely determine if it's phase F-II or F-III or even early F-IIII. Because of both metabolic effect as well as the direct effect in the liver, we should be able to cover the entire spectrum of this patient population. MASH is not just one disease. It's a continuum. People can be at different, you know, on that spectrum. They can be at different places. There may be different treatments that doctors might consider. By combining these two benefits of metabolic effect and the liver effect, we can actually cover the entire spectrum.
The physician can be very comfortable treating as long as they suspect this patient has MASH. They do not have to precisely determine what degree of MASH they have because we have both benefits built into that. I think from that perspective, this puts us in a very good place.
Do you think investors are missing about the pemvidutide story?
I wouldn't say they're missing anything other than there was a lot of focus on obesity alone for a period of time. I think people are realizing that the obesity landscape is changing. We're not giving up on obesity. We're just being more creative how we go after obesity rather than using going after obesity as a pure indication. We're really coming from a side door, if you like. We're treating serious diseases that are caused by obesity and treating obesity at the same time. I think that's a very strong message and people are starting to pay attention.
Right. If we sort of look out or think of a year ahead from now, what are sort of the key milestones of IMPACT coming up this quarter? Presumably, you'll have annual phase II meeting with Workday. You'll have the 48-week readout, you know, sort of the timing of these different milestones and what we can expect.
Yeah, and we've started the AUD trial already. We've also started the ALD trial. Yeah, you got them all. We've got plenty of milestones coming up over the next two hours.
Are there any other questions? Thank you very much.
Thank you.