Good morning, good afternoon, everyone. My name is Alana Lello, and I work with the global biopharma team here at Guggenheim. With me, I have Dr. Vipin Garg and Scott Harris, CEO and CMO of Altimmune. Thanks very much for taking the time to be with us here today. To get started, maybe we can just go over a brief overview of the company of Pemvidutide and what makes Pem unique in the ever-growing incretin space.
Of course. Good morning, and thank you for having us. So Pemvidutide, as you know, is a GLP-1 glucagon dual agonist. What's important is it's a one-to-one balance between GLP-1 and glucagon. So it probably has the highest concentration of glucagon for any glucagon-containing compounds out there. And we believe that as the obesity market matures, it will evolve in such a way that people will be looking at not just weight loss, but comorbidities of obesity. And that's really where glucagon comes in. Because of its direct effect in the liver, we are able to not only show significant weight loss, but we have impact on serum lipids, on liver fat, even body composition. We're showing very good lean mass preservation.
When you combine all of these things, that's really the next frontier in treating obesity and metabolic diseases, quite frankly, liver diseases, because you don't just want to show weight loss, but you want to have direct impact on liver and serum lipids and have good maintenance of lean mass. By combining all of these, we think moving forward, Pemvidutide is going to have a unique place in treating patients not just with obesity, but with liver diseases and dyslipidemia.
Fantastic. Can you just also briefly remind us just what PEM has put up so far in the studies to date, what it showed in MOMENTUM and in the 1B and NAFLD trial?
Yeah. Scott, you want to take that?
We completed a 48-week trial in obesity. That was the MOMENTUM trial, phase II, close to 400 subjects. At the highest dose, 15.6% weight loss. At only 48 weeks, you have to reference the other compounds like Tirzepatide and Semaglutide right at 72 weeks, and when you look at the slope of the line, potential for much more weight loss, so we're really up, we'd be up in the Tirzepatide, Semaglutide category, followed for longer durations. Really prominent effects on serum lipids. We actually saw greater than 20% LDL reduction in subjects with elevated LDL at baseline. Very profound effects on liver fat and other studies that we've conducted, and we're in the process now of completing a committed biopsy-driven trial in MASH. We announced that we completed enrollment in that recently and should have a readout on that in the second quarter of 2024.
Fantastic. Yeah, so that was a great segue and kind of helps explain and set the foundation for why the phase III VELOCITY program was developed in the way it was. So for those who don't know, last week, Altimmune shared that the end of phase II meeting with the FDA regarding MOMENTUM was successful. So congratulations on that.
Thank you.
Can you share a little bit, I guess, how those discussions evolved and what the agency's feedback was? And just at a high-level overview before we kind of dig into some of the trial design, the doses being tested, why those decisions were made, any titration schemes or changes there, the length of the study, et cetera.
Absolutely. So when you look at the VELOCITY program, the first thing that you will notice is that it's not duplication of what others have done, what Tirzepatide and semaglutide have done. It's really designed to obviously show weight loss. That's the primary endpoint of the study, but also to highlight or to leverage some of the unique properties of glucagon, in particular serum lipids, liver fat, and also lean mass composition. So each one of the trials is designed with that in mind. So weight loss is the primary endpoint, but the secondary endpoints are looking at some of these comorbidities of obesity that we believe are going to be important. I think it's really interesting to see that the FDA has bought into that. They actually saw that value proposition that every compound doesn't have to show the same improvement in different types of comorbidities.
The specific compound, the specific mechanism of action, would be designed, can be designed, to address specific patient population that will benefit from the unique properties of the compound, so I think that's important. Also, from a safety point of view, we feel very good. There were no additional safety studies required. That really cuts across all of the indications for Pemvidutide that we think we can develop going forward, so we have firmly established that the drug is safe, it's effective, and the question is, what are the specific patient populations now where we can study the drug to really highlight or to leverage the benefits of glucagon? Scott, would you like to add something?
Yeah, I think, as Vipin said, it's critical that this was a stake in the ground for the safety and efficacy of the program. We've now exposed greater than 500 subjects and completed studies. We'll have many, many more subjects by the time we complete the MASH trial in the second quarter of next year, the phase III program. But this is a wonderful platform upon which to build development because it's confirmation based on an independent review of the agency that they like the safety profile of our compound, confirmed the efficacy as well. As you mentioned, that we will be taking three doses going forward, 1.2 mg, 1.8 mg, and 2.4 mg . Each of these will be an approved dose without intermediate titration steps.
So it gives the opportunity for a physician to prescribe an approved dose and reimburse dose right from the get-go without going through these transition phases of unapproved doses. The trials themselves will be of 60 weeks' duration. We're going to maintain the absence of dose titration at the 1.2 mg dose. We've decided to introduce a four-week titration at the 1.8 mg dose and then take the titration at the 2.4 mg dose, which had been four weeks and extended by four weeks to 2.4 mg, still much shorter than the other programs. We also recently, although not in this discussion with the FDA, allowed for dose reduction.
We think that with the combination of dose reduction, allowing people to reduce their dose if they don't tolerate it, and the extended dose titration, that when we complete a phase III program, that this will be the best tolerated incretin in development.
Yeah, one thing I want to emphasize is that our goal is to get approved, all three doses approved independently. So the idea is that the patients can start at 1.2 mg. There's no titration required. And many patients will actually respond to that, and they may not need a higher dose. If they need to go to 1.8, then they can go to 1.8 mg as the next higher dose, and then all the way to 2.4 mg. So if you think about it, if you have three doses approved, your titration is already built in. Because many of our patients were seeing as much as 15% weight loss at 1.2 mg. On average, the weight loss at 1.2 mg was about 10%, which is very significant. And most of the comorbidities of obesity, patients begin to benefit at 10% weight loss.
So we think it's going to be unique in the marketplace where a primary care doc can see a patient and start them on a dose that's effective, and they can get significant weight loss. If they need to go to a higher dose, they can be brought up to 1.8 mg and 2 mg. That's really how medicine is practiced in many different therapeutic areas. So it's going to be very similar to what people are already doing, and they're quite used to, and they don't have to go through ineffective dosage in order to titrate up to an effective dose.
Makes sense. So within the VELOCITY program, there is no committed type 2 diabetes trial design, but patients with diabetes will still be tested through the registration program. So can you talk a little bit about that? Is there any significance in the fact that a specific type 2 trial wasn't involved? And maybe just to go through just very briefly the four studies and what each is kind of specifically looking at?
Yeah, to your first question, Alana, this is a compound that's not designed to drive down hemoglobin A1c. If you have a subject with uncontrolled diabetes, there are going to be better drugs. But about 50% of diabetics are well controlled, meaning hemoglobin A1c of seven or less. So if the goal is to get effects on the lipids and the liver fat and to preserve body composition, to preserve lean mass, this is really a perfect compound. So based on the fact that there wasn't a logic to proceed with a study committed to lowering hemoglobin A1c, the agency agreed that that study really didn't need to be done. However, we have many patients with type 2 diabetes in the program. In fact, we have a number of these patients in the MASH program as well. So we are not shying away from treating diabetics.
This program has been shown repeatedly and confirmed by the FDA to maintain hemoglobin A1c and glucose homeostasis, but we are not aiming to treat a population that needs hemoglobin A1c reduction, and as you know, only about 20% of the obesity population has diabetes, and with 50% of them being well controlled, you can see that we're treating the vast majority of obese patients. Now, in terms of your second question, which is the individual studies, there are four, and the total program is approximately 5,000 subjects equally distributed between the three Pemvidutide doses and placebo. The first dose is, excuse me, the first study is the largest of the four studies and looks similar to many other programs in that it's a big study, a major study without type 2 diabetes. The other three programs consist of patients with and without type 2 diabetes.
The second study is committed to LDL cholesterol. We're taking patients with elevated levels. A lot of these patients are taking statins. We demonstrated in the past that Pemvidutide on statins actually drives even further LDL reduction. You're probably familiar with the statistics that although statins are great drugs, the compliance with them in the community is not that great. About 50% of patients who take statins fail to achieve LDL goals. This is going to be a very useful tool in primary care, especially as people come in to treat their LDL by pursuing weight loss rather than LDL reduction itself. The third study is a study in MASLD, elevated liver fat, which is a known driver risk factor for cardiovascular disease. In the last study, we're going to build upon our observations of preserving lean mass.
We're class leading for incretins right now, lower than Tirzepatide, Retatrutide, Semaglutide, and actually do a study looking at lean mass and other aspects of body composition, but also looking at function at the same time, concentrating on elderly people and people with sarcopenia who are at risk for the complications of low lean body mass, low lean mass.
And I just want to make a point that this is really important. This is where the obesity space is going. It's going to be all about, not just about the weight loss, the amount of weight loss, but the quality of weight loss. And how long, how do you maintain that quality over a long period of time? It's not just about 48 weeks or 72 weeks. It's really years and years that these patients are going to be on these medications. So what is the impact of these drugs on lean mass preservation? That's going to be very, very important as this field evolves.
Yeah, it's evolving rapidly. So you've said in the past that you will not proceed into a phase III program for obesity without a partner. Just how have those discussions progressed since we've last spoken? And how do you see this update with the successful end of phase II meeting influencing those discussions?
Yeah, so I mean, this is an important de-risking event for the program for Pemvidutide, for Altimmune, but also for our potential partners. So we'll see how those discussions progress on the back of this data, this information. But what we are trying to do is to really create a path forward with or without a partner. We're moving full speed ahead with NASH, with MASH. We actually believe that we could be phase III ready for MASH soon after our 24-week readout because this end of phase II meeting is not just for obesity. It's for Pemvidutide. We have established safety. We have established efficacy. And so I think this will benefit the rest of the programs that we'll build around Pemvidutide. So we're going to move quickly with MASH.
We think we can have an end of phase II meeting by the end of the second half of next year after the data because the whole package is already ready to go. It's simply plugging in the MASH indication instead of obesity indication. We're also looking at additional indications. I know we're going to talk about that later, where we think some of the properties of Pemvidutide, its glucagon effect is especially meaningful in terms of treating some of the comorbidities of obesity, so the idea is that obesity becomes sort of a secondary endpoint, and all of these studies will be looking at weight loss, but we can seek approval for a different indication that's something we can develop on our own and we can even commercialize on our own, so our goal is to continue to build value in the asset.
We think that's going to be attractive to a partner also down the line.
This is a perfect segue, actually, into asking some more questions about the MASH program. So with the phase IIb IMPACT trial that we're now accepting in 2Q25, can you describe kind of the data to be generated, what we should be looking for, and how that kind of relates to and why it was important to actually push out to 2Q25 and with respect to the biopsy readings?
The study has dual primary endpoints of NASH resolution or fibrosis improvement. Either endpoint can be met much like the Resmetirom program. It's important to recognize that we're reading out not at 48 or 72 weeks like Tirzepatide and Semaglutide, but 24 weeks. This is affirmation of the increased potency of Pemvidutide that we believe the molecule has compared to the other incretins. Why the difference? Because with tirzepatide and with semaglutide, the effects in liver fat are indirect, mediated through weight loss. Glucagon has a direct effect on the liver. It's very potent in reducing liver fat. It inhibits lipid synthesis in the liver and also drives beta oxidation of existing lipids. Our liver fat reduction is class leading. So there have been many compounds that have had 60% reduction in liver fat at 24 weeks. The FGF21s with positive readouts at week 24 were at 76%.
So we feel very confident that we'll hit not only MASH resolution and fibrosis improvement at that time point, but also we also have studies in animal models showing a direct antifibrotic effect. All in all, what this is going to mean is that Pemvidutide will be the first incretin-based agent to actually show efficacy in MASH resolution and/or fibrosis improvement of that early time point of 24 weeks. What does it mean? More rapid resolution of disease, greater potency, combined now with weight loss. So when you look at the other compounds which have efficacy at 24 weeks, those are FGF21s. They do not have weight loss. So with this readout, we potentially stand alone at the top of the class in terms of readout at week 24 efficacy and also weight loss. Now, another part of your question was why the pushback to the second quarter.
We elected to institute a rereading of all the biopsies in the study. This was advice given to us by a number of experts in order to control the variability of the reading and reduce any placebo effect that might come out of that variability. We felt it was worth a slight delay to the program to read it out in the second quarter rather than the first quarter in order to have the better quality of the readout.
Makes sense. What about non-invasive tests? What type of data might we see with respect to that? And kind of if you can just remind us the importance of those analyses as well.
Right, so those analyses have been very useful in other programs. We will have a full panel of non-invasive tests, liver fat reduction, FibroScan, ELF, Pro-C3, and the like. I would stress that our primary readout or top line readout in the second quarter will focus on the biopsies. We may or may not have non-invasive data to report at that time, but soon thereafter we will have it. Although the biopsies are done at week 24, the non-invasive tests are actually followed all the way to week 48 along with safety and also body weight reduction, so the primary readout will be at week 24 in the biopsies, but then about six months after that, we'll read out on 48-week weight reduction. We'll read out on the non-invasive markers as well.
Great. So you've spoken a little bit to why you believe PEM is differentiated in MASH compared to, say, Tirzepatide. We've seen the SYNERGY-NASH data. We recently saw Novo's ESSENCE data. What about Survodutide? And can you talk how Pem is differentiated from Survo, which is also a GLP gluc?
Yeah. So the first thing is that Survodutide has a ratio of GLP-1 to glucagon of 8:1 . It's much more heavily biased to GLP-1. We're 1:1 , which means that we have more glucagon potency. So if you believe in glucagon and its effects on liver fat and lipids, we're a preferred molecule. We actually beat Survodutide on their weight loss at 48 weeks given the same statistical analysis. And in addition, we're much better tolerated. Their adverse event discontinuations were in excess of 20% at all of their doses, approaching 30%. In fact, at one study presented at the liver meetings, 47% adverse event discontinuation rates. And now they're announcing titration out to 24 to 32 weeks, whereas we can achieve better than that with a much more limited dose titration.
I think it's also important to realize that we were given a safety bill, clean safety bill of health by the FDA. If you look at the Survodutide phase III program, they actually have a safety study in there that's powered to show non-inferiority to placebo, sorry for the statistical terms, to show no harm greater than placebo, and that's very unusual. We used to see CVOT trials like ESSENCE to show superiority in actually driving down cardiovascular events. This study is designed to show no increase, so that's a bit strange. It hasn't been enforced in any of the other sponsors. They mentioned in a recent publication that glucagon could have cardiotoxic effects. So this is a reasonable study to do. We're speculating that there might be something there that raised the attention of the agency. We don't know for certain.
But I would say, flipping back to Pemvidutide, is that we were given a very good, clean, very clean bill of health by the agency. As we mentioned before, our studies are all efficacy studies. They're not safety studies. We weren't asked to do one by the agency.
Yeah, I just wanted to add in that we think we have a complete solution for MASH. The drugs that are out there that have just been approved and the data that we are seeing from GLP-1s, the really very modest effects they're showing, either it's through weight loss or through liver fat reduction. In spite of that, they're doing pretty well. The recent launch shows that there is demand, there is need in the marketplace. We think we're going to have much more effect than those drugs. There's about 10%-15% addition to placebo. That's really very modest effect if you think about it. We think we're going to have much greater effect. And the reason I say we have a complete solution is that we have direct impact on the liver. So we have a direct acting agent. And on top of that, people are losing weight.
That's really the best way to treat obesity. There's a lot of discussion out there by combining different therapies, one with defatting of liver, with weight loss. That's exactly what we are doing. Pemvidutide is designed to do that. So we feel very, very comfortable saying that we could be the class leading drug for MASH.
Great. Well, very much looking forward to the data in 2Q. So just to wrap up as time is winding down, can you just remind us of the key next upcoming catalyst? I know we have earnings tomorrow. So I'll have a busy day alongside you guys. But yeah, just the key inflection points to pay attention to through the balance of this year and through 2025.
Of course. Well, so we'll have the earnings tomorrow. We recently brought on a CFO, which we're very excited about. Really, the team is complete now. We will be at a number of conferences talking about the data itself as well as the design of our studies. So that's going to be very exciting. In addition, of course, the phase IIb data from MASH, we think that's a major milestone coming up in the second quarter of next year. We'll quickly, as I mentioned earlier, prepare an end-of-phase II meeting with the FDA on MASH. And our goal is to get started on that program by the end of next year.
Fantastic. Well, thank you so much for taking the time to chat with us. Congratulations again on the successful EOP2 meeting. And yeah, thank you very much.
Thank you. Thank you for.