Good morning, and welcome everyone to the eighth annual H.C. Wainwright MASH Conference. I'm Luis Santos, a biotech analyst at H.C. Wainwright, and today it's my pleasure to introduce our next presenters, Vipin Garg, PhD, President and CEO; and Scott Harris, CMO, of Altimmune, a clinical-stage biopharmaceutical company focused on developing innovative next-generation therapeutics, namely pemvidutide, a peptide-based GLP-1 glucagon dual receptor agonist for the treatment of obesity and MASH, also known as metabolic dysfunction-associated steatohepatitis. Vipin, Scott, welcome. It is a pleasure to have you here today.
Yeah, thank you for having us. It's a pleasure to be discussing Altimmune and pemvidutide with you.
Absolutely. So let's begin with the background of Altimmune and the history of pemvidutide. Why did you view it as a differentiated compound, and how did it come to be part of your pipeline?
Yeah, so pemvidutide is a GLP-1 glucagon dual agonist that we acquired back in 2019 from a company called Spitfire Pharma. And it was being developed for MASH for treatment of NASH, what we called back then. And what's unique about pemvidutide is that it's because it's a dual agonist, so it combines two distinct mechanisms, GLP-1 for appetite suppression and glucagon for direct effect, for its direct effect in the liver and lipid metabolism. By combining these two, you know, we're able to get significant weight loss, robust weight loss because of the GLP-1 component, and also at the same time have a significant impact on liver fat reduction. And by combining these two, we think we have a drug that we can develop both for obesity as well as for MASH.
There are a couple of other features of pemvidutide that I would like to highlight. It's a one-to-one balance, so it's been specifically designed to have one-to-one ratio of GLP-1 to glucagon, and that's important because we want to increase the glucagon effect as much as possible and really have a perfect balance between GLP-1 and glucagon. In addition, the drug is designed to have a lower Cmax, so its PK profile is unique amongst incretin-based compounds, a lower Cmax and longer Tmax, and that allows us to have slower entry of the compound into circulation, into blood, and we believe that that gives it better tolerability and safety profile.
That sounds great, so what are the advantages of the dual mechanism of action that you just described in the settings of MASH, obesity, type 2 diabetes, and non-alcoholic fatty disease, NAFLD? Is there anything you'd like to add for each different one, indication?
Yeah, Scott, do you wanna take that?
Yes. So we're well aware of the effects of incretin agents on body weight, and there's been some published data on MASH. But it should be recognized that there are no GLP-1 or GIP receptors in the liver, and the effects of these compounds, whether it's semaglutide or tirzepatide, on liver fat is totally indirect and mediated by weight loss. And because of that, the effects on liver fat are minimized and somewhat slow. With pemvidutide, we have direct effects on the liver because the liver is rich in glucagon receptors. And in fact, we see class-leading reduction of liver fat with pemvidutide, approximately 76% in 24 weeks, but we actually see that effect rapidly, as early as 6 weeks. So we're well aware of the relationship of liver fat to MASH resolution.
It's also important to recognize that there's a direct relationship of liver fat to fibrosis improvement, and that the effects of achieving either of these endpoints in a clinical trial is directly related to the amount of defatting in the liver. On top of that, pemvidutide appears to have a direct anti-fibrotic effect in animal models. So there's a one-two punch here that would deliver early results in MASH, both MASH resolution and fibrosis improvement. Because of that, we feel strongly that we can read out our trial at twenty-four weeks, just like the FGF21s, and in fact, we would distinguish ourselves from the other incretins by being the only incretins to read out as early as twenty-four weeks, compared to forty-eight to seventy-two weeks with the other compounds. But compared to the FGF21s, we will also have weight loss.
So based on that, we will be the most distinguished compound in the field, giving results in NASH resolution and fibrosis improvement at only 24 weeks, plus the weight loss that's not seen with the FGF21s or Rezdiffra. Now, shifting over to obesity, we have close to 16% weight loss at 48 weeks, but that weight loss was continuing at the end of treatment. The trajectory of the curve was still steep, so projecting out to an endpoint of 68-72 weeks, like semaglutide and tirzepatide, you can see that we would have very comparative weight, comparable weight loss to something like tirzepatide and beating semaglutide. So we distinguish from that basis. But in addition, like liver fat, those two compounds, semaglutide and tirzepatide, do not have very productive effects on serum lipids, 'cause remember, the lipids are manufactured in the liver.
Unlike liver fat, the effects of these compounds on serum lipids are very modest. We see very robust reductions of liver fat, so in addition to robust weight loss and also robust reduction of liver fat, we also associate a robust reduction of lipids, and then on top of all of that is our lean muscle or lean mass preserving effects, which are extremely important. We can get into more details about that, but that's class-leading as well, and extremely important as this acute phase of weight loss in the first year starts to shift to the safe maintenance of weight loss. We can prevent the negative outcomes of excessive loss of lean mass, so we think that we're extremely well-positioned both in MASH and in obesity.
That sounds great. Just to clarify that, weight loss, that's, that is preserved at 72 weeks was after how long of a treatment?
We only treated for 48 weeks, but if we look at the trajectory of the curve at 48 weeks, it's clear that if we continued the treatment out as long as tirzepatide, which was 72 weeks, we'd have comparable levels of weight loss.
Great.
Yeah, one of the benefits of glucagon, we believe, is it's fundamentally shifting the metabolism to the use of fat as a source of energy. So as a result, we're not seeing the plateauing effect that you see from GLP-1s, and the weight loss is still continuing beyond 48 weeks.
Great. That's useful. That's great differentiating factor. Thank you. So going into MASH, could you tell us a little bit more about the unmet need and how you plan to address that unmet need, what you're going to tackle?
Yeah, Scott?
Yeah. So, obviously, MASH itself is a very severe disease. It's going to account soon for the leading cause of liver transplantation in the United States. And as you know, it's an obesity-based disease, and obesity is only getting greater with time. So the incidence or prevalence of MASH is only gonna increase with time. What we see here is, you know, just a very important effect on MASH, not only for the liver effects, but also the effects on body weight. Because, while the individuals with advanced MASH, with advanced fibrosis or cirrhosis die of the liver disease, the majority of individuals of MASH die of the complications of obesity, namely cardiovascular.
So offering what we think is a very potent effect on weight loss and serum lipids and liver fat is also a risk factor for cardiovascular disease. We believe that we're gonna be effective in the earlier, more cardiovascular-sensitive phases of MASH, as well as the later phases to treat and prevent cirrhosis. So consequently, we believe that our treatment paradigm includes not only early MASH and early fibrosis, but fibrosis all the way out to F4, so that we're treating the entirety of the MASH spectrum.
Yeah, that sounds great and going a little bit more into pemvidutide's clinical development, so one point that I wanted to touch is that in October last year, the FDA has granted Fast Track designation to pemvidutide for MASH, and this was based on promising phase I data in NAFLD. Can you discuss the read-throughs between these programs?
Right. So there's been a very, very strong correlation between liver fat and improvement of MASH, both MASH resolution and fibrosis improvement. So in the trial that you spoke about, that was a trial of a non-invasive test called MRI-PDFF, which measures liver fat. And with that, we saw a class-leading reduction of liver fat. So that is a direct read-through to the likelihood of success in MASH, and therefore, we were given a Fast Track designation by the FDA. But we've seen a whole variety of other effects in addition to that. We've seen predictive markers of fibrosis and non-invasive tests improving as well, and we presented that at different meetings.
Based on all of this, Luis, we're very excited about our readout that's coming up in our phase IIb biopsy-driven MASH trial, which will occur in the second quarter of next year.
Great. Can you tell... Do you want to tell us more about the data generated to date in the phase IIb program, the IMPACT program?
Right. So that will be a very typical biopsy-driven phase II trial in MASH. The endpoints in that trial will be MASH resolution or fibrosis improvement. Either one of those would suffice for a successful trial. We are enrolling approximately 190 subjects. The arms will be placebo, the 1.2 mg and the 1.8 mg dose. We're placing approximately 76 patients in the placebo arm, and the 1.8 mg arm is the primary comparisons. But we'll also collect data at the 1.2 mg dose. We decided not to proceed to the 2.4 mg dose in the MASH program, unlike the obesity program, because in our critical biomarkers, we saw a plateauing of all of the effects at the 1.8 mg dose. It means that the dose response curve for liver fat reduction, for fibrosis improvement, for MASH resolution appears to occur at the 1.8 mg dose and that level of pemvidutide.
Whereas for obesity, the more you give, the more weight loss you get. So we are continuing the 2.4 mg dose in that trial. Now, the other key features of that trial is that we're enrolling patients with F2 and F3 fibrosis, just like the other trials as well. And you know, we have a very robust program for re-reading the biopsies that we've recently instituted, and we benefited tremendously from the information that has been given to us that have allowed earlier trials to be successful in terms of the actual process for reading the biopsies. So we think based on that, we can get very, very good readouts, keep the placebo response rate down, which will then lead to a higher likelihood of success in those endpoints.
Yeah, one thing I would like to add, Luis, is that this is a twenty-four-week readout. So if you look at other incretin-based studies in MASH, we would be the only compound, only incretin-based compound that would read out at twenty-four weeks. So if we can achieve statistical significance, which we are expecting at twenty-four weeks, we would stand out because of this combination of direct effect on the liver, as well as weight loss. Combining these two, we would really stand out as the class-leading compound for the treatment of MASH, incretin-based compound for the treatment of MASH.
When do you expect that twenty-four-week data? Have you given guidance?
Yes, it's in the second quarter of next year.
Great. And the expectations are for those readouts. We should expect biomarkers on lipids, improvement on lipids, liver fat, liver fibrosis, and you mentioned muscle preservation. Do you want to tell us a little bit more what your expectations are on those points?
Right. So the readout that we have in the second quarter will focus predominantly on the actual liver biopsy endpoints, MASH resolution, and fibrosis improvement. But we do hope to have information on the non-invasive markers as well at that time, which will be the liver fat reduction by MRI-PDFF, and the non-invasive markers of fibrosis, such as ELF and FibroScan as being the major readouts. But we will have eventually a full readout with the top-line data. That's what we expect in the second quarter of next year.
How do you think about the potential in the context of the standard of care and the competitive landscape? Is your ultimate goal to have a broad label that includes both obesity, MASH, and also in both diabetic and non-diabetic patients? Well, I'd like to know how you're thinking about the regulatory bar for success in these different points.
Let me address the regulatory bar, Luis, and I'll hand over to Vipin for more of the commercial aspects. Patients with MASH and obesity are extremely similar. The basic underlying problem is their obesity. But in terms of their diseases, they separate out in a regulatory sense. The endpoints for obesity and MASH are different. They're also reviewed by different divisions. The standard for approval in MASH right now is either MASH resolution and/or fibrosis improvement. You can approve for either in the United States, although there's more focus placed on fibrosis improvement because that leads more to the negative outcomes. With obesity, it is directly the weight loss. Now, we are designing our obesity program, and as you might recall, we have an end of phase II meeting with the FDA for obesity coming up in November.
That program will highlight the attributes of glucagon, the liver fat reduction, the improvement of lipids, and also, as you mentioned before, the preservation of lean mass in susceptible populations. So the lean mass readout is predominantly in the obesity program. We are not anticipating having any data for the MASH readout at this time.
Makes sense.
Yeah, in terms of MASH versus obesity and even other indications, our strategy is to really focus on the benefits of glucagon. So we are looking for subpopulations that way we can highlight the importance or the benefits of glucagon. So MASH is one of that population, because weight loss, a combination of weight loss and liver fat and direct effect on the liver are very beneficial in MASH. Similarly, in obesity patients, number one, the primary endpoint is weight loss. But important secondary endpoints for obesity are serum lipids, liver fat reduction, blood pressure, all of which we do really well as a compound, better than other existing therapies. So if you combine these two, you can go in either direction.
You can go to MASH, you can go to obesity, because you're really focusing on the benefits of glucagon. You talked about diabetes. Our goal here is not to treat diabetes. This is not a drug to treat diabetes per se, but we can treat both MASH and obesity in patients with diabetes. So I think that's an important differentiation, you know, that this is not a diabetes drug. The first generation of incretins, GLP-1s, they really came out as diabetes drugs and eventually became, you know, obesity drugs, so they treat diabetic people with diabetes and obesity. What pemvidutide is better suited for is for treating people with dyslipidemia, with lipid disorders, with high serum lipids, as well as liver fat and obesity.
So it's a combination of two different comorbidities, and as this field evolves, people are gonna shift their focus from diabetes to other comorbidities of obesity, and that's where glucagon comes in.
It's important to recognize that the statins, although they're great drugs, are not treating the necessary target population in totality. Only about 50% of patients who take statins actually reach their LDL targets. With pemvidutide, we saw a 21% reduction in serum lipids in people with elevated LDL cholesterol, for example, and in fact, that effect was even better in people taking statins. So you can see the synergy immediately. People are a little passive about the treatment of their cholesterol, but they're not passive about their weight. They rush to the doctor when these drugs are available. So we can actually implement greater LDL reduction in addition to statins in these patients. We think they're gonna have- it's gonna have very significant cardiovascular effects.
Interesting. That's great. Great insights. So when is the earliest that pemvidutide could be on the market in either indication?
I can handle it.
Go ahead.
Yeah.
Go ahead, Scott.
So in obesity, it could be as early as 2028, although, as we've announced before, we are not going to proceed into a phase III program without a partner at this time. But assuming that happens, with the end of phase II, meaning we think that that would probably be the date of commercialization, and for MASH, it would probably occur in 2030.
How do you see that playing out with the competition and other GLP-1 based obesity drugs? Is the narrative there the improved glucagon effect as well, the dual mechanism?
Yeah, I mean, even though we have GLP-1 in our compound, we really don't consider ourselves just a GLP-1 based drug. Because of the addition of glucagon, it really bringing very different properties, and it's treating or addressing different comorbidities of obesity. Keep in mind that obesity is not just one disease. There are many different comorbidities that will need to be addressed, so weight loss is one component of obesity. What is next? What is the next thing that we need to... that these patients need help with? And that's the cardiovascular outcomes that we are looking for, lipid improvement beyond just diabetes. So that's where pemvidutide fits in well.
So as the whole obesity and MASH market evolves, we're gonna be needing drugs that go beyond just weight loss and have direct effect on dyslipidemia and on lipid parameters across the board, and that's where glucagon would be important.
Got it. Well, this brings us to the end of our Fireside Chats. Vipin and Scott, it was a pleasure. Thank you so much for the overview and discussion.
Yeah, thank you for having us again. It was a pleasure.