My name is Adam Lange. I'm the head of investor relations, and on behalf of the entire Zealand Pharma team, we are very pleased to see so many of you today. Thanks a lot for spending the next few hours with us. Today, it is almost exactly two years ago since we did our last Capital Markets event, our Obesity R&D event in December 2023, where for the first time, at least towards a broader audience of investors and analysts, we really articulated the ambition of Zealand Pharma to become a key player in the management of obesity and highlighted the potential of Amylin analogs to represent a standalone therapy for weight management. A lot of things have happened in the last two years, both for Zealand Pharma specifically and more broadly in the obesity space.
The obesity market has evolved significantly, but in many ways, the key trends, the key dynamics that we see in the real world today strongly reinforce many of those perspectives we shared on that day two years ago. Now, what we will do today is to walk you through how we intend to deliver on the very unique opportunities we have in front of us as we aim to redefine the near-term future of weight management and build an industry-leading metabolic health pipeline. I hope you will find the presentations very interesting and engaging. We will be doing a few Q&A sessions throughout the next couple of hours, one on the Survodutide program, one on petrelintide, and then one final Q&A round in the end before we wrap up, so please, as we open for Q&A, raise your hand and don't be shy to ask questions.
The entire Zealand Pharma management team is with us today, and I know they also look very much forward to continuing the discussion during the break and at the closing reception afterwards. I can see a lot of you. You have these booklets in front of you. That's where you can find the detailed agenda for today, brief bios of all the presenters, and then, of course, as head of IR, I also need to remind you that obviously today we will be making forward-looking statements that are subject to risks and uncertainties. All slides will be available on our company website after the event. Now, before handing over to our CEO, Adam Steensberg, we would actually like to begin with a short video.
Rarely do you get a chance in your career to have an impact of this magnitude.
What we really want to do is to build a generation of biotech.
The people that surround us and the mission that we have in front of us is just once in a lifetime.
Joining Zealand was the easiest career decision in my life.
I've drunk the Kool-Aid. This is a phenomenal organization.
This whole blue, this magic thing that just makes Zealand Zealand.
I think it's one of the best places to do discovery right now.
Metabolic health is an enormous unmet medical need.
By 2030, around half of the population worldwide will be overweight, obese.
For 25 years, our key focus has actually been around peptides for metabolic health.
Peptides are important because they are biological signals that are naturally existing in your body.
All we're doing is making just subtle tweaks to help shift equilibrium within your body in a positive way.
petrelintide is what we describe as our crown jewel. It's a more natural way to help people reduce their energy intake.
This has the potential to impact millions of patients in a very positive way.
Finding a partner for petrelintide was extremely important for us. We signed a deal that was everything that we have dreamed of.
having such a big program as petrelintide is a big jolt for any organization.
I'm extremely excited about the potential of Zealand's pipeline. We need more tools to also address all these comorbidities.
So we're not going to be Vanilla Ice. We're not going to be the one-hit wonder.
That hunger that we have hasn't changed. We'll have to move with speed and agility in ways that some of the bigger companies won't be able to.
We have to anticipate where the puck is going and ski to that spot.
Seniority and rank doesn't really matter at Zealand, and that allows us to always make sure the best ideas win.
We have these really close collaborations across the entire company.
With a base both in Boston and in Copenhagen, I think we're going to see tremendous synergies.
AI and machine learning, the new tools that we have developed to rapidly cycle through opportunities. To me, that is the future.
The sky's the limit right now about what we can really achieve.
It's very rare that you can build to a future that is novel. We have the opportunity to become a generational biotech.
The reason I believe we can do it is really because of our culture. I think that's what makes us us.
If you ask me tomorrow, has this been a success? I would say, absolutely. Do we have the opportunity for even more success? Absolutely.
We are uniquely set up based on our past experience, our current momentum and pipeline, and our will to win to deliver on this vision.
So our past experience, our current momentum, and our will to win sets us up to uniquely deliver on our mission to redefine management of obesity for the future. What the world has experienced today when it comes to treatment of obesity is only GLP-1-based therapies. We know that it takes more than that to truly get around the healthcare crisis that follows the obesity pandemic. We also know that if you ask most people today, it's difficult to envision a different future from what you already have today. But radically different approaches, both when it comes to tools and how we approach the patients, are needed for this healthcare crisis. More of the same will not do it.
We have a vision to transform management by introducing novel tools that the world has not yet seen. In that way, we are not very different from where Henry Ford was 100 years ago, when he had a radically different idea about how to serve and manage future transportation needs for the individual. Had he asked his customers what they would like to see, they would all have been asking for faster or stronger horses because that was what they know at that time. But he knew that cars would provide a more pleasant and more effective way of transporting the millions of people in the future. Great, true innovations require people to look beyond the obvious, and that's what Zealand is here to show. We are not here to create faster horses. We are here to create the future.
So what we are going to talk about today is our ambition to redefine obesity for a new era. We will build a generational biotech company, and in doing so, we will focus on two pillars. Number one is to maximize the value potential of petrelintide, what we believe is the best-in-class Amylin analog, and that growth will allow us to establish a commercial presence in the U.S. Equally important, we are also going to double down and make significant new investments into our pipeline to develop the world's most valuable metabolic health pipeline. Before we get to that, I just want us to take a step back and reconsider the crisis that we are facing. Obesity has turned into a civilization-scale problem. We now have more than 1 billion people living with obesity worldwide, and it's a crisis that we have created in only a few decades.
We have to come to the conclusion that this is not a problem of the individual. This is a problem for society. If we don't do something about this, our healthcare systems will face significant challenges in the future with the disease that follows when you live with obesity for a long period, especially if you live with obesity since childhood. So we need to think differently around how to address this pandemic. We have seen the revolution of GLP-1-based therapies. We have, for the first time, experienced that medical intervention can actually help people lose weight. We have also seen that many patients in the real world experience that 10%-20% weight loss when they are exposed to a GLP-1-based therapy. We have also come now to experience and redefine our expectations for GLP-1 because real-world evidence shows us that many people struggle to stay on a GLP-1.
If you only treat your weight loss and you stop treatment and you regain weight, you'll be back to square one. We need to change our thinking around how we approach obesity radically. We have to move away from just weight loss into weight maintenance. We need durable programs, durable medicines that can help people achieve weight maintenance once they've lost their weight. That is what Zealand is about. That is about truly addressing the healthcare crisis that follows longstanding obesity and not just being part of the weight loss Olympics that has excited many for some period. We believe that Amylin, as such, and more specifically petrelintide, has the potential to radically transform management of obesity. petrelintide has been specifically designed to provide a product that can help people feel full faster instead of losing your appetite.
It's a product that has been designed for durable and high-quality weight loss, and it's a product which we believe, as a standalone medicine, has potential to form the future foundational and first-choice medicine for people who want to lose weight and, importantly, want to maintain that weight loss. In that sense, we also believe that beyond the foundational opportunity for petrelintide, when we combine it with a molecule like CT388, then we have opportunities for patients who want to lose the most weight, so the most morbidly obese patients or people with obesity who live with significant additional disease, overall creating this foundational opportunity for petrelintide. Earlier this year, we announced a partnership with Roche, and just as petrelintide has a transformational potential for patients living with obesity, for healthcare providers, and for society, this partnership also has a transformational potential for Zealand.
The partnership is so much more than just a partnership. This is a shared commitment to go in and lead and redefine how obesity is managed. We will combine the speed of a biotech with the strength of a pharma company, and it uniquely unites the long heritage that Zealand has in metabolic health with the very strong manufacturing and commercial infrastructure that Roche brings to the table. It will also be transformational for Zealand in the sense that it's an equal partnership. We have 50/50 say in the partnership, and then Zealand has a 50% co-commercialization opportunity. And we will leverage this to build commercial infrastructure in the U.S. and thus become a fully integrated biotech company addressing all parts of the value chain. So for Zealand, this is a transformational partnership.
Not long ago, last month, I was sitting down with Teresa, the Pharma CEO of Roche, talking a little bit about the importance of this partnership, and I just want to play a small video from that. I think everyone who works at Zealand, of course, will understand how important it was for us to find the right partner. It's something we've discussed for many years. We needed somebody who had really embraced the magnitude of the problem and was willing to invest and actually pursue that opportunity to make a true difference in what we consider the biggest healthcare challenge.
And we never, ever had any doubt that a partnership with Zealand wasn't going to make a ton of sense. So it was the science, it was the people, it was the shared purpose that we had, the shared vision for where we want to go. We have an opportunity and, frankly, a responsibility to do something really important and great together.
As you can hear, this is the perfect partnership. It is a very, very important pillar in our vision to become a generational biotech, and we will be 100% focused on maximizing the value of petrelintide as we enter this period of accelerated growth. An equally important pillar in our growth and our acceleration towards becoming a generational biotech is the investments we're going to make into the early pipeline to build the world's most valuable metabolic health pipeline. We will increase our investments into research five times over the coming five years as compared to the investments we did in the past five years. It's a significant step up of our research investments. We will start a Boston cutting-edge research hub, which will match what we have in Copenhagen. This Boston site will focus on automation, AI, machine learning, and novel chemistry approaches.
So it will be a complementary site to what we do in Copenhagen, where we have more than 25 years of experience and heritage in peptide and, importantly, metabolic research. So by combining that heritage with the novel AI tools and the very strong internal database we have from those past 25 years, that, I would argue, almost provides Zealand with an unfair competitive advantage towards competitors. Not many other companies can claim 25 years of experience and data in this space, and the AI revolution needs data to materialize into true products. So what we are communicating today is our 2030 ambition called Metabolic Frontier. If you look into this period of accelerated growth that we are looking into now, we will have five launches.
We will also have more than 10 clinical candidates in our pipeline, and we will make sure that we have industry-leading cycles from idea to clinic. That is what will make Zealand a generational biotech company. As we approach this period of accelerated growth, you will also see that there's a very clear path to long-term value creation and significant transformational milestones ahead. Starting already next year, first quarter, we expect to see the phase II data from petrelintide, and we're going to see Survodutide phase III program. Next year is also where we're going to build out our Boston-based research site, and then, as we approach the next period, we will expect to see Survodutide being launched by our partner here in England. We're going to continue to expand our U.S. commercial and medical affairs footprint.
And then, as we approach the latter part of the period, is where we expect to launch petrelintide in partnership with Roche, of course, leveraging also the commercial infrastructure that Zealand has built. That commercial infrastructure is not only for petrelintide. It will also serve as a launchpad for future medicines that Zealand will launch into this space. So it's, of course, clear that just having a very strong pipeline and a strong vision doesn't make it alone. It's really down to the people and the culture. And we have created all that you see today with a group of people that is less than 500 people. Our commitment to you guys as we progress in the next five years is that we will stay true to our DNA. We will continue to be an agile, quick, and powerful organization.
We will continue to operate with the speed of a biotech, but the strength of a pharma company, and that reminds me of a sports person who was also known for punching in a weight class above himself, a person who was not afraid of stepping into the ring and taking the fight up with somebody who would be bigger than himself, and that was Muhammad Ali. And when people asked him, "How do you do it?", the answer was, "I just float like a butterfly and sting like a bee," and when you're going to look at Zealand in the next period, you are going to see a biotech company that will continue to move like a biotech company, but hit with the strength of a pharma company. That is how we will operate.
So with that, I look very much forward, and I hope you guys are as excited as we are for the next few hours where we're going to soon hear about the commercial opportunity and how Zealand thinks about that. We're then going to move in to talk about glucagon GLP-1 biology and why we believe Survodutide has a best-in-class potential for not only managing obesity, but more specifically in the NASH space. Then we're going to talk about Amylin as a new class, the biology behind it, and why we think it's such an exciting opportunity to actually truly get around the obesity pandemic. More specifically, we're going to share our view on petrelintide and the best-in-class potential of this molecule.
After that, we're going to move in to discuss our research ambition and then conclude with how we're going to make sure that we can fund all this, so with that, I would like to invite our Chief Commercial Officer, Eric, up and just reiterate, this is a very unique moment in the history of not only Zealand, but also in this world with the first opportunity to actually seize and maximize this metabolic moment to do something about what we consider the biggest healthcare challenge of our time, and Zealand is at the cusp of transforming into a biotech, generational biotech company. Eric.
Thank you, Adam. And I'm humbled, but yet excited to be here because where I want to focus today is really about bringing you the perspectives of how Zealand thinks about this evolving landscape and giving you insight also into how we are going to move from an R&D organization into a very customer-centric commercial organization that includes medical affairs. I joined about 18 months ago, and what really attracted me to Zealand were three really important things. The first one is the vision. You heard it from Adam. It's bold, it's ambitious, but it's realistic. The second is it's about the opportunity to build something from nothing, and that's building a commercial organization on that journey from an R&D organization to a fully integrated commercial organization. And third, it's about the pipeline.
You're going to hear more about that today, but it truly serves as the foundation for the vision we have to be a leader in this space. Maybe. So let's first start with the vision you just heard from Adam. Our commitment for five launches in five years. Our pipeline situates us extremely well to deliver against it. That starts with our partnered product with BI, which is Survodutide. It has the opportunity to truly reshape the NASH segment and the obesity segment. But let's not forget about our rare disease portfolio. These are innovative medicines and have a tremendous amount of impact, particularly in congenital hyperinsulinism, as well as short bowel syndrome. We're committed to bringing these products forward, but we're going to bring them forward from a commercial perspective through partnerships.
Our crown jewel, you hear it a lot, the petrelintide is our crown jewel. It provides us the launching pad to grow Zealand and really change its trajectory within the obesity space. You're going to hear this a lot, and it's not new news, but it's worthy of repeating once again. That's about the impact of this disease. The obesity class, it's rapidly evolving, but it's the magnitude of what is in front of us. Nearly half of the world's population will be impacted by obesity in the next several years. They're starting to live longer and longer with this disease, and we know the connectivity that comes with it, which is hundreds of comorbidities and complications. What's alarming to see is what's a peek into our future, and that's about the children in the United States.
Right now, a little bit over a third of the children in the United States suffer from obesity and/or overweight. That is just a glimpse into our future. If we don't change that trajectory, we're going to start to see comorbidities that arrive earlier and more of them, and that's our responsibility to take that on, but it's not a simple disease. It's a very, very unique category. It's multifaceted. I don't want to call out two particular things that make this a really unique segment. Number one, it's the role of the consumer. We've not seen a category like this ever. They play a really important role not only in the initiation, but also in the treatment choice, and it's not just a small, but they play the vast majority of what they're doing, and the second one, it's the heterogeneity of the patient journey. What does that mean?
It means that these patients' journeys are very unique. They're individualized and often not the same. But there's one critical component to it as well, and that's the cyclical nature. Many people think about the cyclical nature here. They treat it more like an event than a chronic therapy that it is today. Now, this epidemic that we have in front of us and our greatest healthcare challenge, we've made some strides, but we've just scratched the surface. Here you can see a very, very small portion of patients that are being treated today in the U.S. with GLP-1-based therapies. But what's also important to note is that four times the number of patients that are on it today have tried it. And what does that mean? That means more patients have stopped therapy that are on it today. That's a challenge that's in front of us.
It's about maintaining patients on therapy for a longer period of time to realize the full benefit of this weight loss. Now, this category is still new. It's evolving at a pace we've never seen. I think it's every single day you get a new piece of news that gives you something about this category. But that's the first inflection point. And the first inflection point has been focused on weight and magnitude of weight. And the industry itself and those that follow it, that's where the focus has been, is about magnitude of weight. But that doesn't address all the needs of these patients. And when we think about it, it's a very, very narrow focus. And you couple that with the discontinuation rates that we see that are significantly higher than we'd like to see. What do you see? A second inflection point.
That momentum is starting to shift away from that clear focus on just weight loss and thinking about it more as a balanced approach where it's weight loss and the experience. Those two go hand in hand. We have to continue to fuel that as we go forward. I've been in this category, cardiovascular, renal, metabolism category, for probably 20-plus years. Therefore, I've had the opportunity to see the evolution of many of these categories. They all start with a single class, but they grow quite significantly when they recognize the complexities of the disease. When they add new products and new classes, it expands the treatment segment. That's exactly where we are today. We're dominated by one class of therapy. That's GLP-1-based therapy. That's not enough. It's time for a change, and it's time to add new options.
And we believe that the Amylin class has a tremendous opportunity to create that next foundational therapy. What I've said multiple times is this category is evolving rapidly. It's in its infancy, but yet what's happening is the market starting to shape itself and shape itself with two very, very clear and distinct segments. There's the prescriber segment, or what we would call the specialty-driven segment, and there's the consumer segment. That's the newest segment that we have. It's the fastest growing and one of the largest, but we'll talk about that in a minute. But what makes the prescriber-driven segment different? And what makes it unique? It's a specialty-driven category that follows the tradition of treating the disease itself, and they focus on comorbidities and really try to worry about that long-term benefit. But where does that leave obesity?
Secondary and tertiary and puts the burden or the responsibility back to the consumer, so we talked about comorbidities. We know there's a significant overlap between obesity, overweight, and comorbidities. It tends to gravitate to six core areas, but when we see how much overlap there is between obesity and these categories, we often think of cardiovascular and Type 2 diabetes as the end all be all. However, that's a little bit nearsighted because it forces us to overlook and underestimate some of the other comorbidities that are here. Liver disease is exactly one of those, and whether that's metabolic associated liver disease or that's NASH, and when you take a look at where the overlap occurs, so here you can see the comorbidities. On the right side, probably two, the cardiovascular as well as Type 2 diabetes and even CKD, they have a significant overlap, and they're extremely important.
But you have to take note of where this most significant overlap lies, and that's with liver disease. Think about it. 75% of obese and overweight patients will suffer from some form of liver disease. About a third will actually suffer from the more severe side of it, which is NASH. Now, this category will continue to grow quite significantly over the next decade or decades to come as new products enter the market, as new therapies come in, as new diagnostic tools become available. But today, there's a tremendous unmet need because there's only two products in this category that are currently approved, but also have modest effect in fibrosis. So we're excited about the opportunity of Survodutide as in this category. The phase III program sets it up well to really redefine the treatment patterns in this category.
Now, let's turn a little bit more broadly, talking about the prescribers. Who are the prescribers in this segment, and it might be surprising or it may not, but nine out of 10 scripts originate from a primary care physician. Specialty represents a smaller portion. You may think about the way we typically think about primary care and that they write refill scripts. This is a different category. They write just as many refills as they do initiate therapy, so the role of the primary care physician is quite significant, but we can't forget about the intersection between the consumer and the primary care physician. From a specialty perspective, it's still shaping itself. We expect it to continue to grow as new evidence comes forward, and we've seen more and more.
But as new evidence grows, as new products enter the market, it'll bring new prescribers, just like the hepatologist in NASH. So let's switch gears. We've talked about the prescriber segment. Let's talk about the consumer segment, the newest segment and the most or the fastest growing segment in this category. We're super excited about the opportunity that exists here. It gives us the opportunity to disrupt through innovation. But this segment is really different. And why is it different? It has a focus in primary care. But what's more important? They are the drivers of a lot of decisions, and they focus on obesity and reduction of weight as their primary objective, not secondary or tertiary. They take control of their decisions. Now, all of us have all been in the pharmaceutical industry or followed it for quite some time. We talk about consumer segments.
If you think about the consumer segment and Type 2 diabetes, it has an impact of about 10% in their total prescribing. This category is not your traditional consumer category. This group is extremely engaged, fastest growing, and truly takes ownership of the decisions, which is very similar to what you see of consumers and consumer packaged goods. In fact, almost two-thirds of all discussions start because of the consumer. Yes, there's an engagement that goes on between the physician and the consumer, but we have to think differently about how we engage this segment. Their needs are different than what we think about the specialty. You start to see here there's a triad of needs. And that triad of needs focuses on three key areas. It's the physical side of it. How do they feel? It's the social side of it. It's their appearance and how they fit in.
Then it's the emotional side. It's that confidence. That leads to engagement and the strong willingness to pay. We've seen this segment continue to accelerate in its growth. As we have, despite our focus or the industry focus and those that follow the industry really around more is better, that 25 is the next threshold. That's very one-dimensional and nearsighted and doesn't match what consumers want. Consumers really focus on losing up to 20%. The vast majority, 80% of people want to lose up to 20%. We have to change the conversation to focus more on that balanced approach around delivering the weight that people want, but the experience they desire. Turning to some real-world data. The real-world data moves us from what people desire to the behavior. Here you can see that the vast majority of patients do not escalate their therapy doses.
They never reach the full maximal value of it. Part of that is due to a multitude of reasons, whether it's adverse events, whether they've hit the weight that they want, or others. But when you look at the data itself and what level of weight loss are they achieving, you see that they're achieving high single digits with Wegovy and low double digits with Zepbound. That's significantly different than what we see in the clinical trials. But it's not just about weight loss. It's about the experience and how that's connected to persistency. So I challenge us to think that another opportunity that we have is how do we get people to maintain therapy. Another set of real-world data suggests we have extremely high discontinuation rates. And those discontinuation rates start early. 30% of people stop therapy within the first month, 50% in the first three months.
Knowing this is a chronic disease, you'd expect retention. You have 80% of the people that discontinue within a given year that never realize that full benefit. What you start to see here is a cycling starting to occur. They're treating it as an event-driven disease. As they enter the market, leave the market, and come back in, that poses its own challenges. We have to change the way that we think about it, and we have to offer new options. Just think if there is an opportunity to give people the weight loss that they want or desire, but also with a better experience, that's going to give us the opportunity to realize the full benefit of the weight loss. You may be asking, why are they stopping? The number one reason people are stopping is because of adverse events.
Nearly half of the population that stops because of adverse events, typically GI in nature. And we recognize there's a lot of patients that can respond well to GLP-1s. There's a group that don't respond well to GLP-1s. There's a large group in the middle that are looking for alternatives. So let's go to where we started, and that's about the pipeline that we have. The pipeline we have sets the foundation. It goes against the ambition that Adam has laid out, and it starts with petrelintide. It has the opportunity to reshape how we think about the obesity journey, delivering that weight loss that people desire while giving them the experience that they want. That gives us the opportunity to create it as a foundational therapy as we move forward. But it's not just petrelintide. Also think about the fixed dose combination.
That's petrelintide plus 388 with our partners from Roche. This expands where we want to go. It moves beyond the monotherapy and places that we can't reach. So it's an expansion opportunity for us. And then there's Survodutide. Again, it has the opportunity to really change the treatment patterns in NASH. But we're not done there. We've got more to bring forward, and our CFO will spend a little bit of time talking about our vision and where that innovation goes next. So I've talked a lot about the dynamics of the marketplace, how it's evolving, how it's ripe for disruption and innovation. But let's switch gears just a little bit. Let's talk about how we want to build Zealand as an organization on our journey from an R&D to a fully integrated organization, meaning commercial and medical affairs.
As I remind you, I joined 18 months ago, very, very pivotal time. We were in the middle of our partnership discussions. You heard it from Adam, but we found the ideal partner. They share our vision for the Amylin franchise, and they give us the flexibility to build alongside them at the pace that we want to build ourselves. So as we think about this opportunity, it's a 50/50 co-promote, sorry, co-co, meaning co-development and co-commercialization. It provides us the flexibility as well as the optionality to enter the market alongside Roche, but also establish the foothold that we want to do in our journey to become that generational biotech, but we are committed, and we are committed to driving medical affairs to play a leadership role, and on the commercial side, our focus is going to be unlocking that consumer segment, which we know is extremely important.
So this foundation or this approach, which is very focused for us, will really set us up for the launch of petrelintide, but create the foundation for future launches as we move and deliver against that aspiration of becoming the generational biotech. So I'm going to stop here. We're going to switch gears just a little bit. We're going to go into more of the clinical and the scientific side of things. So, David.
Hey, Eric. It's my pleasure to introduce the clinical and scientific segment of this afternoon's discussions and Capital Market Day. We will begin with discussions of the Survodutide program and glucagon GLP-1 dual agonism. It's my pleasure to welcome back Professor Carel le Roux. He joins us from Dublin, Ireland, where he is a professor of experimental pathology and the head of the Department of Pathology. He did his clinical training all over the earth, but primarily at Barts and the London Hospital, as well as specialty training at Hammersmith, and completed his PhD at Imperial College here in London under the direction of Stephen Bloom, another well-recognized metabolic scientist. He is a physician scientist who's both widely regarded and, I think, exceedingly well-known as a key expert and leader in the fields of metabolic medicine, diabetes, obesity, and other metabolic diseases.
So, Carol, welcome back, and please lead us on the discussion of Survodutide.
Thank you so much. It's a great opportunity to be here. I work as a clinician scientist, and I cut my teeth over at the Hammersmith, originally doing a lot of the first-in-man infusions of these peptides. I think of them in a different way because we sort of lived the dream. I want to bring up this painting that hangs in the London Gallery at the moment of Joseph Wright of Derby. What you can maybe see over here, here is the Zealand scientist discovering Survodutide. You guys can see yourselves because that's you up there with the pen making notes of today, and you can see your customers looking at you, looking to you for advice.
This is a real opportunity to actually have an in-depth discussion and work out just how impactful these discoveries can really be. And as I said, I had the privilege in my misspent youth to actually infuse this natural hormone, Oxyntomodulin, into humans for the first time. And I remember when we injected this hormone, which only has a half-life of about two minutes, naturally made by the gut. You make it every time you have a meal. And when we do bariatric surgery, we increase it by more than three-fold. This is a natural hormone that your body has. And when we infused it into humans, we had this incredible experience where people just said, "I don't feel hungry anymore." They consumed about a quarter or third less food, even in the short term. But of course, it was an infusion.
Then we couldn't do it without an infusion or constant infusion. And when we ran those studies, we also saw an increase in energy expenditure. So it's the only gut hormone that we actually have seen both of this. And why is that? Because Oxyntomodulin is a natural peptide, but it does not have a natural receptor. So what it does is it piggybacks, and it binds both the GLP-1 receptor and it binds the glucagon receptor. So sort of two for the price of one. And this has been sort of the whole principle of building Survodutide, which is a 29 -amino acid peptide that behaves like Oxyntomodulin. And therefore, you get all the benefits of binding the GLP-1, but you also get the benefits of binding the glucagon receptor. Now, what are those benefits? There's direct benefits, and there's indirect benefits.
The direct benefits for binding the glucagon receptor is that you have these benefits within the liver, and we're going to speak a lot about the liver because this is something that, because the liver doesn't have GLP-1 receptors, so therefore, the effects that we see from GLP-1 treatments are indirect, but you also see the benefits of the direct GLP-1 receptor binding, and that's what you and I know, so, for example, the pancreas, the incretin effect, that's obviously what we also talk about the GI effect, and we also, what I'm interested in, is the GLP-1 receptors in the brain, and we think about obesity as a neurological disease, we think of it as a subcortical brain disease that we can now treat if we bind those receptors, so think of this as we go through this.
So let me show you some phase II data that's been out for some time. Now, remember, this is only 16-week data in people who have diabetes and have the disease of obesity. And what you will see is because you bind the GLP-1 receptor, you see this very impressive glucose improvement. So there you have all the benefits from GLP-1. But also in people that have diabetes, you also see substantial weight loss. Now, again, I want to draw your attention. It's only 16-week data. So you see the curves are going down. This is the phase II studies. Now, let's look at the phase II studies in people that have the disease of obesity but do not have diabetes. Now, I'll remind you, and you guys know as well as I do, a phase II study is like the Ride of the Valkyries, right?
You just have to go, and you have to show this clear separation so you have a clear dose response. And that's what this is supposed to do. And also here, you only have 46 weeks. So again, you see the curves going down. So we know we're near nadir yet because it doesn't matter what you do in a human, if it's bariatric surgery or if it's any of the medications that we're using. A human takes about 74 to 85 weeks to get to nadir weight. So the lowest weight you only achieve after about 74 weeks. So it doesn't matter if you use semaglutide or tirzepatide or Survodutide or bariatric surgery, it takes you that long to get to the bottom. So that's what we're expecting now to see with Survodutide in the phase III study. So what you see is that.
But now remember what I said about the Ride of the Valkyries because that also is something that we have learned quite a bit is that, yes, you have these direct effects and also these indirect effects. And some of the effects that you see very early on are what we've just heard so well articulated. It's no longer about weight loss. It's about health gain, right? Because it turns out patients come to me, and you're going to hear come to Luz Clinic in the same way. And they come to us for weight loss. And then we start them on these great drugs. And yeah, they get 20% weight loss, and then half of them stop the drug within six months. Why is that?
And what we have learned on the job in fairness is that weight loss does not appear to be enough of a value proposition to continue the treatment. People come for weight loss, but if you don't switch and actually articulate the health gains that people have, they won't stay on the drug. And we know that because if we use these same drugs in people with Type 2 diabetes, they lose less weight, but they stay on the drug. Why is that? Because they understand the drug's benefit for the health gains for diabetes. So we are learning a lot about that. And here you can see the improvements in blood pressure because that is binding the GLP-1 receptor in the kidney. And we also see some weight loss dependent benefits.
And you can also see the effects of binding the GLP-1 receptor with Survodutide on the sinoatrial node in the heart where we see this increase in blood pressure. So that is as reassuring that the thing is doing exactly what it is supposed to do. But what has also helped us is to articulate that health gain. And we saw that nice comment from ObesityWeek where they said, "See obesity, think liver," and we now say, "Treat the heart," right? So ultimately, that is where your value proposition is going to drive. So what do we see on this, again, coming back to our ride of Valkyries when it comes to side effects? And what we have learned is that these tools, these assets are more powerful than we thought they were.
And we thought in the past that if we increase the dose really rapidly, we're going to get more weight loss. But remember what I said, it takes 74 weeks to actually get to the lowest weight. So it doesn't matter if you go fast or if you go slow, you're going to get the same amount of weight loss. But if you increase the dose too quickly, what we've learned in clinical practice is all you do is you drive a bunch of side effects without any benefits. And you will see the reason why people stop these medications is because they can't tolerate the side effects for the rest of their lives, right? And we always talk about mild, moderate, and severe, and we say this is true. It's absolutely true. That's serving the type.
There's no extra additional side effects that you wouldn't have seen in the GLP-1 class, and remember, Survodutide is a new sort of class of drugs because it's an Oxyntomodulin class, but what we now see is that we should just be a little bit more patient, and when we're actually treating patients in our clinical practice, we have far, far fewer side effects than we would see in clinical trials because we have flexibility, and we just simply change the doses slower, so we will get to the top dose. We will get all the benefits, but we are just patient, right, and I think that is what we are learning as we went from this phase II study into a phase III study, and actually, we are learning, as I said, on the job, and we're going to do even better in clinical practice.
So let's just sort of focus a little bit on the liver. So what we have is we have these stages of liver disease. And what we are seeing is that we are getting better at the non-invasive diagnostics to identify these patients. But what we are now understanding is when a patient does have these diseases, patients who have developed MASH or MASLD, so metabolic dysfunction-associated steatohepatitis, they very often don't die from liver disease. They die from cardiovascular disease. So it really helps us think about that cardiovascular kidney metabolic angle. And that metabolic angle is certainly diabetes. It is liver and also the disease of obesity. So actually showing that you can reverse fibrosis has always been the Holy Grail.
If you look at what we have now with Survodutide, and this is the phase II data over 48 weeks, you can see that 64.5% of patients have MASH resolution without worsening of fibrosis. And that's on the left-hand side. And if you look on the right-hand side, another way to look at it, same numbers, it's easy for me to remember, 64.5% of patients have reversal of fibrosis without worsening of MASH. Now, that is nice data to show, but you need to understand just how impactful it was. So when I was at med school, we were taught that fibrosis is a one-way ticket, right? The best that we could do is slow it down. Now, what this shows us, anything in biology that goes in that direction can also go in the opposite direction if you change the metabolic milieu.
That is what these drugs are doing. This is not just an indirect effect because of the weight loss. This is also a direct effect because Oxyntomodulin and Survodutide bind the glucagon receptor. Now, let me sort of put next to each other the three major studies in this space. Of course, it's always you have to take this with a health warning because these studies were not the same studies, wasn't the same patients. These are big studies, and we actually are quite comfortable. That's why two of these on the left-hand side and in the middle have actually made it now to approval through the FDA. You can see over here what I'm showing you is the number of patients who start with MASH and with liver fibrosis. Then we can show you the improvements in fibrosis.
And on the far right, we have the phase II data from Survodutide. And you can see the step change. So you can see this impressive result, I think, that can change the way we think. Because yes, we are interested in the glucagon receptor in the liver, but we also are quite interested in other organs that have intra-organ fat, organs like the heart, organs like the kidney. And now suddenly coming back to this concept of see obesity, think liver, treat the heart. And that is, I think, where we really can go in the future.
So let me summarize that if you have an Oxyntomodulin analog that's new in class, a new class actually, and it can bind both the glucagon receptor and the GLP-1 receptor at the same time, you're going to have this balance between treating the disease of obesity by both changing what happens from an energy intake, but potentially also, and we need to still show that in humans very clearly, it changes in energy expenditure. So you actually are treating the disease of obesity. These are not weight loss drugs. These are drugs for the treatment of obesity. These are disease-modifying drugs. But what do you get on top of that is you get sort of very powerful clinically meaningful weight loss, of course. You get this improvement in glycemia because you get all the benefits of the GLP-1 system. You also get the benefits from cardiovascular risk factors.
But now you see this additional liver fibrosis that we can see. And ultimately, we are now in clinic becoming really good at making these drugs tolerable, right? So we don't have to, I say to my patients now, if you vomit, it is my fault, right? Because it's not the drug that makes you vomit. It is the dose of the drug that makes you vomit. And how quickly I get to that dose will determine what your risks are. So by just being patient, we can actually now get the vast majority of our patients to the stop level of these medications without the side effects. So I think tolerability is something that we're going to become a lot better as we are learning.
So ultimately, let me summarize by saying this has potential to be competitive when it comes to treating the disease of obesity, but also treating the complications of the disease of obesity. And yes, we've heard that people are prepared to pay out of pocket when it comes to treating the disease of obesity. But healthcare systems around the world, they will pay for the treatment of the complications of obesity. They will treat for us to make patients go into a level of normal glycemia, put their diabetes in glycemic remission, turn the clock back when it comes to the fibrosis, turn the clock back when it comes to the heart, turn the clock back when it comes to the kidney damage. And that, I think, is the potential of thinking about these drugs. So thank you very much.
I'd then be delighted to talk to you, David, again and listen to his next talk. Thank you.
Description of the Status of the Survodutide Clinical Program. Carol will rejoin me with Adam for our initial Q&A. It's my pleasure to share an update of the program for clinical development of Survodutide led by our colleagues at Boehringer Ingelheim, who are solely responsible for the development and commercialization efforts. As Carol mentioned, the discovery of Survodutide has its roots in what we at Zealand have done. As Utpal has stated in the opening video, taking what nature gave us in these naturally occurring peptides like Oxyntomodulin and turning everything up or tweaking it in the positive direction.
As you've seen, the potential impact not just on glycemia, overweight, and obesity, but the impact on liver disease with Survodutide is something that gives us great promise. Carol, thank you for that tour de force. The SYNCHRONIZE program, which is the name given to the development program for Survodutide for the treatment of the disease of obesity, is one of two incredibly exciting data catalysts that are energizing the efforts at Zealand and obviously at Boehringer Ingelheim in 2026. The top line results from SYNCHRONIZE-1 will be available in the first half of 2026. We anticipate the presentation of those data at near-term scientific congress following that. Remember that this is a three-arm trial testing what I'll call the mid and higher dose than was actually tested in phase II.
Carol leads as principal investigator Survodutide one, one of the two key overweight and obesity treatment interventions for the Survodutide program. Important to note the demographics, which Carol and colleagues shared at the recent ObesityWeek. This is, I won't say a fully representative, but I think is becoming at least in part representative of the populations who are seeking treatment. We know that if one balances a population with an excess of female participants, you can amplify the weight loss that is achieved. This has been virtually universal, but clearly in this program, they're assessing this in a broader population, men and women with a high BMI, and as you'll hear in some detail, individuals who are affected by liver disease, so this entire program Survodutide for the evaluation of Survodutide in the treatment of overweight and obesity is large and comprehensive.
They will include a near total of 7,800 participants in the entire trial. As I've already mentioned, Survodutide one should report out in the first half of 2026. But this entire program will report out serially over 2026 and beyond. It will be an incredibly data-rich year for the Survodutide program in the treatment of overweight and obesity. The results of these clinical trials paved the way for regulatory submissions beginning as early as 2026, with the potential launch as Adam alluded to of Survodutide for the treatment of overweight and obesity in 2027 and beyond.
And this we believe positions our BI colleagues not only as the third company who will enter this space for therapeutics for the disease of obesity, but with a highly differentiated asset, this Oxyntomodulin analog and GLP-1 glucagon dual agonist for individuals not just living with obesity, but the important comorbidities that coexist in these individuals. Additionally, the program that Carol alluded to when talking about the effects not just on body weight, food intake is the impact of the liver. And Eric alluded to this in his opening. The overlap of so-called MASLD, MASH, and obesity is one that I think is only now becoming widely recognized. Three of four individuals living with overweight or obesity have liver disease of some form. A third have the more serious condition of metabolic dysfunction associated steatohepatitis.
That's the inflammation and impending fibrosis that ultimately progresses to complications of liver disease and accounts for much of the morbidity and mortality in that population. Survodutide will execute the so-called LIVERAGE program, LIVERAGE in patients with so-called F2 and F3 fibrotic liver disease, but not yet progressed to cirrhosis. The primary endpoint here will be the ones that Carol alluded to in the phase II program, not just resolution of MASH with no progression, but in fact that resolution of fibrosis, turning that process around as he described. The second of the two programs, so-called LIVERAGE -Cirrhosis with even more severe disease. This is F4 disease or cirrhosis where these individuals not only have hepatic complications, but in fact their morbidity and mortality is directed at complications of liver disease.
So as you can see, liver cirrhosis is not simply a measurement of the progression of liver disease, but an outcomes trial, the time to first occurrence of these serious liver-related morbidities. So remember, all of this was initiated on the background of what I would consider groundbreaking phase II, the results, what he showed you in terms of regression of fibrosis. And phase I study that was completed in a population with cirrhosis. All of these were data presented last year in June at the European Association for the Study of Liver Diseases. So we believe, and I know our colleagues at Boehringer Ingelheim are fully supportive of this approach to the development of Survodutide.
It offers the potential to establish itself not only as a leading therapy for overweight and obesity, the first GLP-1 glucagon dual agonist to be registered in Europe and the United States if plans proceed as I've outlined. It's a robust program as described here. It leverages this unique mechanism of action, takes what's learned from the comprehensive phase II program, builds it into the SYNCHRONIZE and LIVERAGE programs, which are actually bridged by one other study, so-called SYNCHRONIZE MASH, which is an intervention for the treatment of the disease of obesity, but in individuals with coexisting MASH or the liver disease associated with steatohepatitis. So they will get an early glimpse of what the potential impact is, even in those with less severe liver disease in the setting of overweight and obesity.
These studies and this entire program include not only interventions for overweight and obesity, but also individuals with Type 2 diabetes, MASH, and obviously in the large cardiovascular trial, individuals at high risk for the complications that result from the threat to the heart component that Carol described. So this program and the pre-existing comprehensive phase II data give us the confidence that this deliberately designed biased to GLP-1, eight to one GLP-1 to glucagon dual agonist program offers the potential to establish Survodutide not only as a therapy for the treatment of these diseases, but as a potential preferred therapeutic option, particularly for those with overweight and obesity co-affected by or complicated by associated liver disease. So with that, we're making good time. Rarely do people complain when a program is ahead of schedule. So I'd like to welcome Adam Lange back up with Adam and Carol.
Please join us.
Carol and Adam, please join us. So before we move on to the next section on Amylin and petrelintide side, we would like to do a Q&A focusing specifically on the Survodutide program and topics related to that. We have handheld mics over here and here. So please raise your question, raise your hand, and we will pass along the mics. Thomas, you can go first. I saw your hand.
Yes, thank you. Thomas Baumers from ECB. So just on Survodutide, so the commercial landscape and also recent pricing dynamics. So how should we think about optimal positioning for Survodutide? Is there sort of a credible path here for the program to maybe more evolve into a premium priced MASH therapy rather than targeting obesity? Thank you.
You want to start?
Yeah.
So of course, this is a program that is being developed and commercialized by Boehringer Ingelheim. People just receive high single to low double digit royalties. And it's for them to comment on the specifics around the pricing strategies and go-to-market. But as both Carol and David alluded to, it's quite clear that where we see this opportunity is, of course, not only for weight loss agent, but also to really make a breakthrough therapy for people with MASH, which speaks a little bit perhaps into the segments that Eric talks about, the prescriber-driven segments where you have a key understanding of the need from a comorbidity perspective. And thus that may also form some pricing considerations. But we cannot comment on their pricing considerations.
But, Thomas, I'll add that clinically, I think the success of Smetram in the U.S., which obviously does not compare, at least in terms of magnitude of effect, shows the desire for treatment in this space, which our BI colleagues clearly recognize. Not to forget too that MASH type is approved in Asia and China. And all indications are this is something that that population is turning to. So I think from a former clinician, now a pharma guy perspective, clearly an unmet need. And maybe Carol, comment on what you're seeing in terms of the need or the desire to fill this position in your clinic.
Yeah. And I think the problem is that people have not been diagnosed with liver disease.
When you actually come into a system, be it primary care and primary care doctor, really the ones driving the system, when they now suddenly make a diagnosis and say to you, it turns out now with our non-invasive tests, you also have liver disease, which they never thought about. It's highly motivating for patients. And it also really comes into that metabolic health gain that people will actually continue a treatment for. So I think this is a real opportunity. Yeah.
Let's go to the next one. Kristy, go ahead. Yeah.
Hi there. Kristy Ross-Stewart from BNP Paribas. So one for Professor le Roux on the receptor chemistry of Survodutide. Your slide mentioned the potency was kind of eight to one on GLP-1 to glucagon. We've obviously seen GLP-1 only receptor agonists have a benefit on fibrosis, but without the glucagon agonism.
Can you elaborate on the benefit of also hitting the glucagon receptor, but also whether you believe that kind of eight to one ratio is optimal and actually whether that will kind of confer a meaningfully differentiated effect on the liver disease versus a pure GLP-1?
I think this ratio does appear to be optimal because what you have is you've got many of the upsides of GLP-1, you have the upsides of glucagon, but we do not see any of the downsides of glucagon. That's why I think the ratio is so important. But what we do see if we actually look at data only driven by GLP-1 based therapies, that the fibrosis appears to be weight loss dependent. That means you've reduced adipocyte mass in the liver, and therefore it allows the liver to recover.
What you now see when you actually have a treatment such as Survodutide, you have all the benefits of the weight loss. So you have the reduction in adipocyte mass, but you have benefits on fibrosis that goes beyond what you would expect. And that's why we see those graphs being substantially different. So the glucagon receptor really makes a difference. But it's not pulling the wagon on its own because it has the benefit of GLP-1. And I think this ratio, which was specifically designed, appears to be an optimal ratio.
Yes. We had a hand over here.
Thank you, Xian from UBS. Maybe the first two questions, please. The first one, maybe just follow up on the previous question, is that you basically mentioned having this glucagon component, you have extra liver benefit on top of the normal GLP-1.
Just wondering, what other sort of data supporting, let's say, per percentage of weight loss, having the glucagon component have extra liver benefit versus your GLP-1? Because we do also see this correlation generally with weight loss as well. So that's the first question. And the second one is just wondering, you also have the phase III ongoing for F4. So just wondering, given previously this is really a hard bar and some of the GLP-1 hasn't been successful, just wondering what gives you the confidence there? Thank you.
So maybe if I take the last one. So the F4 fibrosis where patients have cirrhosis now compensated cirrhosis. I'm not the clinical investigator in that study. I'm the clinical investigator for the Survodutide one. So I give you an opinion as somebody in the field rather than an investigator in that study. I think it is ambitious.
But I think the data that they have so far supports that ambition. And that is something that is also one of these halo effects. If you can actually take patients who previously have been thought of almost now entering into a palliative motion, and you can show that you can actually not only slow it down, but you can reverse it, that would be very, very impressive. You saw that the primary outcome there was not only liver death, but also all-cause mortality. And remember that what we see with a lot of these treatments now, we see that all-cause mortality is really one of the most intriguing things because all-cause mortality is not only driven by reduction in cardiovascular events, it's also driven by reduction in infectious deaths.
And that's something that, again, is, we're learning how these compounds are reducing inflammation and allowing patients to actually deal with infection much better. Now, again, if you think about that cohort of patients who have F4 cirrhosis, why do people die? What's written on the death certificate? It's not a very often liver failure. They died from infection, they died from cardiovascular events. And I think that is part of that ambition. So I think that is the right way to go. And these are one of these things that actually really changes the space. And you know what? If it turns out that that study is neutral, then that would be a massive disappointment for many people in the room. I get that. But for us as clinicians, we go, wow, we have so little to help those patients.
And now we actually have something that not only is going to be safe, but those patients are coming back and say, for the first time in my life, I can play with my children. Not my life. For the first time again, I can play with my children. I can pick things up from the floor. My functionality is so much better. And that's what we see is quality of life with these. And I would expect the same to come out with a Survodutide study. It's the quality of life is not driven by the mental component. So we do not make people thin and we do not make them happy. But what we do do is we make them healthier and we make them more functional. And that's what drives quality of life.
So I think those are why I think it's a good program and that's what I would expect to see.
Yeah. A quick comment on the glucagon component. I started my ill-fated metabolism career studying this sort of forgotten hormone, glucagon. Low-dose glucagon infusion, low exposure has effects on energy expenditure. Obviously, these effects on lipolysis and fat deposition and clearance. When high-dose glucagon exposure obviously can raise plasma glucose, can increase the likelihood of GI side effects. So getting that balance right, having given emergency doses of glucagon, giving high-dose glucagon infusion, you sort of see what happens with too much, just enough or getting this just right, a bit of Goldilocks, I guess, is a tough needle to thread. But I think a long history that that low-dose glucagon exposure has these salutary effects.
All right. Thank you, David. Thank you, Carol. And thanks for the questions, Xian.
I think we have time for one last question before we need to move on. So, Jacob, go ahead.
Yeah. Hi there. And thanks for my question. Jacob Mekhael from KBC Securities. I have a bit of a technical question, if I may, since we have the scientists here. On Survodutide and the fibrosis data that you shared, 38.6% looks really good, but this was post-hoc beta. So, I'm curious, how would you expect that to evolve when looking at intention to treat in phase III, given that this is what the FDA will look at for the approval? And do you think this level can be maintained or should we factor in a drop? And if so, what's the magnitude? If you can give us any indication. Thanks.
So, certainly from my side, and remember, because this is some biopsy data, so biopsies before and biopsies afterwards.
And so therefore, the data has been collected prospectively, but then, of course, analyzed. And it's almost like now when I speak to colleagues at Zealand and others, I say to them, almost like the regulator is the easiest bar to get across, because people didn't actually think this was possible. So actually getting it over the regulatory bar is pretty easy. Now it's like, how do you actually turn this into value for the provider like me or for the patient, but specifically for the payer? So I think those numbers, I think if we see anything above 50%, that would be very impressive. But I think we are in that ballpark, even on an intention to treat analysis. Thank you.
Thank you, Carol. And thanks, Jacob, for the question. I think we are now at the time where we will move on to the next section on Amylin.
So David, introduce them and the external speakers first.
In my role as turning the slides over to our outside speakers. So it's my pleasure to introduce this next section. And we'll change gears from the incretin-based therapies and Survodutide to the Amylin-based therapies and the opportunity to further leverage this emerging class. It's my pleasure to introduce two colleagues, both of whom I've known for a couple of years. Jonathan Roth joins us. He's a recognized leader and an expert in the sci
ence of Amylin. Jonathan and I work together at Amylin Pharmaceuticals, a company named after this peptide. And his work in particular focused on really groundbreaking efforts to describe the unique leptin sensitizing effects of Amylin agonism, much of that completed during his time at Amylin Pharmaceuticals.
Following Jonathan's discussion on the science of Amylin and a little deeper dive into this understanding of leptin biology, Professor Louis Aronne will join us again. Thanks for rejoining us from two years ago. Lou is the Weill Professor of Clinical Medicine at Weill Cornell Medical College. He has spent nearly four decades of his clinical research time in the clinical management of obesity and metabolic health. As he often says, I was doing this before it was cool. Experienced clinician treats a significant number of individuals in their metabolism center and was, in fact, a principal investigator leading the groundbreaking initial trials of pramlintide, the original Amylin agonist for obesity. So Lou, thanks for rejoining us. I'll turn it over to John.
Thank you, David. So to frame today's presentation, this slide summarizes key milestones in the discovery and development of Amylin in metabolic diseases.
The notion of islet hyalinization in the pancreas of diabetic patients was known since the early 1900s, and in 1987, two independent research groups purified and characterized these deposits and found that Amylin was a major component. The potential therapeutic role of Amylin emerged from understanding that Amylin was actually also a beta cell secreted hormone, having synergistic effects with insulin. Insulin is, of course, the master regulator of glucose disposal, and Amylin complements the effects of insulin in three important ways. It reduces food intake by increasing satiety. It slows the rate of gastric emptying from the stomach to the small intestine, and it reduces post-prandial glucagon excursions. These properties led Amylin Pharmaceuticals to develop a stable, non-aggregating form of Amylin known as pramlintide for use in insulin-using diabetics.
In Type 1 and Type 2 insulin-using diabetics, Amylin agonism was shown to meaningfully reduce HbA1c levels and to decrease post-prandial hyperglycemia, enabling these patients to lower their total daily insulin dosage. The FDA ultimately approved SYMLIN for diabetes in 2005. One of the interesting observations during the diabetes program was that some of these patients lost weight, which was unusual in the insulin-using population that would typically gain some weight. That led Amylin to begin exploring pramlintide as a monotherapy for diabetes in obese non-diabetic individuals. In short-term clinical studies, pramlintide treatment was shown to reduce 24-hour caloric intake, reduce meal size, and improve binge eating scores. In longer-term studies, pramlintide was able to sustain weight loss all the way out to 12 months.
An interesting observation in these studies was, or an interesting observation that I'll highlight, is that Amylin agonism appears to restore responsiveness to leptin. And a proof of concept study where subjects took the combination of pramlintide and metreleptin, they achieved double-digit weight loss, which at the time was considered quite impressive. Around the same time, GLP-1s, though, were on the market, getting approved, having benefits in diabetes and obesity. And because pramlintide needed to be injected multiple times a day, interest in this modality diminished for almost a decade. And this dark winter of Amylin agonism continued until the advent of long-acting Amylin analogues came to light. So Cagrilintide demonstrated significant weight loss in individuals with overweight and obesity, as did petrelintide, which also had a very favorable gastrointestinal tolerability profile.
Finally, the fixed dose combination of a long-acting Amylin agonist and a long-acting GLP-1 agonist in CagriSema showed greater weight loss than one can achieve with either agent alone, renewing interest in Amylin as a modality for obesity. Let's take a look at the structure of Amylin and how it can be improved upon as a pharmaceutical. Amylin is co-secreted with insulin from pancreatic beta cells in response to nutrient intake. Native Amylin, though, is not suitable for clinical use because it has strong fibrillating properties. These properties have been attributed to the amyloidogenic region, spanning amino acids 24 through 29. Pramlintide incorporated proline substitutions at amino acids 25, 28, and 29, rendering the molecule non-amyloidogenic. All modern long-acting Amylins have incorporated modifications in this region.
At the other end of the molecule, there is a disulfide bridge between cysteines 2 and 7, which are absolutely necessary for proper folding of the molecule and high-affinity receptor binding. All modern Amylin analogs have left this region reasonably intact. Now, the half-life of native Amylin was only 12 minutes, and incorporating these proline substitutions merely extended it to about an hour, and you still needed to inject it multiple times a day. Modern long-acting Amylins have incorporated various lipidation technologies to extend the half-life, and therefore, these agents need only be injected once per week, so the Amylin receptor is part of the calcitonin receptor family, and there's multiple different receptors and subunits, and the properties of the receptor that confer ligand specificity are summarized on this slide. The Amylin receptor is a member of the G-protein-coupled receptor.
And it is formed from a base calcitonin receptor along with the co-expression of one of three receptor activity modifying proteins to form either the AMY1R, the AMY2R, or the AMY3R receptor. Let's take a look at how incorporating these RAMPs with the calcitonin receptor serves as a pharmacological switch, modifying the potency of agonists like human Amylin and human calcitonin at these receptors. Human calcitonin is highly potent at its own receptor. But you can see from the numbers below that as you incorporate RAMP1 and RAMP3, potency is markedly reduced. On the other hand, human Amylin is only a weak agonist at the calcitonin receptor. But in the presence AMY1R and AMY3R, potency is quite improved. Pramlintide is more of a pure agonist at the AMY1R and AMY3R receptors.
But more modern long-acting Amylins incorporate activity at both the calcitonin receptor and the Amylin receptors as both parts of this receptor complex are being found to be considered important for weight loss. This pharmacological system also ensures that Amylin agonists do not bind meaningfully to other receptor family members. For example, the calcitonin-like receptor, in the presence of either RAMP1 or RAMP2 to form the CGRP receptor or the AM1R , Amylin agonists do not have meaningful activity at these receptors and are more than a thousand-fold less potent than their endogenous agonists. This has important implications from a side effect profile as activation of the CGRP receptor is potentially involved in migraine attacks, and activating the AM1R may carry some oncogenic risks. This slide summarizes physiological and pharmacological effects of Amylin receptor activation spanning decades of research across multiple laboratories.
Recall that the key mechanisms of Amylin are to decrease food intake by increasing satiety, slowing the rate of gastric emptying, and decreasing glucagon, and all of these are mediated via the central nervous system. Perhaps the most well-studied portion of this is the hindbrain area postrema. The effects to improve satiety and reduce body weight are mediated by the area postrema, activating upstream regions in the midbrain and ultimately in the forebrain hypothalamus, and it is activation of this upstream pathway that modulates leptin sensitivity, energy expenditure, and favorable effects upon body composition. The effects of Amylin to decrease, to slow gastric emptying and decrease glucagon are also mediated via the hindbrain area postrema, but in this case, it's through vagal afferents that are terminating either in the gastric wall of the stomach or on alpha cells in the pancreas.
Amylin also has beneficial effects on other target organs. For example, it decreases glucose output from the liver, and in terms of adipose tissue, reduces fat cell accumulation and improves insulin sensitivity. While the previous slide focused on the specific effects of Amylin, advances in both endocrine and neuroscience research have deepened our understanding in the multihormonal regulation of energy homeostasis, and briefly, you have short-term hunger signals such as ghrelin secreted from the stomach, short-term satiety signals like pancreatic Amylin, and anorexic peptides such as PYY3-36, GLP-1, and GIP from the gut. And all of these interact with long-term signals of adiposity, the most important of which is leptin. Ordinarily, all these systems work together harmoniously, helping you maintain a healthy and stable body weight, but under conditions like obesity, it becomes dysregulated.
Much of this can be attributed to your prevailing levels of leptin and its effects upon the brain. Leptin is produced and secreted by adipocytes in direct proportion to your adipose stores. Let's consider how three different levels of leptin are going to impact your hunger and your body weight. The first of these emerged from the discovery of leptin in the early 1990s, where it was found that genetic mutations such as OB/OB in mice or various leptin mutations in humans were associated with a marked and unchecked increase in appetite, which has led to massive obesity in these individuals and metabolic diseases. Metreleptin replacement therapy rapidly reversed the effects on body weight and metabolic disease and was considered to be life-saving in these individuals. Individuals that can produce leptin can also achieve a low leptin state.
For example, if you go on a diet, your fat cells are going to shrink. And that's going to reduce your circulating levels of leptin. What happens then is it signals to the brain to increase appetite, to return your body weight to where it was, and to slow your metabolic rate to conserve energy. Both of these features are one of the reasons why diet-induced weight loss alone is so difficult. Because not only are you fighting powerful hunger signals, but you're doing so against the background of reduced metabolic rate. At healthy body weight and levels of adiposity, your appetite remains in check because you have healthful circulating levels of leptin. Your metabolism is also stable. Or it can even increase, say, it's around the holidays and you've temporarily overeaten, you can still return yourself back to a normal body weight.
The problem emerges when the brain is constantly bathed in these high levels of leptin, and what happens is, as you keep eating, the fat cells expand, more and more leptin gets secreted, and the brain eventually stops listening to this signal, and this is called leptin resistance, and key adaptations include reduced transport of leptin across the blood-brain barrier, decreases in leptin receptor number, and an increase in intracellular signals that turn off leptin receptor signaling. It is, in essence, a state of false starvation where, despite abundant nutrient resources, you have increased appetite, decreased metabolism, leading to further obesity, diabetes, and ultimately MASH, so given this critical role of leptin as a master regulator of energy homeostasis, agents that could restore sensitivity to leptin would be highly desirable, and against this multihormonal framework, we began exploring whether Amylin agonism could restore sensitivity to leptin.
In this first study, diet-induced obese rats were treated with either vehicle or Amylin. A third treatment group did not receive Amylin but was only allowed to consume the daily food intake of the Amylin-treated group. The importance of this pair-fed control group is that it enables you to dissociate direct effects of the drug from indirect effects that are due simply to caloric restriction. What you see in this study is that Amylin-treated rats lose about 11% body weight, and you have similar weight loss in the dieting control group, implying that caloric restriction is the primary driver for weight loss, but when you start looking at mechanistic endpoints, important differences begin to emerge, so although both the Amylin and the dieting group experience a similar drop in leptin levels, you can see that the Amylin treatment group loses almost threefold the amount of fat as the dieting group.
Second, if you look at the energy expenditure in these animals, you get the expected counter-regulatory decline in metabolic rate that I just mentioned, but Emillen-treated animals maintain or even have a slightly elevated metabolic rate relative to vehicle controls, and finally, when we measure hypothalamic satiety signals known to be directly downstream of leptin, we find that signals like pro-opiomelanocortin protein are twofold higher in the Emillen-treated group relative to the vehicle group, so collectively, all of these are hallmarks of improved leptin signaling, and they suggest that Emillen could be a leptin sensitizer. To formally test this hypothesis, we conducted a combination study, so in this study, there were four groups of rats. One was treated with vehicle, one with Emillen monotherapy, one with leptin monotherapy, and one with a combination of Emillen and leptin.
You can see that in blue, leptin monotherapy has no effect on food intake or body weight because these are obese animals and they're leptin resistant. Amylin reduced food intake by 25% and body weight by about 6%. And when you take this ineffective dose of Amylin, ineffective dose of leptin, and combine it with a moderately effective dose of Amylin, you get up to a 50% decrease in cumulative food intake and a 12% reduction in body weight. This finding has been reproduced across multiple laboratories. And true pharmacological synergy was demonstrated in a number of multi-dose combination studies. Some of the underlying mechanisms included that Amylin would restore hypothalamic leptin signaling and augment leptin signaling in the hindbrain. Additionally, Amylin treatment increased leptin receptor number in the hypothalamus and also increased the release of known leptin synergizers like interleukin-6 in the hypothalamus.
To test whether these effects would translate into the clinic, a phase II proof of concept study was conducted. The design of this study was as follows. During a four-week lead-in period, subjects were treated with petrelintide monotherapy. They needed to lose between 2% and 8% of their body weight, at which time they entered into the randomization stage for 20 weeks where they either remained on petrelintide, switched to leptin monotherapy, or received a combination of petrelintide and metreleptin. What you see here is that during the lead-in, they lost about 4% body weight. In the monotherapy arms, weight loss began to plateau at about 6- 7%. By contrast, weight loss in the petrelintide plus metreleptin treatment group experienced more rapid weight loss. They ended up at around 13% after 20 weeks of treatment.
Weight loss did not appear to have yet plateaued and was statistically significantly different from either of the monotherapy arms. When you look at this figure on the right compared to the figure on the left, you see that Amylin agonism restores leptin responsiveness in diet-induced rats and in humans. We've heard about GLP-1 a number of times in today's presentation. Given its use in obesity and diabetes, it's useful to compare some of its core effects to those of Amylin. Both peptides decrease food intake, but they do so in a qualitatively different manner. Amylin is a powerful meal termination or satiety signal. With Amylin administration, what happens is you consume the same number of meals each day. The size of the meals is much smaller, owing to a rapid onset of fullness, which is prolonged.
In the case of GLP-1, it's a different profile. GLP-1 reduces food intake by decreasing the number of meals that are taken. And it implies that there is less food-seeking behavior ongoing. Also, mechanistic studies suggest that the quality of the weight loss is different. For example, Amylin-induced weight loss is associated with improved leptin sensitivity. GLP-1 does not seem to share this attribute, at least in preclinical studies. We know that both of these are useful at improving glycemic control through their effects on food intake, gastric emptying, and to reduce glucagon. But a major differentiating feature between the two is that GLP-1 is also an incretin hormone. So following consumption of nutrients, it is released from intestinal L-cells and acts directly upon its receptor on beta cells to increase insulin release only in the presence of elevated glucose levels.
A lot of these differences between the molecules are attributable to differential activation of brain pathways. And we've discussed Amylin activation of the area postrema, leptin pathways, more satiation satiety-inducing pathways. In contrast, the effects of GLP-1 are more distributed. And it appears to act much more on appetite-suppressing circuitry. Potential clinical implications of these differences are that reducing food intake with Amylin by increasing satiety may lead to a more favorable patient experience where you have durable reduction in body weight with a more optimal side effect profile, less discontinuation, and less GI side effects relative to GLP-1. So in summary, Amylin is a pancreatic hormone that helps regulate meal size and promote fullness. The Amylin receptor system is quite complex, but it enables broad and coordinated physiological effects.
Importantly, Amylin can restore sensitivity to leptin, a key satiety hormone, and its pathways and support the potential for healthier long-term energy balance. And finally, Amylin is quite distinct from GLP-1, increasing satiety and driving earlier fullness rather than decreasing food-seeking behaviors. Thank you for your attention. And it's my pleasure to turn it over to you, Lou.
Thanks very much, Jonathan. And it's really a pleasure and an honor to be able to speak to you today about Amylin and its role in the clinical treatment of obesity. It's only been how long, Steve? David, 20 years since we started doing this. It's pretty amazing to be here talking about this because we recognized when we knew from the animal studies. But when we first saw pramlintide and the results when we would treat people clinically with it, we saw weight loss.
We saw that exenatide would make people vomit before they would lose weight, but pramlintide, despite the fact that it was TID, it worked, even if you gave it twice a day or even once a day, and so it was kind of mystifying when that pathway, the Amylin pathway, was not pursued further, so things have worked out OK. We have a very robust field, but it's taken kind of a 20-year detour to get to this point, and fortunately, a number of us don't get frustrated very easily. We keep going. This is one of the earliest clinical trials we did. Dr. Smith, who's in the audience, led this with a number of us involved, and this was the II-B trial of pramlintide in people with obesity but not diabetes, and you can see there was very good weight loss, maybe not compared to what we're seeing now.
But this is quite reasonable weight loss. At 12 months, 40% of the participants who received 120 micrograms three times a day, which was the standard dose for the treatment of those who were on insulin, lost 10% or more of their body weight versus just 12% of those on placebo. So a very reasonable improvement in outcomes. And yet, it was not pursued by the company that bought this asset from Amylin Pharmaceuticals when the company was sold. And again, it was a little bit of a mystery. But that was their decision. But you see that 20 years ago, we could have had some interesting things going on. One thing I'll point out is that we also did a very small trial where we added it to appetite suppressants that were available at the time. And some are still available.
We found that we got additional weight loss. Again, we could have been where we are now, close to where we are now, a long time ago. When we look at Cagrilintide, which really is leading right now in the data, we see 11.8% weight loss in the phase III REDEFINE trial where it was compared to semaglutide and the combination of Cagrilintide and semaglutide together. This is very reasonable weight loss and far better than what we saw with pramlintide. You'll recall Cagrilintide is a once-weekly combination. Now, I'll point out that in a prior phase IIa trial, higher doses of Cagrilintide were used as much as 4.5 milligrams. That showed even greater weight loss. It was close to the semaglutide result.
So in my opinion, and I've held this opinion for some time, we'd be better served using more of the Amylin analog and less of the GLP-1. I think that as we move forward, we're going to see that that strategy is going to work better because Amylin analogs are better tolerated. I'm going to show you that data in one second. But they seem to be better tolerated. And they can enhance the weight loss seen with semaglutide. It's going to take a few more studies to work this out. But I'm very excited that we are going to see it soon. So here is the data looking at adverse events. And you can see in dark blue, Cagrilintide, in light blue, semaglutide, in gray, placebo. And it's clear that diarrhea, not quite half.
So I'm sorry, nausea, not quite half, diarrhea, about half, vomiting, about a third, less than a third, and constipation, somewhat less, and if you look at what stops people from taking these medicines, I would say that vomiting is the number one problem. When people get nauseated, they can deal with that. They have diarrhea. They can deal with that, but vomiting, that can be a problem. It's a big social problem. All of these can be a problem, but vomiting is the thing that we see in New York City. I don't know what it is here in London or in Dublin, but that's the thing that really is a showstopper, and we've made some progress using ondansetron, the anti-nausea drug, but I think the fact that the vomiting is so much lower is pointing to the advantage of using an Amylin analog.
Now, here we see the severity of these adverse events, and you can see that not only did we have fewer, but they were also not as severe. And in the greenish color are the mild ones, the incidence of mild, in yellow, moderate, and red, severe. And just comparing the Cagrilintide and the semaglutide, you can see that the peaks are much, much lower. And in particular, look at the vomiting. There are very, very few events compared to those with semaglutide, so I think it is quite clear that this is minimally disruptive to daily life. And I'm optimistic that Amylin analogs like Cagrilintide, petrelintide, and others will move forward. In the trials of Cagrilintide and semaglutide, we see that there's an improvement in cardiovascular risk factors. We still don't have the CVOT that we have with semaglutide alone.
One interesting point is that not only do we see an improvement in systolic and diastolic blood pressure, but also a reduction in pulse. One of the criticisms and one of the things that we have always looked out for with our GLP-1 analogs is the increase in pulse rate. You can see that with semaglutide in this trial, there was an increase of about 3½-4 beats per minute. With Cagrilintide, it was lower than seen with placebo. That's because it doesn't hit the SA node. That's number one. Number two, there's greater weight loss. That tends to reduce pulse. When we look at the change in lipids, not that big a change, but certainly no worse.
When we look at the reduction in C-reactive protein, we see a very nice improvement, significantly greater than placebo, maybe not as great as semaglutide. So all of the cardiovascular endpoints that we're looking for are improved. And this would make us enthusiastic that with an Amylin analog alone, like Cagrilintide, that we might see an improvement in a CVOT trial, a reduction in outcomes. Now, here's data on a new compound, retatrutide, phase II trial from Eli Lilly. And saying that it reinforced the potential of Amylin as a standalone therapy for weight management, I think, is modest. So I want to focus on the left side of this slide. So first, let's look at placebo. We see that there was no weight loss. First of all, look at the base BMI, 38.7, and 75% women.
Now look at the incidence of the adverse events: nausea, vomiting, diarrhea, constipation, fatigue, and alopecia. Now look at, in the dotted line, the petrelintide three milligrams producing 12.5% weight loss. 12% placebo-subtracted weight loss. You'll see that the side effect profile is identical to placebo, except for constipation. Whenever people lose weight, they get constipated. We imagine it could be a change in the microbiome. It could be a change neurally in vagal nerve signals, trying to slow down the transit of food through the intestine to try to make you absorb as many nutrients as possible. Aside from that, it is virtually identical with a 12% weight loss. I mean, that is a major advance in treatment because the people who won't take it because of side effects, Carol and I deal with this every day, many times a day.
And these are the kinds of things that, so if you ask, how come cardiologists aren't prescribing GLP-1s? It's because they went into cardiology because they didn't want to deal with stool-related side effects. They didn't want to deal with nausea, vomiting, and all this other stuff. So that's one reason. And there are other reasons. Like in the U.S., you have to do prior authorizations. They think that they're supreme. They shouldn't have to ask an insurance company for coverage for one of the medicines they prescribe. So they just won't do it. So they send the patients to us so we can ask the insurance company to get coverage for the medicine. But those things will straighten out in the future. But what I'm pointing out is that I think that this is the kind of compound that could. This is not petrelintide.
I think petrelintide is going to look very similar, but these compounds, I think, are going to be more interesting to primary care physicians, then when we look at the rest of the slide, you can see that the tolerability data definitely suggests that dose escalation is warranted, and we've seen this with all the peptides, and then finally, on the right side, again, 79% female, BMI of 40, and dose titration over eight weeks, 16.5% weight loss, and side effect profile that is significantly greater. The incidence is greater, but still a very good result, and interestingly, you look at the weight loss here. It is in the same range as the GLP-1 and GLP-1 GIP category. Very, very interesting finding, so when it comes to Type 2 diabetes, there is some evidence that it may be better, may be better than using the GLP-1s.
Here we have weight loss over 32 weeks with Cagrilintide versus semaglutide from an earlier phase II trial in Type 2 diabetes. You can see greater weight loss. I believe that this is going to turn out to be from the insulin and leptin sensitization property of this Amylin analog. I think we're going to see this again and again. In fact, when we look at this comparison, this is not a head-to-head trial. On the left, we see weight loss with semaglutide in the diabetes trial, the step two diabetes trial. The mean body weight at baseline was 100 kilos. This is the obesity and Type 2 diabetes trial. You can see that with 2.4 milligrams of semaglutide, there was about 10.6% weight loss, 7.5% placebo-subtracted weight loss.
On the right, we see that Cagri plus SEMA. We see 15.7% weight loss, which is very, very robust. That's a 12.5% weight loss, which is right there with tirzepatide. This is, in my opinion, maybe a little bit more than tirzepatide when you try to read between the lines. Really, I don't want to call it transformational, but it is transformational because one of the issues, I mean, Dr. Leffro and I deal with this, is that there are more people than you would suspect who don't respond to the drugs we have now. In hypertension, eight categories. Diabetes, eight categories. Hyperlipidemia, eight categories. Obesity, one category. Maybe it's 1.5 because you have GLP and GIP. That's no way to treat people where every single person gets the same treatment. I can tell you, it doesn't work in everybody.
So I think that this is going to dramatically improve outcomes because there are people who are going to respond to just this, or people who are going to respond to Amylin analogs with just a whiff of a GLP-1. And they'll have fewer side effects. Their functioning will be even better. And things will be a lot better for all. So in conclusion, Amylin is a new modality that can expand the chronic weight management toolbox. It's kind of ironic because I look at it as maybe the original new modality. And it delivers weight loss that most people with overweight and obesity desire in that 10%-20% range. And I don't know if you've seen the World Health Organization guidelines that just came out. They're urging earlier treatment, earlier treatment of obesity. That's where it's at.
We're not going to be waiting until people have catastrophic outcomes in the future. We're going to start treating them early when they develop overweight, as soon as they develop complications. I mean, think about it. Who's going to sit around to develop diabetes when you could get treated potentially when you have prediabetes or when your blood pressure starts to go up? Are you going to take a blood pressure medicine that's not going to lower your blood pressure, that's not going to make you lose weight but controls your blood pressure? Or would you take something to lose weight that also lowers your blood pressure? I don't know about you, but I know what I would do.
I think combining Amylin with the other incretin-based therapies is going to be a very good way to go to get the kind of greater weight losses that will treat patients who are in that surgical range. I mean, personally, I see surgery, I don't want to say it's going to vanish, but it's going to be a last-line therapy, a very last-line therapy compared to even where it is now. And I think that the strategy, my personal belief, is that the strategy moving forward is going to be to maximize the Amylin-based compound and then add GLP-1s on top of that. I personally think, based on our experience and some of the animal data, that that will be the best strategy for the greatest weight loss and the greatest tolerability. So thank you very much for your attention. And I think we're there, we go. Yes.
Thanks a lot, Lou. So that was the first half of our Capital Markets Day. We are now ready for the break. And we'll reconvene at 3:45 P.M., so in roughly 45 minutes. Thanks a lot. Welcome back to what Adam led with, and that's our desire, particularly with the patent and IP program and the patent and IP fixed dose combination approaches that we are embracing, to not just lead in Amylin-based therapies and the FDC space. As Lou alluded to, the potential of FDCs with Amylin-based therapies is coming to realization. And in fact, years ago, Lou, Steven Smith, and I were part of studies, both preclinical and clinical, where we were combining the Amylin analogue pramlintide with other centrally acting agents like semaglutide, et cetera.
This concept has been in place for some time, but we now look to establish ourselves with the petrelintide program to lead and to deliver on what has been alluded to, not just efficacy, not just winning the weight loss Olympics, but actually creating a truly unique experience for individuals looking to manage their weight long term. That short-term on-off approach that has been unfortunately common is something we look to avoid and then to win in establishing this new foundation. As Eric alluded to, with lipids, with hypertension, with chronic diseases like type two diabetes, there is no single foundation. It takes multiple stones to establish that foundation. We believe petrelintide and Amylin-based therapies can be that next foundation. Many of you know the history of petrelintide, a unique long-acting Amylin analog that we still maintain has a clear best-in-class potential.
It has a human Amylin backbone, something important, as Jon Roth alluded to. Receptor engagement is an imperfect but still evolving science. And as I often argue, the balanced calcitonin Amylin one Amylin three receptor agonism is intentional. The body rarely puts receptors into systems that it doesn't need. And the hypothalamus, the hindbrain have all three receptors that we believe are critically important to leveraging the pharmacologic effects with petrelintide. So that balanced agonism is critical. Obviously, the physicochemical characteristics of petrelintide are key. It can be co-formulated. It can maintain stability in neutral pH solutions, something that has limited, as you know, the upper doses of GLP-1, which is formulated in an acidic environment.
And then finally, the extended half-life and the consistent half-life that we've observed in the early clinical trials, making it clearly suitable for once-weekly injection with very stable trough to peak variation. And we believe that may leverage into an improved tolerability profile beyond the native capacity of Amylin to be better tolerated. So what about early clinical data? Obviously, we are anxiously awaiting and look forward to the disclosure of the phase II results in the first quarter from ZUPREME-1.
But in this set of figures, not for comparison, but just to give you perspective, highlighted in blue, the early single ascending dose, that's when does the first dose become effective and what's the tolerability that this may give us at least an early indication on potential activity at its very low doses, 0.7 milligrams in this single ascending dose study resulted in a 3.2% weight loss, you know, comparable to, and I would say qualitatively as good as any of those we've listed on the right, the Gubra AbbVIe molecule, the Metsera molecule, Eloralintide, which was featured in Lou's presentation with its phase II results. No nausea and vomiting at that rate. So it suggests, or at that dose, which suggests that tolerability, particularly with appropriate dose escalation schemes, can be leveraged. So we were extremely encouraged by these early results.
And again, as we've highlighted, these studies are typically done in a predominantly male population in early phase. Ours was exclusively male with a near normal BMI, which in many respects is likely to mute the responses you see when you leverage higher BMIs and female participants who tend to lose more weight. You have to take that into mind when cross-comparing or at least trying to get a sense of the qualitative effects. So let's go on to the consistency of data. I think the totality of evidence is what gives us confidence. And now in working with our Roche colleagues to build out the entire clinical program that we'll talk a bit more about, this is what in great part reinforces our vision of a best-in-class molecule.
Fewer GI adverse events were actually reported with petrelintide versus placebo in the first part of the multiple ascending dose study, the six-week trial of 0.6 and 1.2 milligrams in part two, where we extended exposure, did dose escalation up to the higher doses. Recall that not only did we observe this magnitude of weight loss, but again, in a predominantly male cohort at a relatively lower mean BMI of around 29 or 30, and only a single participant actually discontinued due to AEs, which again supports our contention that the tolerability profile can set this apart in not only the Amylin class, but in weight loss therapies. That single patient also reported vomiting, and that was with a higher initial dose, not the dose that is currently being assessed in phase II.
We've also reported these data, and this is from the diabetes meetings in the U.S. earlier this year, which just shows you again, for qualitative assessment in those female participants in each of the dose arms of the part two multiple ascending dose study, on average, that group of females lost in excess of 11% of their body weight, substantially greater than what would be the at least arithmetic mean in the male cohorts. And you can see something else that I think warrants highlighting. Look at where the bars lie relative to baseline. Every single individual lost some weight in this relatively short exposure, which shows the consistency and the potential of a longer-term therapy with petrelintide. Again, indirect comparisons, I want to focus on and highlight the blue, which is petrelintide at its 4.8 and nine milligram dose and the AE profiles.
Just to give you a qualitative sense, these are the placebo-corrected weight reductions at 16 weeks, looking not only at our own part two multiple ascending dose, but also the phase II three trials for GLP-1 and Amylin, but looking at the 16-week data to give you a sense of what we think the run rate could teach us going into phase II and phase III. Certainly, we believe petrelintide demonstrated substantial and consistent and what we would argue is competitive weight loss from its lowest dose up to these higher doses. Tolerability, notable again, that only one participant discontinued treatment due to GI adverse events and virtually all actually followed the dose escalation scheme and continued and adhered to therapy.
Again, considering this is a predominantly male, relatively lower BMI population, to me, these data stand alone from our phase Ib to provide the compelling and strong evidence that further add to our excitement for the phase II data readouts coming in the first quarter and the potential for excellent efficacy, safety, and tolerability with petrelintide. So a reminder of the construct of ZUPREME-1, and this is the second key data catalyst beyond the Survodutide readouts in the first half of 2026. Obviously, there's a lot of activity, as Adam alluded to, in our 2026, 2027, 2028 and beyond timeframe. In the full phase II ZUPREME-1, demographic characteristics show a much more balanced male-to-female participation, higher, and I would say more consistent with longer-term clinical trials in overweight and obesity, a BMI of 37.
In phase III, we fully anticipate that populations will be identified that reflect those that seek weight-lowering therapies. About 60%-70% of weight-lowering therapies are sought by females, not males. Here, this gives us a clear line of sight not to, I'll say, pad the statistics, but rather assess the effects clearly in males and females that will enable phase III initiation in the second half of next year. Obviously, as was seen, I think clearly in the Cagrilintide high dose initial exposure data that we've learned from our phase I studies, it is important to include dose escalation, as we've done here, to not compromise one of the strengths of Amylin-based therapies, which is tolerability. So while many wish to run to the higher dose, as Carol alluded to, this is not a race to the finish.
It is actually about maximizing the effectiveness, but while not sacrificing some of the greater benefits for tolerability. And this study will provide us the necessary data to look at both the phase III program and the progress to phase III. So a reminder, ZUPREME-1 readout in the first quarter. Zupreme two, we expect the top line data from this study in those with overweight and obesity and coexistent type two diabetes in the second half of 2026. And a look forward in the partnership with Roche to the comprehensive phase III program with a clear focus first and foremost on the execution of the phase III -A program, the core program that will bring petrelintide to patients in need as quickly as possible.
Obviously, focusing on the U.S. and global markets, but understanding that the priority is to execute phase III and then a plan for more expansive phase III-B. I was stopped at the break asking about phase III-B plans. First and foremost, phase IIIa and then discussion and rapidly expand into the appropriate related comorbidities, looking at cardiovascular risk, pursuing positioning and mechanistic studies to better unfold the Amylin and the petrelintide story. So exciting days ahead. We're not running out of things to do at Zealand or in the Roche- Zealand Alliance. Also important that we are in the planning stages for the fixed dose combination. So petrelintide as foundational therapy will also serve to support petrelintide as a foundation in appropriate combinations. Lou alluded to clinical data that are already available in the partnership with Roche, adding the very effective GLP-1 GIP agonist, CT388.
This will serve not only as the first, we hope, of several fixed dose combinations, but it allows us to leverage other key strategic objectives noted on the right-hand side of this slide, confirming weight loss superiority of the combination versus either individual component alone. Secondly, to identify not only those doses that optimize weight loss, but continue to leverage the potential for an improved tolerability profile. As was alluded to in the CagriSema program, you step to maximal doses of both. Does that sacrifice the tolerability potential of a very potent and effective Amylin agonist? Would it be better to optimize or maximize the Amylin agonist and optimize the GLP-1 containing component? That will be in our minds as we look to planning this study program.
We believe this combination not only is exciting, but it offers the potential to provide greater weight loss efficacy, particularly for those people who seek higher degrees of weight loss, as alluded to in Eric's discussion of what the population is seeking. And secondly, to provide those added strengths of a GLP-1 or Amylin-based therapy in appropriate circumstances, like improving glycemic control, leveraging the GLP-1 component. We maintain incredible enthusiasm and excitement, as well as confidence in the petrelintide asset and program. This belief is grounded in the overall efficacy, safety, tolerability profile that I hope I've reviewed and outlined for you, and obviously will be the focus of readouts in the phase II program.
But these data are consistent, and we expect that phase II will provide us all the information necessary to leverage not only best-in-class potential, but what I think two years ago when we said 15%-20% weight loss is clearly achievable with foundational Amylin-based therapies. Now, with these data, the data from other programs, this has become a reality. It is not hypothetical anymore. There is exceptional tolerability potential with Amylin-based therapies and this unique mechanism that John reviewed that others have discussed, which is feel full faster. That's satiety feeling that isn't about food aversion or food avoidance, but is rather about continued food intake with a limit on that volume. And finally, targeting the weight loss that most people desire, as Eric alluded to, 10%-20% weight loss is currently the sweet spot for the vast majority of those seeking weight management.
That, while leveraging this unique patient experience and an unmatched patient profile or patient experience, is critical. The clinical package to date, I think, underscores the unique opportunity that we have communicated to you and the value proposition to establish petrelintide as the leading Amylin-based treatment, both as monotherapy and foundational approaches to weight management and in combination with effective therapies like CT388. With that, I appreciate your attention. I'd like to invite Adam, Adam, and Lou back up for Q&A. Thank you very much.
All right. We will now do a Q&A session focusing on the petrelintide program. If you have any questions, please raise your hand and we will pass along mics. Yeah.
Yes, thank you. This is Sushila from Kempen. You've mentioned in the past, it's not only about weight loss.
So how do you expect petrelintide to do on body composition or quality of weight also versus the other Amylin?
Yeah, I'm happy to start. So I think for us, obviously, the consistent preclinical readouts from most Amylin-based therapy programs have shown this difference in preserving lean mass, targeting fat mass. Jon Roth, in his discussion, showed some of the early data with pramlintide and the rat Amylin achieving the same thing. I think for us, given what's been observed with Cagrilintide, we're doing much more careful MR assessments in ZUPREME-1. This would be a value add, a nice to have, and certainly a hope that it could add to the benefits of an Amylin-based therapy. But obviously, effective weight loss, tolerability, and that experience come first for us.
Certainly, if we see improvements in, or at least maintenance in muscle mass, that would be a clear value add. I always say, even with inhibiting the myostatin inhibitors, the best muscle to have is the muscle you started with, in my personal opinion. Lou, I'd love to hear your comments as a clinician.
No, I agree that preventing the loss of lean mass is really going to turn out to be the way to go. And leptin sensitization, I think, could turn out to be a very good way to do this. In our early studies from back in the old days, leptin is one of the key modulators of skeletal muscle mass. And part of losing muscle has to do with low leptin levels.
So if we can keep leptin sensitivity up so that leptin activity is higher, whether the levels are low or high, should preserve lean mass and metabolic mass. So I'm enthusiastic about that.
Yes, looking forward to it. Thank you.
Thanks.
Yeah, go ahead.
I need the mic.
Yeah, we need one mic. Yep.
Thank you so much for taking our question, Yihan Li from Barclays. So I guess my question is really on Amylin's market potential. So to me, I feel like the key differentiations for Amylin versus GLP-1, the first one will be the tolerability. But as Dr. Roth said earlier, so it seems like the tolerability issue should be very minimal as long as the titration is low enough or with the dose reduction.
The second one will be the Amylin plus the satiety enhancement, as you emphasized in the presentation, versus the appetite suppression, just like GLP-1s. But again, in the CagriSema, we defined one study in the appendix. It seems like Cagrilintide showed generally similar incidences of decreased appetite versus semaglutide. I think I'm just curious, first of all, how clinically meaningful or relevant do you expect this regulating meal size to be for real-world positioning for these Amylin-based therapies? And how should we size the true commercial potential for Amylin class over the next decade? Thank you.
The only way to know is to do the study, right? I think that right now, when you look at how we're treating patients with GLP-1s, we're kind of oversuppressing their appetite and their interest in eating food. You've all heard of that.
Examples of that where people lose interest in, we have people who are food critics, put it that way, and we have to back off on the dose because they feel they can't be a food critic because they're not that interested in food with the currently available compounds, so I think that it'll be very interesting to see if we can change that. Are we going to? I don't know. I have a belief that we will, but I'm not certain that we will until we do it, and I'll add that, I mean, decreased appetite can be measured a number of ways. I've eaten and I've eaten enough, my appetite is decreased, or I don't wish to consume food. Both can be reported as measure terms for decreased appetite. I think importantly, both will work.
But as Adam alluded to, that could be a very different experience for those who look to eat, but eat less. And Adam, you'll comment on the market. No, but I would also add, and it has to a little bit align with how I introduced this talk today.
And Eric has also alluded to some of these observations. One thing is what you can do and what you can achieve by careful titration. But it is a little bit, if you think about a category, which is probably going to be the largest health category in the world, it's a strange conversation to have about can you tolerate it and how can I titrate you to be able to tolerate this therapy. And we argue that once you have alternatives, radically different alternatives that we believe Amylin will be, then you will not talk about can you tolerate it.
Then the conversation will be, will you accept it? Will you as a patient accept to have to go through all that struggle to achieve your weight loss? That's number one. So alternative therapies will change the conversation. It is not a natural conversation to have when you think about chronic therapy. Can you tolerate it? In my mind? And number two, with the weight loss experience, I think we underestimate how motivated people are to lose weight. And that's why we see this cyclic use of GLP-1s today, where people use them to lose weight. And then once you have achieved your weight loss, you are less motivated, you will accept less. We know that from any other weight loss program in history. Once you let go of the patient, they will regain weight, most of them, and they're back to square one. And that weight cycling is not healthy.
And if so, if we don't manage to get therapies that people stay on, then we will not achieve the health benefits. So we need to move beyond what we see today and dare to envision a different future, which is more suited into the lives that patients want to live and not the ones that we think they should. And we believe that is what Amylin can provide.
All right. Thanks a lot, Leon, for the question. We have a question here from Lucy. Go ahead.
Hi, Lucy Codrington from Jefferies. So just following on from that, you showed the data at the beginning where you showed the discontinuation rates due to AEs. And I just wondered, do you have a split for that between patients who are being seen by a prescriber, that segment, and the patients who are DTC or consumer-based?
Is it higher in the latter where you aren't being coached through the tolerability, or is that primarily the consumer base? Then the second question, you talked about the best-in-class profile and I understand your arguments for it. But I just guess, what are the chances that it's going to be differentiated enough that you would choose one Amylin over the other when there are two on the market and one of them is being marketed by Lilly?
If I should just start by addressing your first question, and you may have some other data available, but I would say I'm not sure we have those data that breaks down that experience between a very skilled prescriber versus a patient that received this product from a less skilled prescriber base.
But I have no doubt that if you are treated by a very skilled prescriber like Lou or Carol, you can have a much better experience on a GLP-1. And these guys also know how to encourage patients to stay on therapy, as Carol stated, compared to if you just seek these weight loss clinics. But today, the majority of patients are receiving treatments from these weight loss clinics. And that segment will grow in the future, as we heard Eric talk about. And it's coming back to not all patients. Actually, very few patients have the luxury of seeing people that are as skilled as the guys you hear from today. And we need to focus on those people. That is where the big commercial opportunity is. And it's also the big opportunity to actually truly have a global scale health impact. So that would be my first comment.
I don't know if you have. Sure. No, I agree. I think that when we're using these medicines, which are more tolerable, they have fewer side effects. I think it's going to be easier for everybody to prescribe. But the question about which one are you going to pick. I mean, in hypertension, there are over 100 drugs available. Are you aware of that? How many lipid-lowering drugs are there? And when you look at the weight regulating pathways, they're a lot more complicated than those pathways. So my guess is that if there are two or three drugs in a category, I'm sure that the sales team at Roche is itching to get at this problem. And at other companies as well. I'm guessing they can figure out how to help doctors to decide which one to prescribe.
I mean, you guys don't do that part, but I'm guessing that that's part of the equation. I mean, I just see in New York, we have Pfizer. Pfizer is there. I've been advising Pfizer for 15 years, and I see a number of the people on the marketing team. I take care of them, and there are people like that are losing their minds that they don't have a horse in the race, so I'm guessing that when you look at the size of the market, it's going to be $200 billion or something, or who knows what it is, but it's going to be massive, and right now, it's like this, so I think everybody would like an opportunity to convince doctors that their medicine is the best one. Yeah, we'll let you corner Morton and Eric at some point after we break up.
But I also think, Lucy, you point out an opportunity we have, which is these differentiating factors may not be huge, but they could be critically important. How simple is dose escalation? How likely is it that you will stay on maximal dose? I think for all the positives that came out of the lower petrelintide data, the rush to high dose clearly sort of blew up in our face, meaning going on six or nine milligrams gave you beyond GLP-1-like tolerability concerns, whereas their titration scheme, which may have sacrificed a few percentage points. But I know I, our development teams at Roche and at Zealand are excited to look at these opportunities back to the previous question, doing exit interviews to talk about the experience and then building that into mechanistic studies and phase III-B studies where we can bring it forth and say, here's the value.
I think of one other example, which is the thiazolidinediones, rosiglitazone, pioglitazone weren't that different, but there were small pieces to that, the lipid profile, some of the experiences using lower doses of one that ultimately helped differentiate. Both were widely utilized, but there were opportunities that I think we on the development medical commercial side are excited to leverage going forward. So, great question. Thanks.
Yeah, thanks a lot, Lucy. Any additional questions? Rajan over here, if we can get a mic.
Hi, it's Rajan Sharma from Goldman Sachs. Just a couple on petrelintide. So firstly, just thinking about if this does become more of a consumer market, will that influence how you think about a phase III trial?
I'm just thinking, would it be worth at some point, or would you consider running a head-to-head versus a GLP-1 to really hone in on that differentiation or maybe even a reference arm, even if it's not necessarily a regulatory requirement? And then second question, in the Eloralintide phase II, it looked like there was a fatigue signal that seemed to emerge. Do you think that there is a risk that that's a class effect? And specifically, could that be an effect with petrelintide as well? Thanks.
Maybe I can just start and handle one.
So on your first question, Rajan, I would say I think you're absolutely right that with the profile of petrelintide, which has this ability to make hopefully people feel full faster and have a better weight loss experience, it speaks directly into that consumer segment, which Eric also showed that 60% of all scripts today are patient-initiated. So what do you need to differentiate out there, considering that a lot of patients will have conversations around their weight loss experiences once these molecules get to market? That can be a very, very strong sentiment if you hear somebody having had a completely different weight loss experience on an Amylin versus on a GLP-1. So that sentiment around conversations among patients, we think, will be a major driver for success and early uptake.
And since it's really consumers or patients that are initiating most of the conversations, this is probably the area where you could see the fastest swing from one category to another because it doesn't necessarily go through the normal channel, starting with a key opinion leader and then down into the guideline, but actually start with patients, and they have a tendency to talk on social media. So we think we could actually have a very fast swing if we can ultimately, in the real world, provide those experiences that David has talked about today. And I think to your comment about head-to-head and the others, that is part of that phase III-B excitement that we share. But again, we're going to focus on III-A and get this to patients and providers.
I think Lou, he cringed when he said KOLs are no longer important, so I'll let him get the last word.
When you're doing clinical trials, patients are on a forced titration regimen, and we've seen this where people are eating literally nothing because they're sensitive to it, but they're on a dose that's higher than they probably need, and so what are they eating? Yogurt for breakfast and three ounces of chicken and three string beans for dinner, and they're exhausted. They come in the next time. They're exhausted. Of course, they are because they're getting no nutrition, so in my opinion, there are a number of people like that who are going to be mixed in, and they should be on a lower dose. As time goes on and we understand what's happening better, and when I say we understand, we know what's happening.
We just need a more adaptive trial design so that we can focus on side effect profile rather than maximum efficacy because that's what the trials are really focused on now.
I think it's important that the weight loss Olympics were both about speed and magnitude, and that's helpful in clinical trials. It's helpful for you to try to make judgments of the efficacy. Clinical reality and clinical trials are often not terribly well aligned, so thanks for that, Lou. Thanks for that, and on the second part of the question on fatigue, I guess it's also fair to say that, of course, we saw that in some of the treatment arms in the Eloralintide phase II trial, there were relatively high rates of fatigue. With petrelintide, we haven't seen that signal or that imbalance relative to placebo.
I'm quite confident that's the same with petrelintide in the REDEFINE-1 trial where Lou presented clinical data from.
Yeah. I think we have time for one last question before we need to move on. Kristy, go ahead. That's one.
Thanks. I'll be quick. Kristy Stewart from BNP Paribas. Just on the timelines, it showed that you're expecting phase III data for the petrelintide program in 2027-2028. So can you confirm that you'll be able to launch in 2029 at the earlier end of your kind of 2029-2030 estimation? And can you also just provide a quick comment on, I think the ZUPREME-2 timelines have shifted to 2H next year from mid-year? Just what has driven that change?
Yeah, so we can confirm that we are hyper-focused together with our colleagues at Roche to accelerate the program towards market.
And we will do our utmost to get it as soon as possible to patients. But we are not committing to a specific year right now, but 2029 is, of course, a possibility. And on the ZUPREME- 2, David.
Yeah, I think partly the challenges of recruiting a fairly challenging population who were essentially treatment naive in the setting of Type 2 diabetes was something that we obviously succeeded with. We announced recently that we've fully enrolled that trial, but it gave us more precision as to when last patient, last visit, and the data readout would be. So I don't see it as a seismic shift, but just a dose of honesty from us to you. But again, our efforts to initiate phase III are fully tied back to ZUPREME-1. That's what we're using as our guide forward.
ZUPREME-2 is a value add at this point, so it does not change the other timelines. All right. Excellent. Thank you, James.
And thanks a lot, Kristy, for the last question. We will now move on to the next section. So I will be handing over to Utpal to talk about our early stage efforts to build the world's most valuable metabolic health pipeline. Take it away.
Thank you, Adam. So super excited to be here, guys. The last 20 years, almost 20 years of my career has been synonymous with Lilly. And I have to say there are some key learnings about the discipline and target selection, following your conviction, not following like lemmings, your competition like lemmings. But the other part was about speed being the currency within the biotech ecosystem.
So after having spent two decades there, when the opportunity at Zealand came open, I have to say it was a no-brainer to join on several fronts. First, because the company has a deep-rooted heritage in peptide discovery and metabolic health for 25 years, number one. Number two, if you think about where we are today with Amylin, it's really because of the prophetic view of the landscape that this leadership team had to get us to where we are today. But more specifically, I think we're in a really crucial moment here today for Zealand. We have a combination of expertise with 25 years of incretin biology expertise coming together, a bold ambition to fundamentally impact human health and improve health span. Number three, the financial capital to deploy to invest both internally in research, but as well as access external innovation to complement our capabilities.
And finally, just the sheer volume of opportunities that exist today from a medicine creation standpoint that allow us to modulate biology that I have to say five years ago or 10 years ago were nothing more than just a dream. So my aim today is to show you that the unique insights that we have will help us reprogram metabolic health. This is not about doing symptoms. This is actually about affecting the fundamental systems to drive health span. So why us? Why now? And let's jump into that. After 25 years of working in the space, we have unique insights. These insights are feeding into our discovery engine that are driving our engine today. But what really makes us special is not just that.
Not only do we have 25 years of data that we're now going to see that you're going to see, we're going to start partnering with people to build machine learning models and AI/ML models to accelerate our idea to data cycle times, but our close integration with the medical. And this, I think, is a unique secret sauce. having worked across multiple pharma companies, is that integration across research and medical.
The expertise we have in discovery, as well as the expertise we have in medical, with the likes of David Kendall, who's worked at the ADA, Amylin, with the approval of the first generation Amylin therapeutics, with the likes of Steven Smith, who spent decades of his career, not to say anything about his age, but decades of his career working around the forward translation to therapeutics, as well as reverse translation, taking data from the clinic and taking it back to the bench scale for next generation discovery, and finally, Steven Johnson, who spent decades not only in industry, but in FDA and has put his eyes around 60 different NDAs, so you put all that together, I think we have a really unique, and I think, as Adam said, you could even say an unfair advantage compared to our competition.
Now, if that's not enough, we're on the verge of approving five approvals in the next five years. I just want to let that sit in for a little bit, okay? We're a company, when I first joined, of less than 400 people, and now we're committing to you that we're going to have five approvals in the next five years, so that's pretty significant and pretty incredible for any company, let alone a company of our size, so this unique experience has allowed us to address some of the hardest problems in the industry, so we're a company that does hard stuff. That's who we are, and that's what defines us as a company, and there are many examples of that, but let me just share a few. First and foremost, dasiglucagon.
Zealand was one of the first in the industry to stabilize glucagon in aqueous solution so that patients in the cases of emergency hypoglycemia could be administered the medicine directly without having to do an extemporaneous prep or solution prep prior to administration. We were able to solve the stability puzzle when many others struggled. Survodutide, you heard a great seminar today around the value of Survodutide. This is a hidden gem in the industry. It has the potential to deliver some pretty incredible efficacy from a weight loss standpoint, but really breakthrough efficacy in the case of liver disease. And it has the potential to be the first U.S. launch for a GLP glucagon-based therapy. Glepaglutide, the first long-acting GLP-2 analog that will be delivered in an autoinjector. And finally, we come to what our crown jewel is, which is petrelintide.
The ability to actually stabilize some of the and get around some of the long-standing issues around aggregation, solubility, and build a best-in-class molecule that is actually formulated at neutral pH that could allow us to do future fixed-dose combination studies with other products. Now, as a side note, I would encourage you to go check the patent literature for who had some of the early IP around GIP, GLP, as well as GGG, and those will additionally tell you how Zealand has routinely been the first in the industry to solve some very complex peptide engineering problems, so with this expertise, with this track record of being first, and with the insights that we have, we're going to redirect that to probably one of the biggest healthcare challenges in our world. We've all talked about obesity. That's the visible epidemic.
You've heard everyone talk about how important that is. But what I'm here to tell you about is, in addition to that, there is a hidden epidemic around metabolic health. Just in the U.S. alone, we have about 20 million patients who have metabolic dysfunction. On a personal note, I will tell you, as a person of South AXian descent, this is something that in my family is an issue. In spite of exercise, diet, everything, I know many in my family have metabolic dysfunction that put us at high risk for cardiovascular disease, Type 2 diabetes, MASH, and others. Current therapies work. They shrink the overall engine. But if you really go back and take a look at the data around CV outcomes from Lira, Dula, SEMA, it's not clear to me that the outcomes are correlating with weight loss. Clearly, reducing weight loss does deliver improved outcomes.
Does deliver more weight loss deliver better outcomes? The jury is still out for that, so when you combine the two, you realize that we have to address the obesity epidemic, but also fix the underlying machinery that's driving how we take in energy, how we store energy, and how we metabolize the energy. So what I want to share with you is how we're going to go about doing this, and my hope is to convince you that we're not just chasing the next big weight loss drug to get to 20% in two weeks. The reality shows that do that. Our goal is to actually address weight loss, but also get back to the fundamental systems that drive metabolic dysfunction. Our goal here really is around three prongs.
And we're going to go through each of these three prongs in more detail to tell you about the concept that we're exploring. As you can imagine, as I'm focused on discovery research, I'm not going to get into the individual targets, but more on the broader concepts that are driving our efforts. The first is around restoring crosstalk. And I just wish Carol could come back here and just repeat his talk again to speak about how Survodutide was a great example of that. And we'll get to that in a second. Second is around improving peripheral metabolic flexibility and capacity and thinking about weight-independent insulin sensitization. And finally, recognizing that all of these issues around metabolic dysfunction start in the brain, and we have to directly develop pharmacologies and therapeutics that target the brain. So let's start with the first pillar. You guys have seen this graph.
I think John did a really good job talking about the fact that under normal homeostasis conditions, all of these pathways are in very nice equilibrium with each other. What we've done with GLP-based therapies is taken one of the pathways and hit that really hard. If you take a step back and use an analogy of a sound equalizer, what we have done with current therapeutics, we've really dialed up the GLP-1. With that has come efficacy, but that's also come distortion, has come adverse effects. My thesis to you is that we can actually modulate multiple different pathways, not by hammering each one as hard as we can, but just by tickling the receptor to get enough efficacy without hitting the adverse effect ceilings.
And over time, as you add in the pharmacology in a single molecule, so a huge med chem effort, mind you, but in a single molecule, you can dial in the efficacy and dial out the adverse effects. The whole idea here is to build on the legacy that we have and see if we can actually treat the metabolic health as a system and tweak the different elements and the interdependencies across those different elements to restore metabolic balance and metabolic health. The second part of our strategy is directly targeting the brain. Historically, we have evolved to live in a feast and famine cycles. But obviously, with the modern environment, with constant surplus, that delicate balance of how insulin and leptin work in the brain has created a disconnect such that you have hyperinsulinemia, and you also have very high levels of leptin.
The brain, the hypothalamus in particular, as John talked about, becomes resistant, I should say, to a lot of the peripheral signals. Our goal is to develop therapeutics that fundamentally increase the sensitivity in the hypothalamus to these peripheral signals. But also fundamental to this is the fact that if you take a look at all of the emerging data, it's very clear, even for GLP-1-based therapies, that the brain is playing a fundamental role in driving weight loss and metabolic function, as well as playing a critical role in driving inflammation and immune response. Our focus is to directly target the brain. And you can imagine the kind of technologies that you would need for that to target the brain in a way to target the homeostatic pathways, but not go down the hedonistic or aversive pathways within the brain.
Finally, focused on our peripheral metabolic capacity and flexibility. Now, I like to use this analogy of an engine. GLP-based therapies have shrunk the engine, and that's helpful. When you shrink an engine, inherently, there's a level of efficiency associated with that. But the reality is more complex. If you think about the fuel injection system, the overall cylinders and whatnot within the engine, they're fundamentally clogged. Nothing has been done to affect that. All the insulin sensitization that you're seeing are weight-dependent insulin sensitization. Start with the liver. For Type 2 diabetes, you see that your hepatic glucose production is 2x plus what are normal physiological levels. With GLP-based therapies and all the GLP studies that you've seen published, typically, you'll see about maybe a 30%, give or take, improvement in your hepatic glucose production.
So still, under fasting conditions, you're seeing hepatic glucose production that's much higher than what's needed or should be happening. Why is that important? Because your beta cells, the next organ, are already impaired. And now with GLP-based therapies, not only are you continuing to get increased hepatic glucose production, but now you're taking a golden hammer to the beta cells, asking it to secrete more insulin, resulting in very likely its decay and deteriorating its health further. Then you go into something like your skeletal muscle. What do your GLP medicines do? The GLP therapeutics start reducing the overall energy. You start seeing reduction in muscle mass, a lean muscle mass loss. That's significant. That's reducing the overall peripheral metabolic capacity. Typically, muscles take in about 70% of your overall glucose within your body.
If you start shrinking the amount of muscle, that's fundamentally not a good thing from an overall metabolic capacity standpoint. Finally, the adipose tissue. Far, adipose tissue has always been thought of as a mechanism just to store energy. The reality is they're far more complex. You're starting to see some evidence with the current therapies that you reduce the adipose tissue. What you haven't done is increase the adipose insulin. You haven't fundamentally remodeled the adipose tissue or changed its insulin sensitivity. The only therapies that have ever shown to do that were TZDs ages ago, which had their own set of challenges. We need to come back and be able to directly target the adipose tissue and get to improving its overall insulin sensitivity.
If you put all of this together, the key theme here is not about weight loss Olympics, but getting to weight-independent insulin sensitization mechanisms that not only can you use as an add-on to GLP, but also you can use it in patients that are metabolically dysfunctional that have a BMI less than 25. So as you think about our three pillars, our hope is that by hitting these three between the crosstalk axis, targeting the brain, and targeting the peripheral weight-independent insulin sensitization, our hope is to deliver higher quality weight loss, deeper efficacy, more durability, get at some of the therapies that could potentially be disease-modifying in Type 1, Type 2 diabetes, as well as overall improve bone and muscle health. So this is great. That's where we aim to be. But to do this, you need molecular innovation.
You need good medicinal chemistry to actually make the therapies that you need to drive these outcomes. GLP-1s are a great example of this. The first GLP-1s were approved in 2005, and almost every four to five years since then, Lilly and Novo have gone back and forth developing better medicines from Lira to Dula to SEMA to Tirzepatide, but to make that happen requires two things. One, persistence, recognizing that you have to cannibalize your own innovation, otherwise others will. Number two, recognizing that you need advances in medicinal chemistry and molecular innovation to get to some of these advances of the biology. The stability and the DPP-4 resistance was important, half-life extension, certainly the oral delivery technologies for oral SEMA using SNAC-based formulations.
Finally, signal engineering using the GIP, GLP, as well as what you've seen with Survodutide, with GLP glucagon being one of the first. As John pointed out, this started well for Amylin. For a number of reasons listed above, there was actually about almost a two-and-a-half-decade-long winter from the first approval of pramlintide to probably later in this decade to get the next generation Amylin approved. There were a number of reasons for that. Some of them were on medicine creation. Some of them was really around the fact of not recognizing that this biology has market potential. Those efforts that we've invested in, the first that we've had around medicine creation, have also resulted in some pretty interesting molecules that we have in the clinic and will go in the clinic.
Kv1.3 is the potential to be a pipeline in a molecule where we're directly targeting overexpression and memory cell driving chronic inflammation and autoimmune disease. GIP will be going into the clinic, I think, sometime next year with the potential to provide not only enhanced weight loss, but increased adipose insulin sensitivity as well to allow a combination with other therapeutics. Now, if you take a step back, that's a lot. That's a lot that we're saying that we're going to do in terms of impacting human health, and that's a lot that we're committing to for a company our size. Key to this is going to be external innovation that augments our internal capabilities, and there are going to be three approaches for how we're going to access external innovation. First and foremost, we are going to expand our toolbox.
And you saw the first press release this morning around the use of oral therapeutics to complement our capabilities. That's just the start. And you're going to see a lot more of this because we're going to actually deploy the financial capital to increase the number of tools we have in our toolbox because we recognize that we need to expand the scope of the pharmacology that we're going to exploit. Number two, we're going to strengthen our platform. The 25 years of data, we're actually going to share that with some very key strategic partners to help them bring their data science and modeling expertise to build out these global models that we can then use to drive and accelerate our idea to data discovery cycle times.
And finally, also now we have the financial capital to fuel our pipeline by getting either clinically ready programs or near-clinically ready programs to supplement our pipeline. But let's talk first about expanding the toolbox. And our first example of that with oral therapeutics. We're going to be building oral Amylin-based therapy. I think it's important from an oral standpoint that you get lower manufacturing costs, simplify supply chain, and just a broader acceptability. But in addition to that, we're also focused on intentionally designing long-acting Amylin. Now, you guys have seen the press release of companies that have designed QW molecules, once-a-week molecules, and trying to push that into monthly. I would posit that if you really look at the PK profiles of those, there are inherent risks going down that path, not only from an efficacy standpoint, but very likely from a tolerability standpoint.
But we're going to design molecules that intentionally allow us longer half-life to get to once monthly or maybe even beyond. What this really allows is that it gives patients a choice. And regardless of the choice that they have, regardless of the choice that they make, we at Zealand are going to have an answer for them and a solution for them. Now, this is probably one of the most important slides, but probably one of the last slides I'll talk to because all of the innovation that we talked about, all of the biology that we talked about, none of it happens if you actually can't make the molecule, if you can't make the medicine to take it forward.
And if you think about how peptide discovery has been done, and I'll tell you as a small molecule medical chemist, peptide discovery has very much lagged behind in the use of tools and technologies compared to antibodies and small molecules. And that's been done in many cases because you're actually taking a hormone that's already present in the human body and making just slight tweaks to it. It's much harder to start using some of the technologies that you use for small molecules for peptides because peptides are long, they're flexible, and they're not stable. So inherently, they make it harder to work with. But you're starting to see some pretty incredible advances in protein folding technologies where we can now very accurately and very rapidly predict and understand how peptides are folding. But it's not just about how peptides are folding.
It's about understanding how that peptide folds and how the different folds then interact with how it actually binds into the receptor. But it's not just about that. It's actually the dynamics for how all of that comes together. Because remember, biology is not static. Your receptors are constantly wiggling around. Your protein is wiggling around. You have to understand how the two come together. And the dynamics is where the answer is at. Because the dynamics is what's going to help you understand the stability and the flexibility. It's going to help you expose new pockets, be able to optimize the peptide in ways that you couldn't before. But the really interesting thing comes in is to be able to find some novel pharmacology through a new pocket to deliver you the type of activity that you wouldn't generally predict. So you put all that together.
I think we have pretty ambitious goals that we have set for ourselves. With those ambitious goals, I think our physical reality also has to evolve. This is why you see us making a communication around investing in Boston. Before we talk about Boston, let's start with the heritage that we have in Copenhagen. One of my biggest surprises when I joined Zealand and came to Copenhagen is how incredibly thriving the Medicon Valley ecosystem is with respect to the number of biotechs and the sheer volume of medicines that are coming out of that ecosystem. That's going to continue. We're going to strengthen that foundation. In addition to that, we're also going to grow in Boston. To be very clear, this is not about adding more chairs or more capacity. This is not about just more numbers.
The growth in Boston is very much a push around automation. It's a push on taking our data and working closely with partners that are co-located in that area to build models to accelerate our design, make, test, analyze cycles. It's about starting to expand our toolbox, evolve our platform. If we want to be successful in developing weight-independent insulin sensitization, it's very clear we need to develop technologies that are able to directly target certain tissues. That's going to require us to bring in expertise and technologies that are present within that ecosystem. So the key here is to take two of what I would argue the most thriving ecosystems in the world and bring the best of the two together to fundamentally impact human health. So that's a lot that I just said. My commitment to you is as follows.
Number one, we're going to focus on what we are really good at, and that's on the cross-tuning axis. That's on our peptide heritage historically around metabolic health. We will commit to focusing on what is best, what we are the best at. At the same time, we also commit to partnering with experts externally to augment our capabilities, and third, speed is our currency. We commit to actually, by 2030, if not earlier, be the fastest discovery engine in the industry by benchmark, number one, and number two, we deliver at least 10 molecules into the clinic before the end of the decade. With that, what I'd like to do is introduce Henriette, who's actually going to tell you how we're going to fund some of this ambition.
Thank you, Utpal. What an exciting update, so thank you so much, so I'm here to talk a little bit about how we are going to fund, but of course, also scale this as Utpal talked about. I think today you have now heard about our mission, our aspiration for the company, how we are going to focus in on building the most valuable Amylin-based franchise, but also how we are going to build the most valuable metabolic health pipeline for the future, and these two strategic pillars are clearly at the core of our resource allocation. We have the finances to invest behind these. We have the finances to invest behind our contractual obligations towards Roche, and we have the finances to invest beyond into new opportunities. We have built a pharma pipeline. We will build a pharma pipeline with our biotech financial discipline.
We have outlined three priorities for our capital allocation. Let's just look at what these are. Number one, we will invest to establish a leading multi-asset Amylin-based franchise, both in terms of R&D investments, but also commercial investments, as you heard Eric talk about today. These investments will, of course, mainly go into parenteral-type monotherapy. As you also heard, we will pursue combination, and we will pursue new emerging opportunities. We'll also invest to accelerate and strengthen our research engine. Utpal has just talked us through the step change we'll do in research over the coming years. Lastly, number three, we'll pursue inorganic investments to enhance our R&D capabilities and our pipeline. As Utpal mentioned today, we announced the first exciting new partnership with OTR. This will give us more capabilities and strength in order to build out our pipeline.
We will do more of these. In the short to midterm, our focus will be on research collaborations, but in the mid to long term, we could consider also to in-license clinical stage-ready assets. Rest assured, we will invest in both a balanced, structured, and controlled manner. We have, over the last couple of years, focused on strengthening our financial infrastructure. We built a new ERP system. We built new management tools in terms of following up on our finances. We have automated reporting systems, all of this to ensure transparency, but also financial discipline across the company. At the same time, we are actively managing our portfolio. We are evaluating each business case, both when it comes to clinical differentiation, but also, of course, commercial impact. We are looking for the best and most valuable opportunities that can drive future value.
We have just demonstrated this with the pause of the epiglutide and the partnership we did today with OTR, and this is why we believe we will build a pharma pipeline with a biotech financial discipline, and this discipline is reflected in our strategic resource allocation. This has, of course, evolved over the past three years while I've been here, and I can assure you it will continue to evolve over the coming five years. Let's just look at this. In 2022, a large allocation of our resources still went to the rare disease programs and our U.S. commercial efforts. Our obesity efforts at this point in time are still very early stage. In 2025, this year, the majority of our resources was allocated to the obesity portfolio and, of course, taken petrelintide-type through phase II.
When we look ahead, the share of petrelintide costs with Roche will, of course, increase, and we are very ambitious when it comes to the clinical conduct, but also the commercial efforts. We will allocate significant funding to the clinical conduct, of course, to phase IIIa, which is expected to finalize around 2028, and then continue phase III-B trials. We will, together with Roche, also ensure commercial launch efforts that can position petrelintide as first choice, and these efforts will be starting in the late 2020s and into the 2030s, and at the same time, we will invest in research for future growth, but as you can also see on the graph, it takes a smaller share of the overall resources, so just let's look at how we anticipate our resources to be allocated into the 2030s.
Based on the current plans, we expect the development cost for paternal-type franchise to peak by 2030. This is when we have completed the phase IIIa, but also when we have, of course, ongoing phase III-B trials and the FTC in late-stage development. We do expect to see significant progress, as Utpal talked about, in our research efforts, and as he mentioned, by 2030, we expect to have more than 10 new clinical assets in development, and in terms of research, this will be a step change. We have, over the last five years, spent less than DKK 1 billion on research. We will increase this fivefold, so we, in the coming five years, will spend around DKK 5 billion on research activities. This will allow us to be number one when it comes to speed.
But this is also what will fuel our pipeline in the coming decade, as Utpal just talked about. And we will, together with Roche, prepare a commercial launch that can position petrelintide as first choice, but also establishing the leading Amylin-based franchise. The year before launch, the year of launch, and the coming years after that, of course, you will see a significant step up in our sales and marketing expenses. We share these costs 50/50 with Roche. But no matter who actually, you could say, executes these activities, we will have to fund half. But we have an opportunity to participate in half of these activities and the commercial conduct in the U.S. and Europe. So when you look at it, by 2030s, you will have a balanced resource allocation between our obesity and inflammation development effort and our commercial efforts that will support a petrelintide launch.
We will continue to invest into our research activities. As Adam just mentioned earlier today, we have very strong and committed partners in Roche and Boehringer Ingelheim to do this. One thing is, of course, the financial commitments we see from these partners. Another thing is the flexibility and the opportunity that's been built into the Roche agreement that gives us opportunities for us as a company to build out due to the 50/50 profit sharing we see in the U.S. and Europe. We have received the first upfront from Roche. The short-term sequence top line will be driven by milestone payments from Roche. Next year, we do expect $125 million in anniversary payments and another $575 million in connection with phase IIIa start. We expect the same to follow in 2027.
Remember, Roche is fully responsible for commercial supply, and they will apply their competencies in order to build this out. We have no cost penalty on Zealand Pharma for this. With the Licensing Agreement with Boehringer, on the other hand, we actually soon look to receive high single-digit to low double-digit royalties on global sales. This comes without any cost penalty on us and, of course, 100% EBIT margin, so one thing is, of course, the very strong financial terms we have with these partners. When you combine this with our very solid cash position at hand, this is what allows us to invest, and we will invest. We will invest to maximize the value of paternal-type and building the most valuable metabolic health pipeline, and we can do this without having to raise additional capital in the market.
As you can see on this graph, we have a very nice cash inflow expected in the coming period. And we have a clear path towards profitability in the early 2030s. And with that, I think we sit with a unique opportunity to invest and fund the journey of Zealand Pharma to become a generational biotech. We have the cash and the financial discipline to do so. You heard we have the competencies and capabilities to do it. We have the pipeline, and we are building more. And most importantly, we have the will to do so. And this is what and how we will build a pharma pipeline with a biotech financial discipline. And with that, we are ready for a broader Q&A. So I would like to invite the team up here.
All right, so we will open up for additional questions. Of course, you're also very welcome to ask follow-up questions on parenteral-type and subcutaneous type if you had any additional questions you didn't get an opportunity to ask before, but other than that, more broadly, various topics before our CEO, Adam, has his concluding remarks. I think we have one over here to start with. Jacob, you can go ahead.
Okay. Yeah, hi. I had a question maybe on your commercial plans for petrelintide in the U.S.. Now that the Roche partnership has evolved quite a bit and it's been a few months since you've had it, how has your thinking evolved there? And what kind of commercial model do you think would be suitable for Zealand? And yeah, what would be a good fit in that sense? And how do you take into account DTC and also the rise of telehealth into all of those plans?
Thanks, Jacob. Perhaps Eric, any initial thoughts?
Yes. So it's a little bit early to kind of have some of these conversations. I mean, the market's evolving at a speed that we're trying to keep up with. I mean, we've just gone through the discussions with Roche, and then we're in those early discussions, so I think probably over the next several months or next several quarters, we'll start to kind of materialize how we're thinking about this, but I think to your question on the DTP side of it, I think you'll start to see, and we've seen DTP be an extremely important role. We know it's a consumerized category, and we still think it's going to be consumerized as we go forward, so it is about unlocking that opportunity. I don't think it's direct to consumer. I think it's more around DTP.
Yeah. Thank you, Jacob. We have Thomas over here.
Thank you. Thank you, Thomas from ECB. Firstly, just a question on the partnership you just announced this morning as well. That platform, very early stage company, no real disclosed partnership so far. How did you validate that platform going into oral small molecules? And then second question, just on the whole talk about leptin sensitizing. I'm just wondering if there's anything, any evidence for pramlintide that maybe has a stronger leptin sensitizing effects than what you see with the other Amylins, potentially.
All right. Thanks a lot, Thomas. I think we will start with Utpal with some remarks on the OTR Therapeutics collaboration announced this morning, and then we can get back to leptin afterwards with David initially.
Yeah. Yeah, look, I think on the OTR Therapeutics, we're really excited about the collaboration. I think if you look at their leadership expertise and the capabilities that they've built in very short order, as well as you take a look at some of the support that they've had from the venture fund to raise their Series A, we're very confident that this is the right team to deliver on our ambitions on the small molecule space. You also take a look at what we have learned with converting peptides into small molecules. There are ways that now the industry has learned how to do that. And I think there are mechanisms now in place. And certainly, OTR is going to be building on that.
Thanks, Utpal. And David, leptin, what do we know, what do we not know, and anything in relation to the different attributes of Amylin analogs that could play an important role for leptin?
Yeah, I think, I mean, we're working with Utpal and the biology group to obviously more thoroughly assess petrelintide in animal models. The human model is the one of greatest importance to us. So going forward, mechanistic studies to look not only at energy expenditure, some of the indirect measures, soluble leptin receptor, all of those things. So we don't have the data today to say it's better, worse, no different. I think Jonathan didn't allude to it in detail, but consistently, native Amylin, rat Amylin, pramlintide, Amylin agonism has been shown universally to be leptin sensitizing. Jonathan can storm the stage if I'm speaking out of school. But I think that gives us confidence that we are as good, and we will take opportunities with both human mechanistic studies and leveraging Utpal and his group to get the biology to confirm that for petrelintide.
Excellent. Thanks, David. Thanks, Thomas. I believe we have a hand over here from Håkon.
Yes, thank you, Håkon Hemme from Danske Bank. And on the next era, treatment beyond GLP-1-type, how should we think of the innovation in the metabolic field? I mean, have we reached a point where we should expect only incremental improvements for the next generation innovations? And second question, you have previously shown financial discipline on pausing dapiglutide and focus on the most promising assets. So how do you navigate aiming for plus 10 clinical trials programs, which is a quite ambitious target, while also keep critically assessing your pipeline assets? Just want your reflections on that.
Maybe I will start on this one, and then Utpal, you can fill in, and Henriette, you can end. I think if we start by recognizing that obesity is driving the biggest health crisis across the globe, and we also look at the curves for how many patients have been exposed to a GLP-1 and how many patients are on a GLP-1 today, I think we will all realize that we are in the very early days of treatment and getting our hands around this health crisis that is needed in order not for the breakdown of our healthcare system. So you ask, can we only expect slight innovations in the next products that come out? And that, of course, depends on the eyes that you look with.
If we talk about weight loss, the weight loss in GLP-1s, I think you can only expect slight improvements because we have already seen very, very deep and very fast weight loss. Where you can see significant breakthrough innovation is in how you address metabolic health. When it comes to weight loss, as we have argued today, it's not about speed or depth of the weight loss. It's about the durability and the quality of that weight loss. We think that wave of step changes, a breakthrough change in management of obesity, that is what Amylin brings along, in particular with petrelintide. If you then think further into the future, we need to keep a firm eye on what has also been shared by some of the experts that we need different tools.
Also, some patients, of course, there will be patients who don't respond as well as others to the Amylin category because it's such a heterogeneous disease. That doesn't remove what we believe that GLP-1-type will form the foundation for the most patients and the first choice, but as we move into what Utpal talked about, it's really about metabolic health and beyond weight loss.
Yeah, absolutely, and I will point you to my comments around the weight-independent insulin sensitization. If you really think about the therapies that are out there for truly weight-independent insulin sensitization, there really aren't many, if any, on that space, and I come back to that analogy of the engine and the parts like fuel injection system. We've shrank the engine with the current therapeutics, but the system itself is still clogged, right?
I think we need to get to the point where we have improved insulin sensitivity and metabolic flexibility such that you can switch from different fuel sources in fed and fasted conditions. I think the opportunity that's left, even with current therapeutics, is significant. The question now is really going to be, as a scientist, which of that biology actually translates in a meaningful way to have that impact?
And I'll add one example. I think Type 2 diabetes, where we see with GLP-1-based therapies, you clearly lower the curve, meaning glycemic control improves, but the progressive deterioration in beta cell function is still evident in longer-term follow-up. So we've moved the curve, but we haven't changed the shape. So disease-modifying therapies in both Type 1 and Type 2 diabetes are essentially unheard of today. If that can be brought to bear, that will be a seismic change in metabolic health. And I think similarly, Survodutide, instead of just winning the numbers game, to leverage that potential impact on liver disease is transformational. If this becomes the drug of choice or an approach of choice for that population, to me, that would be transformative.
All right. Thank you, David.
I believe the second part of your question, Håkan, that was on the financial discipline and how are we going to make sure that we have the finances in place to have plus 10 clinical programs by 2030?
Why not? I think what we just discussed here, I mean, of course, you need to take risk in the early phases. We did that with Amylin. We were the early ones out to actually take that risk. But we also clearly could see the commercial opportunity. There was a clear differentiation into the market. And I think this approach both looked at the science and the clinical data or the preclinical data, and then, of course, positioning your target up against a potential market opportunity. And there you need constantly to evaluate that opportunity because the market opportunity or the market as such also evolved over time. And then, of course, we need to watch also competition and what is coming out to see if we have the right positioning.
Great. Thank you, Henriette. We have Xian down here. Yeah, go ahead, Xian.
Thank you for taking my question, Xian from UBS. So, two, please. The first one kind of also going back to metabolic health. I'm very intrigued by one of your comments, Utpal, saying there are many people that actually have BMI that's smaller than 25, but actually have metabolic dysfunction. Also, as you alluded to, for example, the BMI definition for overweight is also different for ethnicities as well, right? So if I may take a step back, actually, how do we know how to define metabolic health? What exactly are you measuring? So why are some people who are, for example, who can eat a lot but never really gain much weight, whereas others can cycle a lot, but there's not much happening? So how can you actually, do we actually know what's the difference? So that's kind of the first question.
I guess the second one is particularly in Amylin analog, in terms of comments throughout the day in terms of maintenance and also the consumer driver. So just wondering, in terms of actual maintenance therapy, again, just wondering, what exactly would you consider as maintenance therapy? Because in real world, we already see on social media people doing microdosing or whatnot every three months or whatnot. So what exactly constitutes as maintenance and what will you actually measure in the study? Would it actually be a very long-term study, like two-year outcome and things like that? What would you actually be measuring? Thank you.
I'll start with metabolic health. Great question, first of all. Thank you for asking that. On metabolic health, from a very fundamental standpoint, as I said, it's about energy intake, energy storage, energy metabolism on a fundamental sense, right? Now, as you think about it in the preclinical way, the way I'm thinking about this is really going to be around certainly weight loss as one component. We'll have that. There's also around insulin sensitization, in particular, weight-independent insulin sensitization, as well as around some of the insulin leptin sensitization centrally. That's how we think about it preclinically. Now, as you go into clinics, certainly those measures change significantly. Ultimately, as you advance in the clinic, your insulin sensitization is still going to be a significant measure for that. But what we believe, if you focus on these elements preclinically, they'll translate into much better outcomes.
You will actually see improvement in absolute risk ratio for CKD, CVOT, cardiovascular, et cetera. So I think it really metabolic health means different things, but from a clinical standpoint, from a patient standpoint, it means improved outcomes around cardiovascular, renal, et cetera.
Any thoughts, Utpal, Adam, David, on the question in relation to maintenance therapy and the ideal profile for such a drug?
I think the dilemma today is that we have already seen from the GLP-1s the value of maintenance, at least a few years in clinical setting. The problem is, in a real world, very few patients get to that benefit because, as Eric showed us, 80% will be off therapy within a year, and we know that cycling your weight is actually unhealthy. You often would consider, will you just get back to square one? No, you will actually very often be worse off once you are back because you put on a few more pounds, so we don't want to be in that situation, and as David also alluded to, GLP-1s, and we heard from some of the speakers, stimulates insulin. Amylin potentially will not do it. It's not stimulating insulin.
And exhausting beta cells, if you think about treatment five to 10 years in, may not be the smartest thing to do if you want to achieve metabolic health. And this is why, if you think about it, if we, with the Amylin category, deliver what we have set out to deliver in a clinical setting, we think it will translate directly into real-world experiences because people will actually manage to stay on therapy and gain those health benefits that we think we can achieve on an Amylin.
And to add to that, I think Utpal alluded to it, but expanding and improving health span, and Lou's comment about why should I wait till I've had a stroke and MI, hypertension, dyslipidemia, Type 2 diabetes? If we can get on the front end of that, and many of you know the famous Nike curve of deterioration in glycemic control that occurs in Type 2 diabetes, you get on the front end and you maintain all of these measures at a stable level, almost independent of the weight number you achieve. To me, that's part of our desire with metabolic health, which is to expand health span, not simply get the number possible.
And I actually just want to build on this and also referring a little bit back to some of the presentations before. As an industry, and those of you who have been around for a long time know that we have been talking about preventive medicine when it comes to chronic diseases and many other diseases. It's an incredibly difficult thing to approach because society finds it difficult to pay for it, and patients often find it difficult to engage in it because the benefits are so far out. Now we're looking at a category where patients, they receive immediate benefit in the weight loss, which we've also heard from Eric, is what they seek.
So we are actually now in a situation for the first time where we can think about preventive earlier interventions and not just have it as an intellectual conversation, but a practical conversation because patients are ready to engage in those efforts as long as they fit into the aspirations of their life. And that is why it's such an exciting moment right now and why we talk about this metabolic moment where for the first time we actually have a practical solution to achieve what Utpal is talking about, metabolic health, increasing metabolic lifespan.
Great. Thanks a lot, Adam. I think we have time for at least another round of questions. I see over here in the back, perhaps. Yeah.
Thanks very much, Callum from Berenberg. My question is around the petrelintide phase III. You mentioned earlier, obviously, you need sort of 68, 72 weeks to reach that nadir of weight loss. But given, I guess, petrelintide weight loss isn't, you're not trying to get to that 20-plus category, is a more milder weight loss. And the probability of you guys being third to market, is there a possibility of maybe a shorter interim data readout in the phase III that you might be able to go to regulators with? And then the second question, it's probably quite early to talk about pricing, but given your messaging around tolerability and ability for patients to stay on drugs, do you think this gives you more flexibility around pricing compared to the GLP-1 assets? Thank you.
Maybe I can start and hand over to you. Because I want to reiterate something we also shared two years back. When you sit with what we consider a crown jewel like patent-type, you don't want to do shortcuts in development. That's why we designed the phase II study the way we did with a 50-50 balance of males to females and not an 80% female, 20% males, where you don't learn a lot about your molecule in males. So this is about doing it right. If you truly have a crown jewel that can form the future foundation of weight management and become a first choice, you have to do it right. And that also means we should not do shortcuts in phase III.
having said that, we are, of course, hyper-focused on accelerating anything possible to get to market as early as possible to provide this new potential solution for patients, transformative solution. And this is how we will continue to push this forward with maximum focus on acceleration, but also life has taught most people, I think, that shortcuts may feel nice short term, but long term, they don't.
I'll add to that. I mean, it's sort of the think fast, think slow, meaning do as much as you can to bring these forward and do this as thoughtfully as possible. Some of the happiest days of my current life are when Steven Johnson and Utpal joined, and I could share some of the interest. But I think the regulatory requirements for phase III in obesity and the critical importance of demonstrating both safety and efficacy, not just tolerability, and that's why I mentioned all three, are part of the benefits of these extended programs, not solely the weight nadir. Again, clinical trials represent clinical trials, not clinical reality. We hope to gather as much as possible, then use phase III-B once the III-A submission is expedited as much as possible. All right. Thanks a lot, Callum.
I think it's time for us to conclude the Q&A session, and I'll now hand over to Adam for final remarks for today. There you go.
Yes, so thank you for attending today. I hope you are as excited as we are about the coming period for Zealand's accelerated growth towards becoming a generational biotech where we focus on maximizing the value of patent portfolio building commercial infrastructure so we will become a fully integrated biotech company and also investing into research to build the most valuable metabolic health pipeline. What you have heard us talk about today is the ambition and the vision for Zealand to address what is the biggest healthcare challenge of our time. Obesity and the civilization scale health shift that is coming along will define our industry in the next decade, and Zealand is going to take a leading position in driving that change. You heard about Survodutide and how it has groundbreaking potential in MASH.
The data that we have seen on fibrosis for the first time may provide something that is a step change difference opportunity for patients who live with very severe liver disease beyond the potential for weight management, not only looking on reducing your energy intake, but also looking at increasing energy expenditure due to the slight touch of glucagon and having the right balance, as we also heard Utpal talk about. Amylin biology is still an emerging class. We have seen two years ago when we spoke about Amylin, the world was in a situation where people would say, well, that's maybe something you could add on top of a GLP-1 to get a little bit more weight loss. Now we talk about Amylin as a future leading class in weight management and metabolic health.
We talk about petrelintide as a future foundational therapy and first choice, a product that may give patients the weight loss experience they're going for, the product and the category that can make us move away from the weight loss Olympics, which only interests companies and some investors, but not really the patients and not society because we need to get to durable, high-quality weight loss. That is the promise of petrelintide. Then you have heard of our very ambitious strategy to fuel the pipeline with Utpal steering this new activity, expanding into Boston, tapping into these two promising and vibrant ecosystems in Copenhagen and Boston, leveraging our 25 years of data. It's so nice to talk about AI and machine learning, but if you don't have proprietary data, you don't have something that others have. You do not have anything that others do not have.
That is why we see this as our opportunity to build the most valuable metabolic health pipeline. It's almost an unfair competition for others because we have all these data. That is what Utpal is committed to leverage now, also bringing in external innovation that can complement where we are the strongest. As Henriette shared, we have the financial position to fuel all this and to provide our commitments and serve our commitments into maximizing the value of patent portfolio, building out commercial infrastructure, and doubling down on our research efforts. That is why we have so much confidence that we will deliver on this vision to redefine obesity for a new era. With that, I hope you have had an interesting day, and we are here fully committed to maximize this metabolic moment.
It's really the opportunity to join this journey and have an impact beyond an impact you can have in other therapeutic areas by addressing the biggest health challenge of our time being metabolic health, one which we think and are certain will continue to define the healthcare space in decades to come. Thank you very much for attending today, and we look forward to future interactions.
Where would you get a chance in your career to have an impact this magnitude?
What we really want to do is to build a generational biotech.
The people that surround us and the mission that we have in front of us is just once in a lifetime.
Joining Zealand was the easiest career decision in my life.
I've drunk the Kool-Aid. This is a phenomenal organization.
This whole clue, this magic thing that just makes Zealand Zealand.
I think it's one of the best places to do discovery right now.
Metabolic health is an enormous unmet medical need.
By 2030, around half of the population worldwide will be overweight, obese.
For 25 years, our key focus has actually been around peptides for metabolic health.
Peptides are important because they are biological signals that are naturally existing in your body.
All we're doing is making just subtle tweaks to help shift equilibrium within your body in a positive way.
petrelintide is what we describe as our crown jewel. It's a more natural way to help people reduce their energy intake. This has the potential to impact millions of patients in a very positive way.
Finding a partner for petrelintide was extremely important for us. We signed a deal that was everything that we have dreamed of.
having such a big program as parenteral-type is a big jolt for any organization.
I'm extremely excited about the potential of Zealand's pipeline. We need more tools to also address all these comorbidities.
So we're not going to be Vanilla Ice. We're not going to be the one-hit wonder.
That hunger that we have hasn't changed. We'll have to move with speed and agility in ways that some of the bigger companies won't be able to.
We have to anticipate where the puck is going and ski to that spot.
Seniority and rank doesn't really matter at Zealand, and that allows us to always make sure the best ideas win.
We have these really close collaborations across the entire company.
With a base both in Boston and in Copenhagen, I think we're going to see tremendous synergies.
AI and machine learning, the new tools that we have developed to rapidly cycle through opportunities. To me, that is the future.
The sky's the limit right now about what we can really achieve.
It's very rare that you can build to a future that is novel.
We have the opportunity to become a generational biotech.
The reason I believe we can do it is really because of our culture. I think that's what makes us us.
If you ask me tomorrow, has this been a success, I would say absolutely. Do we have the opportunity for even more success? Absolutely.
We are uniquely set up based on our past experience, our current momentum and pipeline, and our will to win to deliver on this phase.